Srdjan Djurovic

• Fuhrer, Julian; Shadrin, Alexey; Hughes, Timothy; Parker, Nadine; Hindley, Guy Frederick Lanyon & Frei, Evgeniia [Vis alle 12 forfattere av denne artikkelen] (2026). Beyond exons: Linking noncoding heritability and polygenicity across complex human traits and disorders. American Journal of Human Genetics. ISSN 0002-9297. s. 1–13. doi: 10.1016/j.ajhg.2026.08.012. Fulltekst i vitenarkiv
• Koch, Elise; Parker, Nadine; Mohammad, Helin; Lenk, Hasan Cagin; Ystaas, Lars Andreas Rømo & Jaholkowski, Piotr Pawel [Vis alle 13 forfattere av denne artikkelen] (2026). Genetic overlap between treatment-resistant schizophrenia and smoking initiation. International Journal of Neuropsychopharmacology. ISSN 1461-1457. 29(7). doi: 10.1093/ijnp/pyag035. Fulltekst i vitenarkiv Vis sammendrag

  Background Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Objective Here, we aim to identify genetic variants associated with TRS by leveraging overlapping genetic variants with smoking initiation to increase statistical power. Methods We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes. Results We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 P = .0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. Mendelian randomization indicates putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses suggest that alpha-1-adrenergic receptors may be involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs. Conclusion In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.

• Mlakar, Vid; Forti, Marta Di; Halff, Els F.; Srivastava, Deepak P.; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Vis alle 13 forfattere av denne artikkelen] (2026). Health behaviours and telomere biology in severe mental disorders. Translational Psychiatry. 16(1). doi: 10.1038/s41398-026-04362-2. Fulltekst i vitenarkiv Vis sammendrag

  Alterations in telomere length (TL), a marker of cellular ageing, have been reported in individuals with severe mental disorders (SMD). Epidemiological studies of the general population have highlighted that unhealthy lifestyles may exacerbate telomere attrition. However, the impact of lifestyle on TL within the context of SMD remains unexplored. The study consisted of 410 participants (schizophrenia spectrum [n = 225] and affective disorder [n = 185]) collected as part of the Norwegian Thematically Organised Psychosis (TOP) study. Leukocyte TL was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR). Patients provided self-report data on six lifestyle domains including: diet, exercise, smoking, alcohol consumption, substance use, and coffee consumption. A global dichotomised (healthy vs unhealthy) lifestyle variable was created, as well as a health behaviour variable, indicating the level of unhealthy behaviours. Individuals with an unhealthy lifestyle had shorter TL compared to those with a healthy lifestyle (Cohen’s d = 0.58, F = 8.62, p = 0.004). A relationship was observed between increasing number of unhealthy behaviours and shorter TL (F = 2.69, p = 0.02), adjusted for age, sex, ethnicity, trauma exposure, medication daily defined dose (DDD), years of education and diagnosis. In terms of base-pair loss, individuals with healthy lifestyles exhibited a roughly 6-year lower biological age, compared to individuals with unhealthy lifestyles. Our study indicates that a healthier lifestyle is associated with longer TL in SMD. This highlights the importance of health behaviours as potential clinical targets for ensuring healthier cellular ageing in psychiatric populations.

• Tesfaye, Markos; Shadrin, Alexey; Parker, Nadine; Jaholkowski, Piotr Pawel; Parekh, Pravesh & Kutrolli, Gleda [Vis alle 16 forfattere av denne artikkelen] (2026). Comorbidity Alters the Genetic Relationship Between Anxiety Disorders and Major Depression. Biological Psychiatry. ISSN 0006-3223. 100(6), s. 689–698. doi: 10.1016/j.biopsych.2026.04.026. Fulltekst i vitenarkiv
• Streit, Fabian; Awasthi, Swapnil; Hall, Alisha S.M.; Braun, Alice; Niarchou, Maria & Marouli, Eirini [Vis alle 152 forfattere av denne artikkelen] (2026). Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders. Nature Genetics. ISSN 1061-4036. 58, s. 1831–1844. doi: 10.1038/s41588-026-02654-3. Fulltekst i vitenarkiv Vis sammendrag

  Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

• Rødevand, Linn Nilsen; Rahman, Mohammad Zillur; Jaholkowski, Piotr Pawel; Parker, Nadine; Valdimarsdóttir, Unnur Anna & Smeland, Olav Bjerkehagen [Vis alle 14 forfattere av denne artikkelen] (2026). Evidence for overlapping genetic architecture between lifestyle factors and severe mental disorders with different patterns across diagnoses. EBioMedicine. 128. doi: 10.1016/j.ebiom.2026.106304. Fulltekst i vitenarkiv
• Assis, Denis Reis de; Pentz, Atle Bråthen; Osete, Jordi Requena; Ievglevskyi, Oleksandr; Vandenberghe, Matthieu & Akkouh, Ibrahim Ahmed [Vis alle 12 forfattere av denne artikkelen] (2026). Investigating neural impairments in psychotic disorders using electroencephalography and cortical spheroids. Translational Psychiatry. 16(1). doi: 10.1038/s41398-026-03863-4. Fulltekst i vitenarkiv Vis sammendrag

  Synaptic dysfunction is a candidate mechanism in psychotic disorders, yet the precise underlying substrates remain elusive. We investigated how combining in vivo electroencephalography (EEG) and in vitro human cortical spheroid (hCS)-based methods can further our understanding of psychosis pathophysiology during fetal stages of neurodevelopment. Ten individuals with schizophrenia (SZ) or bipolar disorder (BD; 5 males and 5 females) and five controls (CTRL; 3 males and 2 females) underwent EEG assessments, including long-term potentiation (LTP)-like cortical plasticity and mismatch negativity (MMN). hCS were generated from induced pluripotent stem cells of all participants, and immunohistochemistry, Seahorse bioenergetics and patch-clamp recordings were performed. EEG-based LTP-like plasticity was reduced in individuals with SZ and BD. Basal respiration was decreased in BD hCS and VGLUT1 levels were reduced in both SZ and BD hCS. There was a positive association between EEG-based LTP-like plasticity and hCS basal respiration which survived correction. Our data provide further support for roles of mitochondrial and glutamatergic impairments in the synaptic dysfunction of psychosis and demonstrate the potential of combining EEG- and hCS-based methods for early development mechanistic studies of brain disorders.

• Eissa, Ahmed; Fredrik Kismul, Jan; Pentz, Atle Bråthen; Elvsåshagen, Torbjørn; Metzner, Christoph & Akkouh, Ibrahim Ahmed [Vis alle 12 forfattere av denne artikkelen] (2026). Computational Modelling of Novelty Detection in the Mismatch Negativity Protocols and Its Impairments in Schizophrenia. European Journal of Neuroscience. ISSN 0953-816X. 63(6). doi: 10.1111/ejn.70453. Fulltekst i vitenarkiv
• Holen, Børge; Rahman, Mohammad Zillur; Shadrin, Alexey; Icick, Romain; O'Connell, Kevin Sean & Rødevand, Linn [Vis alle 14 forfattere av denne artikkelen] (2026). Shared genetic variants across substance use disorders implicate common neurobiological pathways, a genome‐wide mixed methods study. BMJ General Psychiatry (GPSYCH). ISSN 2096-5923. 39(2). doi: 10.1002/gps3.70017. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT Background Substance use disorders (SUDs) are highly heritable, but the extent of shared and distinct genetic architecture across different SUDs is unclear. Aims To compare the genetic architectures of alcohol use disorder (AUD), cannabis use disorder (CUD) and opioid use disorder (OUD) and to identify shared and unique genetic loci. Methods We analysed large‐scale genome‐wide association study (GWAS) summary statistics from individuals of European ancestry recruited in Europe and the USA. The mixture model MiXeR was used to estimate the unique genetic architecture characteristics of each SUD, including its polygenicity, single nucleotide polymorphism (SNP)‐heritability and discoverability, a measure of the distribution of genetic signal across all causal variants. Pairwise conditional/conjunctional false discovery rate (cond/conjFDR) analyses identified shared loci, followed by biological annotation of implicated genes. Results AUD demonstrated the highest polygenicity, followed by CUD and OUD. SNP‐based heritability was 0.10 for AUD and OUD and 0.01 for CUD. Discoverability was highest for OUD, followed by AUD and CUD. Currently, genome‐wide significant SNPs explain 2.0% of AUD, 0.3% of CUD and 0.2% of OUD variance. Cond/conjFDR identified 39 novel loci for AUD, 10 for CUD and 1 for OUD. Of implicated genes, most were expressed in the brain, including several involved in gamma‐aminobutyric acid and dopaminergic neurotransmission, opioid neurophysiology, myelination, DNA recombination, apoptosis and ubiquitin‐dependent protein catabolism. Conclusions SUDs have polygenic architectures with many shared loci and are similar with regards to some characteristics. However, the level of polygenicity differs across SUDs, with AUD being considerably more polygenic than OUD, whereas CUD is intermediate in terms of its polygenicity. The novel loci implicate genes primarily expressed in the brain, involving a variety of biological functions. The findings expand our view of the aetiology of these disorders, while supporting the hypothesis of a shared set of pleiotropic SUD genes.

• Stinson, Sara E.; Shadrin, Alexey; Rahman, Mohammad Zillur; Rødevand, Linn; Broce, Iris J. & Selbæk, Geir [Vis alle 17 forfattere av denne artikkelen] (2026). Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap. EBioMedicine. 127. doi: 10.1016/j.ebiom.2026.106254. Fulltekst i vitenarkiv Vis sammendrag

  Background: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear. Methods: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses. Findings: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = −0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling. Interpretation: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

• Akdeniz, Bayram Cevdet; Bahrami, Shahram; Hagen, Espen; Fuhrer, Julian; Fominykh, Vera & Shadrin, Alexey [Vis alle 108 forfattere av denne artikkelen] (2026). Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer’s Disease in European Populations: Development and Validation. medRxiv. doi: 10.1101/2025.07.28.25332293. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objectives Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer’s disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. Methods We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E ( APOE ) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. Results The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 – 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. Conclusion Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

• Wiström, Erik David; Fuhrer, Julian; Shadrin, Alexey; Fominykh, Vera; O'Connell, Kevin Sean & Jaholkowski, Piotr Pawel [Vis alle 17 forfattere av denne artikkelen] (2026). Dissecting the genetic relationship between severe mental disorders and autoimmune diseases. Brain, Behavior, and Immunity. ISSN 0889-1591. 133. doi: 10.1016/j.bbi.2025.106249. Fulltekst i vitenarkiv Vis sammendrag

  Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies. While MD was positively genetically correlated with five autoimmune diseases, BD and SCZ were only positively correlated with IBD, suggesting differences in the genetic signal shared with autoimmunity across these mental disorders. A considerable fraction of genetic variants influencing autoimmune diseases (range 17.1–88.4 %) was estimated to overlap with mental disorders; however, this constitutes only a minor part of genetic variants influencing the more polygenic mental disorders. Finally, we identified 172 genetic loci jointly affecting mental disorders and autoimmune diseases, implicating both lipid metabolism and TNF signaling. In conclusion, MD, BD, and SCZ have a small but distinct genetic overlap with autoimmune diseases, which may inform new possible immune targets for treatment in mental illness.

• Höffler, Kira Daniela; Katrinli, Seyma; Halvorsen, Matthew W.; Stavrum, Anne-Kristin Støbakk; O'Connell, Kevin Sean & Shadrin, Alexey [Vis alle 18 forfattere av denne artikkelen] (2025). Optimizing genetic ancestry adjustment in DNA methylation studies: a comparative analysis of approaches. Epigenetics & Chromatin. 18, s. 1–14. doi: 10.1186/s13072-025-00627-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry. Methods We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control probe PCs, sex, age, and cell type proportions to remove the effects of technical and biological factors, and (2) integrating the residualized data with genotype calls from the SNP probes (commonly referred to as rs probes) present on the arrays, before calculating PCs and evaluated the clustering ability and relationship to genetic ancestry. Results The PCs generated by EpiAnceR+ led to improved clustering for repeated samples from the same individual and stronger associations with genetic ancestry groups predicted from genotype information compared to the original approach. EpiAnceR+ also outperformed the use of DNA methylation PCs or surrogate variables for ancestry adjustment. Conclusions We show that the EpiAnceR+ approach improves the adjustment for genetic ancestry in DNA methylation studies. EpiAnceR+ can be integrated into existing R pipelines for commercial methylation arrays, such as 450 K, EPIC v1, and EPIC v2. The code is available on GitHub (https://github.com/KiraHoeffler/EpiAnceR).

• Colbert, Sarah M. C.; Monson, Eric T.; Andreassen, Ole; Ayinde, Olatunde O.; Barr, Peter B. & Bejan, Cosmin A. [Vis alle 314 forfattere av denne artikkelen] (2025). Defining suicidality phenotypes for genetic studies: perspectives of the Psychiatric Genomics Consortium Suicide Working Group. Molecular Psychiatry. ISSN 1359-4184. 30(12), s. 6144–6154. doi: 10.1038/s41380-025-03271-y. Fulltekst i vitenarkiv Vis sammendrag

  Suicidality phenotypes, consisting of suicidal ideation (SI), suicide attempt (SA), and suicide death (SD), are all heritable but present unique challenges in genome-wide association studies (GWAS) due to their individual complexity, overlap with each other and with related self-harm phenotypes, and varying associations with psychiatric disorders. GWAS have uncovered several loci associated with suicidality phenotypes by meta-analyzing data from multiple cohorts. However, combining datasets from many research groups, where each group may use different study designs, phenotyping instruments, and definitions of suicidality phenotypes, presents challenges. Heterogeneity resulting from these differences can limit genetic discovery; harmonizing phenotype definitions to ensure consistency will greatly improve results. Here, we describe a standardized phenotyping protocol that draws on the expertise of a subgroup of clinicians, researchers, and experts from the Psychiatric Genomics Consortium Suicide Working Group to propose consensus definitions for SI, SA, and SD for genetic studies.

• Shadrin, Alexey; Hindley, Guy; Hagen, Espen; Parker, Nadine; Tesfaye, Markos & Jaholkowski, Piotr Pawel [Vis alle 16 forfattere av denne artikkelen] (2025). Distinct patterns of genetic overlap among multimorbidities revealed with trivariate MiXeR. Genome Medicine. 17. doi: 10.1186/s13073-025-01528-3. Fulltekst i vitenarkiv Vis sammendrag

  Background: Multimorbidities are a global health challenge. Accumulating evidence indicates that overlapping genetic architectures underlie comorbid complex human traits and disorders. This can be quantified for a pair of phenotypes using various techniques. Still, the pattern of genetic overlap between three distinct complex phenotypes, which is important for understanding multimorbidities, has not been possible to quantify. Methods: Here, we present and validate the novel trivariate MiXeR tool, which disentangles the pattern of genetic overlap between three complex phenotypes using summary statistics from genome-wide association studies. Our simulations show that trivariate MiXeR can reliably reconstruct different patterns of genetic overlap and estimate the proportions of genetic overlap between three phenotypes. Results: We found substantial genetic overlap between gastro-intestinal and brain diseases supporting a genetic basis of the gut-brain axis—the pattern consistent with pairwise analysis. However, the pattern of genetic overlap between three diverse cardiometabolic and renal health indicators and three immune-linked disorders revealed a much larger genomic component shared between all phenotypes than expected from separate pairwise analyses. This suggests the existence of core pathways underlying distinct but related chronic conditions. Conclusions: Overall, trivariate MiXeR offers a novel and efficient tool for investigating patterns of genetic overlap among three complex phenotypes. This contributes to a better understanding of genetic relationships between complex traits and disorders, potentially providing new insights into the mechanisms underlying common multimorbidities. Trivariate MiXeR is freely available at https://github.com/precimed/mix3r .

• Mlakar, Vid; Forti, Marta Di; Halff, Els F.; Srivastava, Deepak P.; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Vis alle 13 forfattere av denne artikkelen] (2025). Coffee intake is associated with telomere length in severe mental disorders. BMJ Mental Health. 28(1). doi: 10.1136/bmjment-2025-301700. Fulltekst i vitenarkiv
• Hope, Sigrun; Lin, Aihua; Rødevand, Linn; Hübenette, Saira Jameela; Quintana, Daniel & Sønderby, Ida Elken [Vis alle 17 forfattere av denne artikkelen] (2025). Shared genetic architecture between autism spectrum disorder, loneliness, and social isolation reveals novel genetic loci. Psychiatric Genetics. ISSN 0955-8829. doi: 10.1097/ypg.0000000000000406. Fulltekst i vitenarkiv Vis sammendrag

  Objective: Deficits in social communication and social interaction are core features of autism spectrum disorder (ASD), and studies suggest that loneliness and social isolation are common. ASD has a strong genetic basis, but the genetic architecture and overlap with social phenotypes are not clear. Methods: We analyzed summary statistics from genome-wide association studies on ASD (46 350), loneliness (452 302), and social isolation (288 950), using linkage disequilibrium score regression, local analysis of covariant annotation (LAVA), bivariate causal mixture model (MiXeR), and the conditional/conjunctional false discovery rate (cond/conjFDR). Results: For ASD and social isolation, we found nonsignificant global genetic correlation ( r g = 0.02, P  = 0.8), but LAVA identified 72 genomic regions with bidirectional correlations, and MiXeR estimated that 8.7 k of 13.1 k variants (81%) were shared, of which 53% had concordant effect directions. For ASD and loneliness, we found a positive genetic correlation ( r g = 0.26, P  = 2e-10), LAVA identified 80 genomic regions with bidirectional genetic correlations, and MiXeR suggested that at least 3.8 k variants were shared. We identified nine specific shared genetic loci between ASD and loneliness and eight between ASD and social isolation (conjFDR < 0.05). Of these, 12 loci were novel for ASD. Genes mapped to these loci are involved in γ-aminobutyric acid (GABA), glutamate, calcium, and stress hormone signaling, cerebral glucose transport, TAU-accumulation, and immune function. Conclusion: We found extensive overlap in genetic architecture between ASD, loneliness, and social isolation, with bidirectional effects. By leveraging data for ASD and social traits, we identified 12 novel ASD related genetic loci implicating several genes, thereby elucidating potential pathways underlying their shared genetic architecture.

• Smeland, Olav B.; Kutrolli, Gleda; Bahrami, Shahram; Fominykh, Vera; Parker, Nadine & Fuhrer, Julian [Vis alle 21 forfattere av denne artikkelen] (2025). A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders. Nature Neuroscience. ISSN 1097-6256. 28(12), s. 2439–2450. doi: 10.1038/s41593-025-02090-2. Fulltekst i vitenarkiv Vis sammendrag

  Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

• Ormerod, Monica Bettina E. Greenwood; Sheikh, Mashhood Ahmed; Ueland, Thor; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Vis alle 15 forfattere av denne artikkelen] (2025). Minor immunomodulatory effects of psychotropics suggested in severe mental disorders: Associations of antipsychotics with beta defensin 2, antidepressants with C-reactive protein, and mood stabilizers with soluble interleukin 2 receptor. European psychiatry. ISSN 0924-9338. 68(1). doi: 10.1192/j.eurpsy.2025.10104. Fulltekst i vitenarkiv Vis sammendrag

  Background: Immunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs. Methods: We included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference. Results: AP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) ( β  = 0.094, p  = 0.8E-4), AD use with higher serum levels of CRP ( β  = 0.072, p  = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) ( β  = 0.063, p  = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels ( β  = 0.045, p  = 2.3E-4), AD dose with CRP levels ( β  = 0.039, p  = 0.001), MS dose with sIL-2R levels ( β  = 0.048, p  = 0.001), and serum concentration of AD was nominally positively associated with CRP ( β  = 0.072, p  = 0.002). Conclusions: The findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.

• Akkouh, Ibrahim Ahmed; Osete, Jordi Requena; Szabo, Attila; Andreassen, Ole & Djurovic, Srdjan (2025). Neurobiological Perturbations in Bipolar Disorder Compared With Schizophrenia: Evidence From Cell Cultures and Brain Organoids. Biological Psychiatry. ISSN 0006-3223. 98(4), s. 322–332. doi: 10.1016/j.biopsych.2025.02.012. Fulltekst i vitenarkiv Vis sammendrag

  Bipolar disorder (BD) and schizophrenia (SCZ) are uniquely human disorders with a complex pathophysiology that involves adverse neuropathological events in brain development. High disease polygenicity and limited access to live human brain tissue make these disorders exceedingly challenging to study mechanistically. Cellular cultures and brain organoids generated from human-derived pluripotent stem cells preserve the genetic background of the donor cells and recapitulate some of the defining characteristics of human brain architecture and early spatiotemporal development. These model systems have already proven successful in deciphering some of the neuropathological perturbations in BD and SCZ, and methodological advancements, such as the functional integration of 2 or more region-specific organoids and organoid transplantation in animals, promise to deliver increasingly refined insights. Here, we review a selection of recent discoveries achieved by stem cell–based models, with a particular focus on patterns of cellular and molecular convergence and divergence between BD and SCZ. First, we provide a brief overview of the evidence from glial and neuronal cell cultures and brain organoids, centering our discussion on several key functional domains, including neuroinflammation, neuronal excitability, and mitochondrial function. Then, we review recent findings demonstrating the power of integrating stem cell–based systems with gene editing technologies to elucidate the functional consequences of risk variants identified through genetic association studies. We end with a discussion of current challenges and some promising avenues for future research.

• Koch, Elise; Shadrin, Alexey; Parker, Nadine; Lock, Siobhan K.; Smith, Robert Løvsletten & Frei, Oleksandr [Vis alle 11 forfattere av denne artikkelen] (2025). Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis. Neuropsychopharmacology. ISSN 0893-133X. 50, s. 947–955. doi: 10.1038/s41386-025-02054-x. Fulltekst i vitenarkiv Vis sammendrag

  While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci. We used the largest available GWAS summary statistics of clozapine metabolism (clozapine-to-norclozapine ratio) and clozapine-induced agranulocytosis, applying the conditional false discovery rate (condFDR) method to increase power for genetic discovery by conditioning on granulocyte counts variants. To investigate potential causal effects of shared loci, we performed Mendelian Randomization analyses. After conditioning on granulocyte counts, we identified two novel loci associated with clozapine-to-norclozapine ratio. These loci were significantly associated with clozapine metabolism in a validation sample of 392 clozapine-treated individuals. For clozapine-induced agranulocytosis, five loci were identified after conditioning on granulocyte counts. These five loci were significantly associated with reduced granulocyte counts in a small independent sample of clozapine-treated individuals. Genetic liability to slow clozapine metabolism (high clozapine-to-norclozapine ratio) showed evidence of a causal effect on reduced neutrophil counts, and genetic liability to low neutrophil counts exhibited weak evidence of a causal effect on clozapine-induced agranulocytosis. Our findings of shared genetic variants associated with clozapine metabolism and granulocyte counts may form the basis for developing prediction models for clozapine-induced agranulocytosis.

• Ormerod, Monica Bettina E. Greenwood; Ueland, Thor; Aas, Monica; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Vis alle 16 forfattere av denne artikkelen] (2025). Limited evidence of association between dysregulated immune marker levels and telomere length in severe mental disorders. Acta Neuropsychiatrica. ISSN 0924-2708. 37. doi: 10.1017/neu.2024.62. Fulltekst i vitenarkiv Vis sammendrag

  Objective: Accelerated ageing indexed by telomere attrition is suggested in schizophrenia spectrum- (SCZ) and bipolar disorders (BD). While inflammation may promote telomere shortening, few studies have investigated the association between telomere length (TL) and markers of immune activation and inflammation in severe mental disorders. Methods: Leucocyte TL defined as telomere template/amount of single-copy gene template (T/S ratio), was determined in participants with SCZ (N = 301) or BD (N = 211) and a healthy control group (HC, N = 378). TL was analysed with linear regressions for associations with levels of 12 immune markers linked to SCZ or BD. Adjustments were made for a broad range of potential confounding variables. TL was measured by quantitative polymerase chain reaction (qPCR) and the immune markers were measured by enzyme immunoassays. Results: A positive association between levels of soluble tumour necrosis factor receptor 1A (sTNF-R1) and TL in SCZ (β = 0.191, p = 0.012) was observed. Plasma levels of the other immune markers were not significantly associated with TL in the BD, SCZ or HC groups. Conclusion: There was limited evidence of association between immune markers and TL in SCZ and BD. The results provide little support for involvement of immune dysregulation, as reflected by current systemic markers, in telomere attrition-related accelerated ageing in severe mental disorders.

• O'Connell, Kevin Sean; Koromina, Maria; Veen, Tracy van der; Boltz, Toni; David, Friederike S. & Yang, Jessica Mei Kay [Vis alle 313 forfattere av denne artikkelen] (2025). Genomics yields biological and phenotypic insights into bipolar disorder. Nature. ISSN 0028-0836. 639, s. 968–975. doi: 10.1038/s41586-024-08468-9. Fulltekst i vitenarkiv Vis sammendrag

  Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

• Laszlo, Marcell; Vigh, Judit; Kocsis, Anna; Porkolab, Gergo; Hoyk, Zsofia & Polgar, Tamas [Vis alle 15 forfattere av denne artikkelen] (2025). N,N-dimethyltryptamine mitigates experimental stroke by stabilizing the blood-brain barrier and reducing neuroinflammation. Science Advances. 11. doi: 10.1126/sciadv.adx5958. Fulltekst i vitenarkiv Vis sammendrag

  N,N-dimethyltryptamine (DMT) is a psychoactive molecule present in the human brain. DMT is under clinical evaluation as a neuroprotective agent in poststroke recovery. Yet, its mechanism of action remains poorly understood. In a rat transient middle cerebral artery occlusion stroke model, we previously showed that DMT reduces infarct volume. Here, we demonstrate that this effect is accompanied by reduction of cerebral edema, attenuated astrocyte dysfunction, and a shift in serum protein composition toward an anti-inflammatory, neuroprotective state. DMT restored tight junction integrity and blood-brain barrier (BBB) function in vitro and in vivo. DMT suppressed the release of proinflammatory cytokines and chemokines in brain endothelial cells and peripheral immune cells and reduced microglial activation via the sigma-1 receptor. Our findings prove that DMT mitigates a poststroke effect by stabilizing the BBB and reducing neuroinflammation. Such interactions of DMT with the vascular and immune systems can be leveraged to complement current, insufficient, stroke therapy.

• Wiström, Erik David; O'Connell, Kevin Sean; Koch, Elise; Jaholkowski, Piotr Pawel; Hindley, Guy & Steen, Nils Eiel [Vis alle 14 forfattere av denne artikkelen] (2025). The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6. Journal of Affective Disorders Reports. 20, s. 1–10. doi: 10.1016/j.jadr.2025.100889. Fulltekst i vitenarkiv Vis sammendrag

  Background: Immune dysregulation may contribute to the pathophysiology of major depressive disorder (MDD). Here we aimed to identify genetic architecture jointly associated with MDD, white blood cell (WBC) count and interleukin 6 (IL-6) levels. Methods: Using genome-wide association studies summary statistics on MDD (330,173 cases and 727,595 controls), WBC counts (nmax = 563,946) and IL-6 (n = 52,654), we performed linkage disequilibrium (LD) score regression, bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and Mendelian randomization (MR) analyses. Additionally, we used an independent MDD dataset (9,582 cases and 84,670 controls) from the Norwegian Mother, Father and Child Cohort Study for polygenic risk score (PRS) analyses. Findings: We found a significant positive genetic correlation (rg = 0.22) between MDD and IL-6. MiXeR estimates indicated substantial differences in the polygenicity of MDD (13.7K variants), WBC subgroups (0.8K-1.8K variants), and IL-6 (0.2K variants), with 10.1 %-31.4 % of the variants influencing WBC subgroups overlapping with MDD. We identified MDD risk loci shared with basophils (8), eosinophils (17), lymphocytes (23), monocytes (14), neutrophils (20), and total WBC counts (20), as well as two loci shared between MDD and IL-6, at conjFDR <0.05. PRS analysis showed a weak, but significantly increased risk for MDD dependent on monocyte count. Limitations: The analyses only included European ancestry samples, and the causal genes associated with the identified genetic loci were not experimentally validated. Conclusions: MDD shares genetic underpinnings with immune system components, which implicates immune-mediated pathways in the pathophysiology of MDD. However, this connection may only be relevant for a minority of patients.

• Fominykh, Vera; Shadrin, Alexey; Jaholkowski, Piotr Pawel; Fuhrer, Julian; Parker, Nadine & Wiström, Erik David [Vis alle 11 forfattere av denne artikkelen] (2025). Mapping the genetic landscape of immune-mediated disorders: potential implications for classification and therapeutic strategies. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1543781. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: Based on clinical, biomarker, and genetic data, McGonagle and McDermott suggested that autoimmune and autoinflammatory disorders can be classified as a disease continuum from purely autoimmune to autoinflammatory with mixed diseases in between. However, the genetic architecture of this spectrum has not been systematically described. Here, we investigate the continuum of polygenic immune-mediated disorders using genome-wide association studies (GWAS) and statistical genetics methods. Methods: We mapped the genetic landscape of 15 immune-mediated disorders using GWAS summary statistics and methods including genomic structural equation modeling (genomic SEM), linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and Gaussian causal mixture modeling (MiXeR). We performed enrichment analyses of tissues and biological gene sets using MAGMA. Results: Genomic SEM suggested a continuum structure with four underlying latent factors from autoimmune diseases at one end to autoinflammatory on the opposite end. Across disorders, we observed a balanced mixture of negative and positive local genetic correlations within the major histocompatibility complex, while outside this region, local genetic correlations were predominantly positive. MiXeR analysis showed large genetic overlap in accordance with the continuum landscape. MAGMA analysis implicated genes associated with known monogenic immune diseases for prominent autoimmune and autoinflammatory component. Conclusions: Our findings support a polygenic continuum across immune-mediated disorders, with four genetic clusters. The “polygenic autoimmune” and “polygenic autoinflammatory” clusters reside on margins of this continuum. These findings provide insights and lead us to hypothesize that the identified clusters could inform future therapeutical strategies, with patients in the same clusters potentially responding similarly to specific therapies.

• Adams, Mark J.; Streit, Fabian; Meng, Xiangrui; Awasthi, Swapnil; Adey, Brett N. & Choi, Karmel W. [Vis alle 51 forfattere av denne artikkelen] (2025). Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. Cell. ISSN 0092-8674. 188(3), s. 640–652.e9. doi: 10.1016/j.cell.2024.12.002. Fulltekst i vitenarkiv Vis sammendrag

  In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment.

• Strom, Nora I.; Gerring, Zachary F.; Galimberti, Marco; Yu, Dongmei; Halvorsen, Matthew W. & Abdellaoui, Abdel [Vis alle 214 forfattere av denne artikkelen] (2025). Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder. Nature Genetics. ISSN 1061-4036. 57, s. 1389–1401. doi: 10.1038/s41588-025-02189-z. Fulltekst i vitenarkiv Vis sammendrag

  Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

• Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Parker, Nadine & O'Connell, Kevin Sean [Vis alle 20 forfattere av denne artikkelen] (2025). Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder. Nature Mental Health. 3(2), s. 253–265. doi: 10.1038/s44220-024-00353-8. Fulltekst i vitenarkiv Vis sammendrag

  Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies can provide new evidence regarding the etiology of AUD. We report a multi-ancestry genome-wide association study focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals (102,079 cases; European, 75,583; African, 20,689 (mostly African American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent). Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci (105 variants) were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes, which show altered expression in brain regions relevant for AUD (striatum, hypothalamus and prefrontal cortex) and encode potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting that they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically relevant comorbidities.

• Meer, Dennis van der; Rahman, Mohammad Zillur; Ottas, Aigar; Parekh, Pravesh; Kutrolli, Gleda & Stinson, Sara Elizabeth [Vis alle 37 forfattere av denne artikkelen] (2025). Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers. Nature Communications. 16(1). doi: 10.1038/s41467-025-60058-z. Fulltekst i vitenarkiv Vis sammendrag

  Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism.

• Inova, Amina; Birkenæs, Viktoria; Quintana, Daniel; Ormerod, Monica Bettina E. Greenwood; Ueland, Torill & Ueland, Thor [Vis alle 10 forfattere av denne artikkelen] (2024). Cortisol and C-reactive protein (CRP) regulation in severe mental disorders. Psychoneuroendocrinology. ISSN 0306-4530. 172. doi: 10.1016/j.psyneuen.2024.107272. Fulltekst i vitenarkiv Vis sammendrag

  Background People with schizophrenia (SZ) and bipolar disorder (BD) show abnormalities in the biological stress system and low-grade inflammation. However, whether the hypothalamic-pituitary-adrenal (HPA) axis-immune regulation is disrupted in SZ and BD, is yet to be determined. Methods Cortisol and C-reactive protein (CRP) were measured in blood samples collected at or before 10 am in participants with SZ (N = 257), BD (N = 153), and healthy controls (N = 40). Cortisol/CRP ratio was calculated as an indicator of the balance between HPA axis activity and inflammatory activity, called HPA axis-immune regulation. Global functioning and symptom levels were obtained using the Global Assessment of Functioning (GAF) Scale and Positive and Negative Syndrome Scale (PANSS). Standardized neuropsychological tests were used to assess cognitive function. All analyses were adjusted for demographic variables (age and sex) and the time of blood sampling. Results Participants with a SZ or BD diagnosis had lower cortisol/CRP ratios (F=5.93, p = 0.003) compared to healthy controls. The difference was no longer statistically significant (p > 0.1) when BMI was added as a covariate to the model. Within patients, those on psychotropic treatment (n = 337) had lower cortisol/CRP ratio than those not taking psychotropic agents (n = 59) (F=4.72, p = 0.03). Compared to HC, only patients on regular psychotropic agents had lower cortisol/CRP ratio (p = 0.02). Within the SZ group, lower cortisol/CRP ratio was associated with having poorer general functioning as measured by GAF (ß=-0.18, p = 0.01), and more severe negative and general symptomatology as measured by PANSS (ß=0.19, p = 0.007 and ß=0.18, p = 0.01, respectively). In SZ, lower cortisol/CRP ratio was also associated with poorer verbal memory, learning, and processing speed (ß=-0.20 p = 0.007, ß=-0.19 p = 0.01, ß=-0.25, p > 0.001, respectively). No associations were observed between cortisol/CRP ratio and clinical and cognitive functioning in the BD group. Conclusion These findings may indicate HPA axis-immune dysregulation in SZ. Our study further indicates that disrupted HPA axis-immune regulation in people with SZ and BD is associated with psychotropic treatment and fat mass, highlighting the clinical importance of weight control and regular psychotropic treatment follow-ups within this group.

• Jaholkowski, Piotr Pawel; Bahrami, Shahram; Fominykh, Vera; Hindley, Guy; Tesfaye, Markos & Parekh, Pravesh [Vis alle 23 forfattere av denne artikkelen] (2024). Charting the shared genetic architecture of Alzheimer's disease, cognition, and educational attainment, and associations with brain development. Neurobiology of Disease. ISSN 0969-9961. 203. doi: 10.1016/j.nbd.2024.106750. Fulltekst i vitenarkiv Vis sammendrag

  The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the ‘cognitive reserve’ hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested. Using the largest samples to date and novel statistical tools, we aimed to investigate shared genetic variants between Alzheimer's disease, and measures of cognitive reserve; cognition and educational attainment to identify molecular and neurobiological foundations. We applied the causal mixture model (MiXeR) to estimate the number of trait-influencing variants shared between Alzheimer's disease, cognition, and educational attainment, and condFDR/conjFDR to identify shared loci. To provide biological insights loci were functionally characterized. Subsequently, we constructed a Structural Equation Model (SEM) to determine if the polygenic foundation of cognition has a direct impact on Alzheimer's disease risk, or if its effect is mediated through established risk factors for the disease, using a case-control sample from the UK Biobank. Univariate MiXeR analysis (after excluding chromosome 19) revealed that Alzheimer's disease was substantially less polygenic (450 trait-influencing variants) compared to cognition (11,100 trait-influencing variants), and educational attainment (12,700 trait-influencing variants). Bivariate MiXeR analysis estimated that Alzheimer's disease shared approximately 70 % of trait-influencing variants with cognition, and approximately 40 % with educational attainment, with mixed effect directions. Using condFDR analysis, we identified 18 loci jointly associated with Alzheimer's disease and cognition and 6 loci jointly associated with Alzheimer's disease and educational attainment. Genes mapped to shared loci were associated with neurodevelopment, expressed in early life, and implicated the dendritic tree and phosphatidylinositol phosphate binding mechanisms. Spatiotemporal gene expression analysis of the identified genes showed that mapped genes were highly expressed during the mid-fetal period, further suggesting early neurodevelopmental stages as critical periods for establishing cognitive reserve which affect the risk of Alzheimer's disease in old age. Furthermore, our SEM analysis showed that genetic variants influencing cognition had a direct effect on the risk of developing Alzheimer's disease, providing evidence in support of the neurodevelopmental hypothesis of the disease.

• Knol, Maria J.; Poot, Raymond A.; Evans, Tavia E.; Satizabal, Claudia L.; Mishra, Aniket & Sargurupremraj, Muralidharan [Vis alle 304 forfattere av denne artikkelen] (2024). Genetic variants for head size share genes and pathways with cancer. Cell Reports Medicine. 5(5). doi: 10.1016/j.xcrm.2024.101529. Fulltekst i vitenarkiv
• Mlakar, Vid; Akkouh, Ibrahim Ahmed; Halff, Els F.; Srivastava, Deepak P.; Birkenæs, Viktoria & Ueland, Torill [Vis alle 12 forfattere av denne artikkelen] (2024). Telomere biology and its maintenance in schizophrenia spectrum disorders: Exploring links to cognition. Schizophrenia Research. ISSN 0920-9964. 272, s. 89–95. doi: 10.1016/j.schres.2024.08.011. Fulltekst i vitenarkiv Vis sammendrag

  Objective Contemporary research suggests reduced telomere length in schizophrenia spectrum disorders (SZ) compared to age-adjusted non-affected individuals. However, the role of telomere maintenance and telomere repair in SZ is poorly understood as well as the involvement of telomere biology in cognitive abnormalities in SZ. Methods The study consisted of 758 participants (SZ [n = 357] and healthy controls, HC [n = 401]) collected as part of the Norwegian TOP study. Participants were assessed with standardized neuropsychological tests measuring five cognitive domains. Leucocyte telomere length (TL) was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio), used to estimate the mean telomere length. Telomerase activity was assessed by the expression levels of the Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC) genes. To assess telomere maintenance and telomere repair we calculated the telomerase expression to TL ratio (TERT/TL and TERC/TL respectively). Results Patients had reduced TERT (F = 5.03, p = 0.03), but not TERC expression (F = 1.04, p = 0.31), and higher TERT/TL (F = 6.68, p = 0.01) and TERC/TL (F = 6.71, p = 0.01), adjusted for age, sex, and ethnicity. No statistically significant association was observed between any of the telomere biology markers and the cognitive domains (p > 0.05). Conclusion Our study shows changes in TERT expression and telomere maintenance and telomere repair in SZ compared HC. However, the role of telomere biology in the mechanism underlying cognitive impairment in psychosis seems limited.

• Koch, Elise Mirjam; Pardiñas, Antonio F.; O'Connell, Kevin Sean; Selvaggi, Pierluigi; Camacho-Collados, Jose & Babic, Aleksandar [Vis alle 26 forfattere av denne artikkelen] (2024). How real-world data can facilitate the development of precision medicine treatment in psychiatry. Biological Psychiatry. ISSN 0006-3223. 96, s. 543–551. doi: 10.1016/j.biopsych.2024.01.001. Fulltekst i vitenarkiv Vis sammendrag

  Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements—well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms—to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.

• Andreou, Dimitrios; Steen, Nils Eiel; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne & Barth, Claudia [Vis alle 19 forfattere av denne artikkelen] (2024). Toxoplasma gondii infection associated with inflammasome activation and neuronal injury. Scientific Reports. 14(1). doi: 10.1038/s41598-024-55887-9. Fulltekst i vitenarkiv Vis sammendrag

  Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

• Tissink, E.P.; Shadrin, Alexey; Meer, Dennis van der; Parker, Nadine; Hindley, Guy & Roelfs, Daniel [Vis alle 18 forfattere av denne artikkelen] (2024). Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study. Nature Communications. 15. doi: 10.1038/s41467-024-46817-4. Fulltekst i vitenarkiv Vis sammendrag

  Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N = 34,029) and ABCD Study (N = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition.

• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Vis alle 18 forfattere av denne artikkelen] (2024). Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology. Neurology: Genetics. 10(3). doi: 10.1212/NXG.0000000000200143. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives: Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences. Methods: We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples. Results: The epilepsies (2.4 k–2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples. Discussion: Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.

• Ivarsdottir, Erna V.; Gudmundsson, Julius; Tragante, Vinicius; Sveinbjornsson, Gardar; Kristmundsdottir, Snaedis & Stacey, Simon N. [Vis alle 58 forfattere av denne artikkelen] (2024). Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. Nature Genetics. ISSN 1061-4036. 56(11), s. 2422–2433. doi: https:/rdcu.be/dYuc6. Fulltekst i vitenarkiv
• Bahrami, Shahram; Nordengen, Kaja; Rokicki, Jaroslav; Shadrin, Alexey; Rahman, Mohammad Zillur & Smeland, Olav Bjerkehagen [Vis alle 17 forfattere av denne artikkelen] (2024). The genetic landscape of basal ganglia and implications for common brain disorders. Nature Communications. 15(1). doi: 10.1038/s41467-024-52583-0. Fulltekst i vitenarkiv Vis sammendrag

  The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P < 0.05 and 87.5% showed the same direction, revealing a distributed genetic architecture across basal ganglia structures. Of these, 50 loci were novel, including exonic regions of APOE, NBR1 and HLAA. We examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The strongest genetic overlap was between basal ganglia and Parkinson’s disease, as supported by robust LD-score regression-based genetic correlations. Mendelian randomization indicated genetic liability to larger striatal volume as potentially causal for Parkinson’s disease, in addition to a suggestive causal effect of greater genetic liability to Alzheimer’s disease on smaller accumbens. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders.

• Bakke, Laura Anne Wortinger; Stavrum, Anne-Kristin Støbakk; Shadrin, Alexey; Szabo, Attila; Rukke, Sondre Høeg & Nerland, Stener [Vis alle 17 forfattere av denne artikkelen] (2024). Divergent epigenetic responses to perinatal asphyxia in severe mental disorders. Translational Psychiatry. 14. doi: 10.1038/s41398-023-02709-7. Fulltekst i vitenarkiv Vis sammendrag

  Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case–control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

• Szabo, Attila; O'Connell, Kevin Sean; Akkouh, Ibrahim Ahmed; Ueland, Thor; Sønderby, Ida Elken & Hope, Sigrun [Vis alle 16 forfattere av denne artikkelen] (2024). Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder. Psychiatry Research. ISSN 0165-1781. 342. doi: 10.1016/j.psychres.2024.116245. Fulltekst i vitenarkiv Vis sammendrag

  Background Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified. Methods We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods. Results We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro. Conclusion Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

• Sæther, Linn Sofie; Szabo, Attila; Akkouh, Ibrahim Ahmed; Haatveit, Beathe; Mohn, Christine & Vaskinn, Anja [Vis alle 14 forfattere av denne artikkelen] (2024). Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain. Brain, Behavior, and Immunity. ISSN 0889-1591. 118, s. 287–299. doi: 10.1016/j.bbi.2024.03.014. Fulltekst i vitenarkiv Vis sammendrag

  Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

• Szabo, Attila; Akkouh, Ibrahim Ahmed; Osete, Jordi Requena; Assis, Denis Reis de; Kondratskaya, Elena & Hughes, Timothy [Vis alle 9 forfattere av denne artikkelen] (2024). NLRP3 inflammasome mediates astroglial dysregulation of innate and adaptive immune responses in schizophrenia. Brain, Behavior, and Immunity. ISSN 0889-1591. 124, s. 144–156. doi: 10.1016/j.bbi.2024.11.030. Fulltekst i vitenarkiv Vis sammendrag

  Mounting evidence indicates the involvement of neuroinflammation in the development of schizophrenia (SCZ), but the potential role of astroglia in this phenomenon remains poorly understood. We assessed the molecular and functional consequences of inflammasome activation using induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Screening protein levels in astrocytes at baseline identified lower expression of the NLRP3-ASC complex in SCZ, but increased Caspase-1 activity upon specific NLRP3 stimulation compared to CTRL. Using transcriptional profiling, we found corresponding downregulations of NLRP3 and ASC/PYCARD in both iPSC-derived astrocytes, and in a large (n = 429) brain postmortem case-control sample. Functional analyses following NLRP3 activation revealed an inflammatory phenotype characterized by elevated production of IL-1β/IL-18 and skewed priming of helper T lymphocytes (Th1/Th17) by SCZ astrocytes. This phenotype was rescued by specific inhibition of NLRP3 activation, demonstrating its dependence on the NLRP3 inflammasome. Taken together, SCZ iPSC-astrocytes display unique, NLRP3-dependent inflammatory characteristics that are manifested via various cellular functions, as well as via dysregulated innate and adaptive immune responses.

• Tesfaye, Markos; Jaholkowski, Piotr Pawel; Shadrin, Alexey; Meer, Dennis van der; Hindley, Guy & Holen, Børge [Vis alle 18 forfattere av denne artikkelen] (2024). Identification of novel genomic loci for anxiety symptoms and extensive genetic overlap with psychiatric disorders. Psychiatry and Clinical Neurosciences. ISSN 1323-1316. 78(12), s. 783–791. doi: 10.1111/pcn.13742. Fulltekst i vitenarkiv Vis sammendrag

  Aims: Anxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders. Methods: We included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders. Results: Anxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k–11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD (n=47), BIP (n=33), SCZ (n=71), ADHD (n=20), and ASD (n=5). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci. Conclusions: Anxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Vis alle 50 forfattere av denne artikkelen] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), s. 1310–1318. doi: 10.1038/s41588-024-01771-1. Fulltekst i vitenarkiv
• Koch, Elise Mirjam; Kämpe, Anders; Alver, Maris; Sigurðarson, Sindri; Einarsson, Guðmundur & Partanen, Juulia [Vis alle 21 forfattere av denne artikkelen] (2024). Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study. Neuropsychopharmacology. ISSN 0893-133X. 49, s. 1113–1119. doi: 10.1038/s41386-023-01792-0. Fulltekst i vitenarkiv
• García-Marín, Luis M.; Campos, Adrian I.; Diaz-Torres, Santiago; Rabinowitz, Jill A.; Ceja, Zuriel & Mitchell, Brittany L. [Vis alle 190 forfattere av denne artikkelen] (2024). Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries. Nature Genetics. ISSN 1061-4036. 56(11), s. 2333–2344. doi: 10.1038/s41588-024-01951-z. Fulltekst i vitenarkiv
• Fongang, Bernard; Sargurupremraj, Muralidharan; Jian, Xueqiu; Mishra, Aniket; Damotte, Vincent & Rojas, Itziar De [Vis alle 51 forfattere av denne artikkelen] (2024). A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer's & Dementia. ISSN 1552-5260. 20(9), s. 5973–5995. doi: 10.1002/alz.14115. Fulltekst i vitenarkiv Vis sammendrag

  INTRODUCTION: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: * We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). * Known genetic variants associated with AD were replicated for ACD and VaD. * Functional analyses identified novel loci for ACD and VaD. * Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Vis alle 19 forfattere av denne artikkelen] (2024). Unraveling the shared genetics of common epilepsies and general cognitive ability. Seizure. ISSN 1059-1311. 122, s. 105–112. doi: 10.1016/j.seizure.2024.09.016. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Cognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown. Methods We investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes ‘all epilepsy’, focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples. Results Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ‘all epilepsy’, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k – 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ‘all epilepsy’, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ‘all epilepsy’ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10–7; ‘all epilepsy’: p = 2.58 × 10–3). Conclusion Our study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

• Baune, B.T.; Fromme, S.E.; Aberg, M.; Adli, M.; Afantitis, A. & Akkouh, Ibrahim Ahmed [Vis alle 75 forfattere av denne artikkelen] (2024). A stratified treatment algorithm in psychiatry: a program on stratified pharmacogenomics in severe mental illness (Psych-STRATA): concept, objectives and methodologies of a multidisciplinary project funded by Horizon Europe. European Archives of Psychiatry and Clinical Neuroscience. ISSN 0940-1334. doi: 10.1007/s00406-024-01944-3. Fulltekst i vitenarkiv Vis sammendrag

  Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal. The Psych-STRATA consortium addresses this research gap through a seven-step approach. First, transdiagnostic biosignatures of SCZ, BD and MDD are identified by GWAS and multi-modal omics signatures associated with treatment outcome and TR (steps 1 and 2). In a next step (step 3), a randomized controlled intervention study is conducted to test the efficacy and safety of an early intensified pharmacological treatment. Following this RCT, a combined clinical and omics-based algorithm will be developed to estimate the risk for TR. This algorithm-based tool will be designed for early detection and management of TR (step 4). This algorithm will then be implemented into a framework of shared treatment decision-making with a novel mental health board (step 5). The final focus of the project is based on patient empowerment, dissemination and education (step 6) as well as the development of a software for fast, effective and individualized treatment decisions (step 7). The project has the potential to change the current trial and error treatment approach towards an evidence-based individualized treatment setting that takes TR risk into account at an early stage.

• Trastulla, Lucia; Dolgalev, Georgii; Moser, Sylvain; Jiménez-Barrón, Laura T.; Andlauer, Till F. M. & Scheidt, Moritz von [Vis alle 310 forfattere av denne artikkelen] (2024). Distinct genetic liability profiles define clinically relevant patient strata across common diseases. Nature Communications. 15(1). doi: 10.1038/s41467-024-49338-2. Fulltekst i vitenarkiv Vis sammendrag

  Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

• Holmgren, Asbjørn; Akkouh, Ibrahim Ahmed; O'Connell, Kevin Sean; Osete, Jordi Requena; Bjørnstad, Pål Marius & Djurovic, Srdjan [Vis alle 7 forfattere av denne artikkelen] (2024). Bipolar patients display stoichiometric imbalance of gene expression in post-mortem brain samples. Molecular Psychiatry. ISSN 1359-4184. 29. doi: 10.1038/s41380-023-02398-0. Fulltekst i vitenarkiv Vis sammendrag

  Bipolar disorder is a severe neuro-psychiatric condition where genome-wide association and sequencing studies have pointed to dysregulated gene expression as likely to be causal. We observed strong correlation in expression between GWAS-associated genes and hypothesised that healthy function depends on balance in the relative expression levels of the associated genes and that patients display stoichiometric imbalance. We developed a method for quantifying stoichiometric imbalance and used this to predict each sample’s diagnosis probability in four cortical brain RNAseq datasets. The percentage of phenotypic variance on the liability-scale explained by these probabilities ranged from 10.0 to 17.4% (AUC: 69.4–76.4%) which is a multiple of the classification performance achieved using absolute expression levels or GWAS-based polygenic risk scores. Most patients display stoichiometric imbalance in three to ten genes, suggesting that dysregulation of only a small fraction of associated genes can trigger the disorder, with the identity of these genes varying between individuals.

• Mäki-Marttunen, Tuomo; Blackwell, Kim T.; Akkouh, Ibrahim Ahmed; Shadrin, Alexey; Valstad, Mathias & Elvsåshagen, Torbjørn [Vis alle 10 forfattere av denne artikkelen] (2024). Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 121(34). doi: 10.1073/pnas.2312511121. Fulltekst i vitenarkiv Vis sammendrag

  Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.

• Lenk, Hasan Cagin; Koch, Elise Mirjam; O'Connell, Kevin Sean; Smith, Robert Løvsletten; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Vis alle 8 forfattere av denne artikkelen] (2024). Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment. Human Genomics. ISSN 1473-9542. 18(1). doi: 10.1186/s40246-024-00673-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively. Results We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively. Conclusions We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

• Steen, Nils Eiel; Rahman, Zillur; Szabo, Attila; Hindley, Guy; Parker, Nadine & Cheng, Weiqiu [Vis alle 20 forfattere av denne artikkelen] (2023). Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), s. 1345–1354. doi: 10.1093/schbul/sbad082. Fulltekst i vitenarkiv Vis sammendrag

  Background: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. Study Design: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. Study Results: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%–59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. Conclusions: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

• Rødevand, Linn Nilsen; Rahman, Zillur; Hindley, Guy Frederick Lanyon; Smeland, Olav Bjerkehagen; Frei, Oleksandr & Filiz, Tahir Tekin [Vis alle 15 forfattere av denne artikkelen] (2023). Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors. American Journal of Psychiatry. ISSN 0002-953X. 180(11), s. 815–826. doi: 10.1176/APPI.AJP.20220660. Fulltekst i vitenarkiv
• Jaholkowski, Piotr Pawel; Shadrin, Alexey; Jangmo, Anders Andreas Krister; Frei, Evgeniia; Woldeyohannes, Markos Tesfaye & Hindley, Guy Frederick Lanyon [Vis alle 23 forfattere av denne artikkelen] (2023). Associations Between Symptoms of Premenstrual Disorders and Polygenic Liability for Major Psychiatric Disorders. JAMA psychiatry. ISSN 2168-6238. doi: 10.1001/jamapsychiatry.2023.1137. Fulltekst i vitenarkiv
• Aas, Monica; Andreassen, Ole; Gjerstad, Johannes; Rødevand, Linn; Hjell, Gabriela & Johansen, Ingrid Torp [Vis alle 12 forfattere av denne artikkelen] (2023). Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders. Scientific Reports. 13:13845, s. 1–9. doi: 10.1038/s41598-023-40310-6. Fulltekst i vitenarkiv Vis sammendrag

  Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.

• Hindley, Guy; Drange, Ole Kristian; Lin, Aihua; Kutrolli, Gleda; Shadrin, Alexey & Parker, Nadine [Vis alle 20 forfattere av denne artikkelen] (2023). Cross-trait genome-wide association analysis of C-reactive protein level and psychiatric disorders. Psychoneuroendocrinology. ISSN 0306-4530. 157. doi: 10.1016/j.psyneuen.2023.106368. Fulltekst i vitenarkiv Vis sammendrag

  C-reactive protein (CRP) tends to be elevated in individuals with psychiatric disorders. Recent findings have suggested a protective effect of the genetic liability to elevated CRP on schizophrenia risk and a causative effect on depression despite weak genetic correlations, while causal relationships with bipolar disorder were inconclusive. We investigated the shared genetic underpinnings of psychiatric disorders and variation in CRP levels. Genome-wide association studies for CRP (n = 575,531), bipolar disorder (n = 413,466), depression (n = 480,359), and schizophrenia (n = 130,644) were used in causal mixture models to compare CRP with psychiatric disorders based on polygenicity, discoverability, and genome-wide genetic overlap. The conjunctional false discovery rate method was used to identify specific shared genetic loci. Shared variants were mapped to putative causal genes, which were tested for overrepresentation among gene ontology gene-sets. CRP was six to ten times less polygenic (n = 1400 vs 8600–14,500 variants) and had a discoverability one to two orders of magnitude higher than psychiatric disorders. Most CRP-associated variants were overlapping with psychiatric disorders. We identified 401 genetic loci jointly associated with CRP and psychiatric disorders with mixed effect directions. Gene-set enrichment analyses identified predominantly CNS-related gene sets for CRP and each of depression and schizophrenia, and basic cellular processes for CRP and bipolar disorder. In conclusion, CRP has a markedly different genetic architecture to psychiatric disorders, but the majority of CRP associated variants are also implicated in psychiatric disorders. Shared genetic loci implicated CNS-related processes to a greater extent than immune processes, which may have implications for how we conceptualise causal relationships between CRP and psychiatric disorders.

• Hjell, Gabriela; Rokicki, Jaroslav; Szabo, Attila; Holst, Rene; Tesli, Natalia & Bell, Christina [Vis alle 19 forfattere av denne artikkelen] (2023). Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy. BMC Psychiatry. 23(1). doi: 10.1186/s12888-023-05154-4. Fulltekst i vitenarkiv Vis sammendrag

  Background Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. Methods Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. Results Impulsivity was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. Conclusions We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

• Hope, Sigrun; Shadrin, Alexey; Lin, Aihua; Bahrami, Shahram; Rødevand, Linn & Frei, Oleksandr [Vis alle 17 forfattere av denne artikkelen] (2023). Bidirectional genetic overlap between autism spectrum disorder and cognitive traits. Translational Psychiatry. 13(1), s. 1–9. doi: 10.1038/s41398-023-02563-7. Fulltekst i vitenarkiv Vis sammendrag

  Autism spectrum disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. We analyzed data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, local analysis of co-variant annotation (LAVA) to estimate local genetic correlations, conditional false discovery rate (cond/conjFDR) to identify specific overlapping loci. The MiXeR analyses showed that 12.7k genetic variants are associated with ASD, of which 12.0k variants are shared with EDU, and 11.1k are shared with INT with both positive and negative relationships within overlapping variants. The majority (59–68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (rg = 0.21, p = 2e−13) and INT (rg = 0.22, p = 4e−12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR<0.05), of which 27 were novel for ASD. Functional analysis revealed significant differential expression of candidate genes in the cerebellum and frontal cortex. To conclude, we quantified the genetic architecture shared between ASD and cognitive traits, demonstrated mixed effect directions, and identified the associated genetic loci and molecular pathways. The findings suggest that common genetic risk factors for ASD can underlie both better and worse cognitive functioning across the ASD spectrum, with different underlying biology.

• Bang, Lasse; Bahrami, Shahram; Hindley, Guy; Smeland, Olav Bjerkehagen; Rødevand, Linn & Jaholkowski, Piotr Pawel [Vis alle 18 forfattere av denne artikkelen] (2023). Genome-wide analysis of anorexia nervosa and major psychiatric disorders and related traits reveals genetic overlap and identifies novel risk loci for anorexia nervosa. Translational Psychiatry. 13. doi: 10.1038/s41398-023-02585-1. Fulltekst i vitenarkiv Vis sammendrag

  Anorexia nervosa (AN) is a heritable eating disorder (50–60%) with an array of commonly comorbid psychiatric disorders and related traits. Although significant genetic correlations between AN and psychiatric disorders and related traits have been reported, their shared genetic architecture is largely understudied. We investigated the shared genetic architecture of AN and schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), mood instability (Mood), neuroticism (NEUR), and intelligence (INT). We applied the conditional false discovery rate (FDR) method to identify novel risk loci for AN, and conjunctional FDR to identify loci shared between AN and related phenotypes, to summarize statistics from relevant genome-wide association studies (GWAS). Individual GWAS samples varied from 72,517 to 420,879 participants. Using conditional FDR we identified 58 novel AN loci. Furthermore, we identified 38 unique loci shared between AN and major psychiatric disorders (SCZ, BIP, and MD) and 45 between AN and psychological traits (Mood, NEUR, and INT). In line with genetic correlations, the majority of shared loci showed concordant effect directions. Functional analyses revealed that the shared loci are involved in 65 unique pathways, several of which overlapped across analyses, including the “signal by MST1” pathway involved in Hippo signaling. In conclusion, we demonstrated genetic overlap between AN and major psychiatric disorders and related traits, and identified novel risk loci for AN by leveraging this overlap. Our results indicate that some shared characteristics between AN and related disorders and traits may have genetic underpinnings.

• Karadag, Naz; Shadrin, Alexey; O'Connell, Kevin Sean; Hindley, Guy Frederick Lanyon; Rahman, Zillur & Parker, Nadine [Vis alle 18 forfattere av denne artikkelen] (2023). Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders. Brain. ISSN 0006-8950. 146(8), s. 3392–3403. doi: 10.1093/brain/awad038. Fulltekst i vitenarkiv Vis sammendrag

  Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

• Jaholkowski, Piotr Pawel; Hindley, Guy; Shadrin, Alexey; Tesfaye, Markos; Bahrami, Shahram & Nerhus, Mari [Vis alle 19 forfattere av denne artikkelen] (2023). Genome-wide Association Analysis of Schizophrenia and Vitamin D Levels Shows Shared Genetic Architecture and Identifies Novel Risk Loci. Schizophrenia Bulletin. ISSN 0586-7614. 49(6), s. 1654–1664. doi: 10.1093/schbul/sbad063. Fulltekst i vitenarkiv Vis sammendrag

  Low vitamin D (vitD) levels have been consistently reported in schizophrenia (SCZ) suggesting a role in the etiopathology. However, little is known about the role of underlying shared genetic mechanisms. We applied a conditional/conjunctional false discovery rate approach (FDR) on large, nonoverlapping genome-wide association studies for SCZ (N cases = 53 386, N controls = 77 258) and vitD serum concentration (N = 417 580) to evaluate shared common genetic variants. The identified genomic loci were characterized using functional analyses and biological repositories. We observed cross-trait SNP enrichment in SCZ conditioned on vitD and vice versa, demonstrating shared genetic architecture. Applying the conjunctional FDR approach, we identified 72 loci jointly associated with SCZ and vitD at conjunctional FDR < 0.05. Among the 72 shared loci, 40 loci have not previously been reported for vitD, and 9 were novel for SCZ. Further, 64% had discordant effects on SCZ-risk and vitD levels. A mixture of shared variants with concordant and discordant effects with a predominance of discordant effects was in line with weak negative genetic correlation (rg = −0.085). Our results displayed shared genetic architecture between SCZ and vitD with mixed effect directions, suggesting overlapping biological pathways. Shared genetic variants with complex overlapping mechanisms may contribute to the coexistence of SCZ and vitD deficiency and influence the clinical picture.

• Jaholkowski, Piotr; Shadrin, Alexey A.; Jangmo, Andreas; Frei, Evgeniia; Woldeyohannes, Markos Tesfaye & Hindley, Guy F. L. [Vis alle 23 forfattere av denne artikkelen] (2023). Associations Between Symptoms of Premenstrual Disorders and Polygenic Liability for Major Psychiatric Disorders. JAMA psychiatry. ISSN 2168-6238. 80(7), s. 738–742. doi: 10.1001/jamapsychiatry.2023.1137. Fulltekst i vitenarkiv
• Oddsson, Asmundur; Sulem, Patrick; Sveinbjornsson, Gardar; Arnadottir, Gudny A.; Steinthorsdottir, Valgerdur & Halldorsson, Gisli H. [Vis alle 54 forfattere av denne artikkelen] (2023). Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nature Communications. 14(1). doi: 10.1038/s41467-023-38951-2. Fulltekst i vitenarkiv Vis sammendrag

  Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

• Holen, Børge; Shadrin, Alexey; Icick, Romain; Filiz, Tahir Tekin; Hindley, Guy Frederick Lanyon & Rødevand, Linn [Vis alle 19 forfattere av denne artikkelen] (2023). Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression. Addiction Biology. ISSN 1355-6215. 28(6). doi: 10.1111/adb.13282. Fulltekst i vitenarkiv Vis sammendrag

  Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity and mortality. The causes underlying this relationship are poorly understood. Although these conditions are highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, schizophrenia (SCZ), bipolar disorder (BD) and major depression (MD) of European ancestry. Next, we characterized the identified shared loci using biological annotation resources. OUD data were obtained from the Million Veteran Program, Yale-Penn and Study of Addiction: Genetics and Environment (SAGE) (15 756 cases, 99 039 controls). SCZ (53 386 cases, 77 258 controls), BD (41 917 cases, 371 549 controls) and MD (170 756 cases, 329 443 controls) data were provided by the Psychiatric Genomics Consortium. We discovered genetic enrichment for OUD conditional on associations with SCZ, BD, MD and vice versa, indicating polygenic overlap with identification of 14 novel OUD loci at condFDR < 0.05 and 7 unique loci shared between OUD and SCZ (n = 2), BD (n = 2) and MD (n = 7) at conjFDR < 0.05 with concordant effect directions, in line with estimated positive genetic correlations. Two loci were novel for OUD, one for BD and one for MD. Three OUD risk loci were shared with more than one psychiatric disorder, at DRD2 on chromosome 11 (BD and MD), at FURIN on chromosome 15 (SCZ, BD and MD) and at the major histocompatibility complex region (SCZ and MD). Our findings provide new insights into the shared genetic architecture between OUD and SCZ, BD and MD, indicating a complex genetic relationship, suggesting overlapping neurobiological pathways.

• Meer, Dennis van der; Cheng, Weiqiu; Rokicki, Jaroslav; Fernandez-Cabello, Sara; Shadrin, Alexey & Smeland, Olav Bjerkehagen [Vis alle 19 forfattere av denne artikkelen] (2023). Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation. Schizophrenia Bulletin. ISSN 0586-7614. 50(2), s. 327–338. doi: 10.1093/schbul/sbad140. Fulltekst i vitenarkiv Vis sammendrag

  Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

• Wortinger, Laura Anne; Shadrin, Alexey; Szabo, Attila; Nerland, Stener; Smelror, Runar & Jørgensen, Kjetil Nordbø [Vis alle 13 forfattere av denne artikkelen] (2023). The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02639-4. Fulltekst i vitenarkiv Vis sammendrag

  The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genomewide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = −2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = −2.71, p = 0.005) and also found with their adult ICV (t = −1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

• Akkouh, Ibrahim Ahmed; Ueland, Thor; Szabo, Attila; Hughes, Timothy; Smeland, Olav Bjerkehagen & Andreassen, Ole [Vis alle 8 forfattere av denne artikkelen] (2023). Longitudinal Transcriptomic Analysis of Human Cortical Spheroids Identifies Axonal Dysregulation in the Prenatal Brain as a Mediator of Genetic Risk for Schizophrenia. Biological Psychiatry. ISSN 0006-3223. 0(7), s. 1–12. doi: 10.1016/j.biopsych.2023.08.017. Fulltekst i vitenarkiv Vis sammendrag

  Background Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain. Methods We generated induced pluripotent stem cell–derived organoids, termed human cortical spheroids (hCSs), from a large, genetically stratified sample of 14 SCZ cases and 14 age- and sex-matched controls. The hCSs were differentiated for 150 days, and comprehensive molecular characterization across 4 time points was carried out. Results The transcriptional and cellular architecture of hCSs closely resembled that of fetal brain tissue at 10 to 24 postconception weeks, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3520 genes were differentially modulated between SCZ and control hCSs across organoid maturation, displaying a significant contribution of genetic loading, an overrepresentation of risk genes for autism spectrum disorder and SCZ, and the strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A, the first a promoter of synaptic functions and the second a repressor, were downregulated and upregulated, respectively, in SCZ hCSs. This expression pattern was confirmed at the protein level and replicated in a large postmortem sample. Conclusions Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder.

• Parker, Nadine; Cheng, Weiqiu; Hindley, Guy; O'Connell, Kevin Sean; Karthikeyan, Sandeep & Holen, Børge [Vis alle 19 forfattere av denne artikkelen] (2023). Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts. Biological Psychiatry. ISSN 0006-3223. 95(1). doi: 10.1016/j.biopsych.2023.06.008. Fulltekst i vitenarkiv Vis sammendrag

  Background For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Methods Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Results Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; rg_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. Conclusions The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.

• Osete, Jordi Requena; Akkouh, Ibrahim Ahmed; Ievglevskyi, Oleksandr; Vandenberghe, Matthieu; Assis, Denis Reis de & Ueland, Thor [Vis alle 14 forfattere av denne artikkelen] (2023). Characterization of lithium (Li) treated human cortical spheroids (hCS). Molecular Psychiatry. ISSN 1359-4184. 28(7). doi: 10.1038/s41380-023-02300-y. Fulltekst i vitenarkiv
• Hindley, Guy Frederick Lanyon; Shadrin, Alexey; Meer, Dennis van der; Parker, Nadine; Cheng, Weiqiu & O'Connell, Kevin Sean [Vis alle 23 forfattere av denne artikkelen] (2023). Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy. Nature Human Behaviour. 7, s. 1584–1600. doi: 10.1038/s41562-023-01630-9. Fulltekst i vitenarkiv
• O'Connell, Kevin Sean; Koch, Elise; Lenk, Hasan Cagin; Akkouh, Ibrahim Ahmed; Hindley, Guy Frederick Lanyon & Jaholkowski, Piotr Pawel [Vis alle 16 forfattere av denne artikkelen] (2023). Polygenic overlap with body-mass index improves prediction of treatment-resistant schizophrenia. Psychiatry Research. ISSN 0165-1781. 325. doi: 10.1016/j.psychres.2023.115217. Fulltekst i vitenarkiv Vis sammendrag

  Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

• Parker, Nadine; Cheng, Weiqiu; Hindley, Guy; Parekh, Pravesh; Shadrin, Alexey & Maximov, Ivan [Vis alle 12 forfattere av denne artikkelen] (2023). Psychiatric disorders and brain white matter exhibit genetic overlap implicating developmental and neural cell biology. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-023-02264-z. Fulltekst i vitenarkiv
• Bøen, Rune; Kaufmann, Tobias; Frei, Oleksandr; Meer, Dennis van der; Djurovic, Srdjan & Andreassen, Ole [Vis alle 9 forfattere av denne artikkelen] (2023). No signs of neurodegenerative effects in 15q11.2 BP1-BP2 copy number variant carriers in the UK Biobank. Translational Psychiatry. 13:61, s. 1–6. doi: 10.1038/s41398-023-02358-w. Fulltekst i vitenarkiv Vis sammendrag

  The 15q11.2 BP1-BP2 copy number variant (CNV) is associated with altered brain morphology and risk for atypical development, including increased risk for schizophrenia and learning difficulties for the deletion. However, it is still unclear whether differences in brain morphology are associated with neurodevelopmental or neurodegenerative processes. This study derived morphological brain MRI measures in 15q11.2 BP1-BP2 deletion (n = 124) and duplication carriers (n = 142), and matched deletion-controls (n = 496) and duplication-controls (n = 568) from the UK Biobank study to investigate the association with brain morphology and estimates of brain ageing. Further, we examined the ageing trajectory of age-affected measures (i.e., cortical thickness, surface area, subcortical volume, reaction time, hand grip strength, lung function, and blood pressure) in 15q11.2 BP1-BP2 CNV carriers compared to non-carriers. In this ageing population, the results from the machine learning models showed that the estimated brain age gaps did not differ between the 15q11.2 BP1-BP2 CNV carriers and non-carriers, despite deletion carriers displaying thicker cortex and lower subcortical volume compared to the deletion-controls and duplication carriers, and lower surface area compared to the deletion-controls. Likewise, the 15q11.2 BP1-BP2 CNV carriers did not deviate from the ageing trajectory on any of the age-affected measures examined compared to non-carriers. Despite altered brain morphology in 15q11.2 BP1-BP2 CNV carriers, the results did not show any clear signs of apparent altered ageing in brain structure, nor in motor, lung or heart function. The results do not indicate neurodegenerative effects in 15q11.2 BP1-BP2 CNV carriers.

• Mlakar, Vid; Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Ormerod, Monica Bettina E. Greenwood; Quintana, Daniel & Ueland, Torill [Vis alle 13 forfattere av denne artikkelen] (2023). Telomere length and verbal learning in bipolar disorders. Journal of Affective Disorders. ISSN 0165-0327. 339, s. 555–560. doi: 10.1016/j.jad.2023.07.087. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning. Methods: The study consisted of 647 participants (bipolar disorder [n =246] and healthy controls [n =401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity. Results: Patients had shorter telomere lengths than healthy controls (Cohen’s d =0.11, p =0.01). Within patients’ , a positive association was observed for verbal learning and telomere length (β =0.14, p =0.025), along with a trend for verbal memory and telomere length (β =0.11, p =0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1). Conclusion: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.

• Villar, Jonelle Marie Dickow; Stavrum, Anne-Kristin Støbakk; Spindola, Leticia Maria Nery; Torsvik, Anja; Bjella, Thomas & Steen, Nils Eiel [Vis alle 10 forfattere av denne artikkelen] (2023). Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02507-1. Fulltekst i vitenarkiv Vis sammendrag

  Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00–19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00–19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00–14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.

• Osete, Jordi Requena; Akkouh, Ibrahim Ahmed; Ievglevskyi, Oleksandr; Vandenberghe, Matthieu; Assis, Denis Reis de & Ueland, Thor [Vis alle 14 forfattere av denne artikkelen] (2023). Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Molecular Psychiatry. ISSN 1359-4184. 28, s. 3033–3043. doi: 10.1038/s41380-023-01944-0. Fulltekst i vitenarkiv Vis sammendrag

  Lithium (Li) is recommended for long-term treatment of bipolar disorder (BD). However, its mechanism of action is still poorly understood. Induced pluripotent stem cell (iPSC)-derived brain organoids have emerged as a powerful tool for modeling BD-related disease mechanisms. We studied the effects of 1 mM Li treatment for 1 month in iPSC-derived human cortical spheroids (hCS) from 10 healthy controls (CTRL) and 11 BD patients (6 Li-responders, Li-R, and 5 Li non-treated, Li-N). At day 180 of differentiation, BD hCS showed smaller size, reduced proportion of neurons, decreased neuronal excitability and reduced neural network activity compared to CTRL hCS. Li rescued excitability of BD hCS neurons by exerting an opposite effect in the two diagnostic groups, increasing excitability in BD hCS and decreasing it in CTRL hCS. We identified 132 Li-associated differentially expressed genes (DEGs), which were overrepresented in sodium ion homeostasis and kidney-related pathways. Moreover, Li regulated secretion of pro-inflammatory cytokines and increased mitochondrial reserve capacity in BD hCS. Through long-term Li treatment of a human 3D brain model, this study partly elucidates the functional and transcriptional mechanisms underlying the clinical effects of Li, such as rescue of neuronal excitability and neuroprotection. Our results also underscore the substantial influence of treatment duration in Li studies. Lastly, this study illustrates the potential of patient iPSC-derived 3D brain models for precision medicine in psychiatry.

• Docherty, Anna R.; Mullins, Niamh; Ashley-Koch, Allison E.; Qin, Xuejun; Coleman, Jonathan R.I. & Shabalin, Andrey [Vis alle 51 forfattere av denne artikkelen] (2023). GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. American Journal of Psychiatry. ISSN 0002-953X. 180(10), s. 723–738. doi: 10.1176/appi.ajp.21121266. Fulltekst i vitenarkiv Vis sammendrag

  Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10–8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10–80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

• Holen, Børge; Kutrolli, Gleda; Shadrin, Alexey; Icick, Romain; Hindley, Guy & Rødevand, Linn [Vis alle 16 forfattere av denne artikkelen] (2023). Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability. Drug and Alcohol Dependence. ISSN 0376-8716. 256. doi: 10.1016/j.drugalcdep.2023.111058. Fulltekst i vitenarkiv Vis sammendrag

  Background Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG. Methods We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources. Results We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia. Conclusion We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG.

• Fominykh, Vera; Shadrin, Alexey; Jaholkowski, Piotr Pawel; Bahrami, Shahram; Athanasiu, Lavinia & Wightman, Douglas P. [Vis alle 13 forfattere av denne artikkelen] (2023). Shared genetic loci between Alzheimer's disease and multiple sclerosis: Crossroads between neurodegeneration and immune system. Neurobiology of Disease. ISSN 0969-9961. 183. doi: 10.1016/j.nbd.2023.106174. Fulltekst i vitenarkiv Vis sammendrag

  Background Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

• Woldeyohannes, Markos Tesfaye; Jaholkowski, Piotr Pawel; Hindley, Guy; Shadrin, Alexey; Rahman, Zillur & Bahrami, Shahram [Vis alle 17 forfattere av denne artikkelen] (2023). Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis. Genome Medicine. 15(1). doi: 10.1186/s13073-023-01212-4. Fulltekst i vitenarkiv Vis sammendrag

  Background: Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, and the genetic overlap with psychiatric and somatic disorders is not quantified beyond genome-wide genetic correlations. Here, we characterize the genetic architecture of IBS, further, investigate its genetic overlap with psychiatric and gastrointestinal phenotypes, and identify novel genomic risk loci. Methods: Using GWAS summary statistics of IBS (53,400 cases and 433,201 controls), and psychiatric and gastrointestinal phenotypes, we performed bivariate casual mixture model analysis to characterize the genetic architecture and genetic overlap between these phenotypes. We leveraged identified genetic overlap to boost the discovery of genomic loci associated with IBS, and to identify specific shared loci associated with both IBS and psychiatric and gastrointestinal phenotypes, using the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework. We used functional mapping and gene annotation (FUMA) for functional analyses. Results: IBS was highly polygenic with 12k trait-influencing variants. We found extensive polygenic overlap between IBS and psychiatric disorders and to a lesser extent with gastrointestinal diseases. We identified 132 independent IBS-associated loci (condFDR < 0.05) by conditioning on psychiatric disorders (n = 127) and gastrointestinal diseases (n = 24). Using conjFDR, 70 unique loci were shared between IBS and psychiatric disorders. Functional analyses of shared loci revealed enrichment for biological pathways of the nervous and immune systems. Genetic correlations and shared loci between psychiatric disorders and IBS subtypes were different. Conclusions: We found extensive polygenic overlap of IBS and psychiatric and gastrointestinal phenotypes beyond what was revealed with genetic correlations. Leveraging the overlap, we discovered genetic loci associated with IBS which implicate a wide range of biological pathways beyond the gut-brain axis. Genetic differences may underlie the clinical subtype of IBS. These results increase our understanding of the pathophysiology of IBS which may form the basis for the development of individualized interventions.

• Torsvik, Anja; Brattbakk, Hans-Richard; Trentani, Andrea; Holdhus, Rita; Stansberg, Christine & Bartz-Johannessen, Christoffer [Vis alle 12 forfattere av denne artikkelen] (2023). Patients with schizophrenia and bipolar disorder display a similar global gene expression signature in whole blood that reflects elevated proportion of immature neutrophil cells with association to lipid changes. Translational Psychiatry. 13. doi: 10.1038/s41398-023-02442-1. Fulltekst i vitenarkiv Vis sammendrag

  Schizophrenia (SCZ) and bipolar disorder (BD) share clinical characteristics, genetic susceptibility, and immune alterations. We aimed to identify differential transcriptional patterns in peripheral blood cells of patients with SCZ or BD versus healthy controls (HC). We analyzed microarray-based global gene expression data in whole blood from a cohort of SCZ (N = 329), BD (N = 203) and HC (N = 189). In total, 65 genes were significantly differentially expressed in SCZ and 125 in BD, as compared to HC, with similar ratio of up- and downregulated genes in both disorders. Among the top differentially expressed genes, we found an innate immunity signature that was shared between SCZ and BD, consisting of a cluster of upregulated genes (e.g., OLFM4, ELANE, BPI and MPO) that indicate an increased fraction of immature neutrophils. Several of these genes displayed sex differences in the expression pattern, and post-hoc analysis demonstrated a positive correlation with triglyceride and a negative correlation with HDL cholesterol. We found that many of the downregulated genes in SCZ and BD were associated with smoking. These findings of neutrophil granulocyte-associated transcriptome signatures in both SCZ and BD point at altered innate immunity pathways with association to lipid changes and potential for clinical translation.

• Cheng, Weiqiu; Parker, Nadine; Karadag, Naz; Koch, Elise; Hindley, Guy Frederick Lanyon & Icick, Romain [Vis alle 22 forfattere av denne artikkelen] (2023). The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study. The Lancet Psychiatry. ISSN 2215-0374. 10(6), s. 441–451. doi: 10.1016/S2215-0366(23)00143-8. Fulltekst i vitenarkiv Vis sammendrag

  Background The relationship between psychotic disorders and cannabis use is heavily debated. Shared underlying genetic risk is one potential explanation. We investigated the genetic association between psychotic disorders (schizophrenia and bipolar disorder) and cannabis phenotypes (lifetime cannabis use and cannabis use disorder). Methods We used genome-wide association summary statistics from individuals with European ancestry from the Psychiatric Genomics Consortium, UK Biobank, and International Cannabis Consortium. We estimated heritability, polygenicity, and discoverability of each phenotype. We performed genome-wide and local genetic correlations. Shared loci were identified and mapped to genes, which were tested for functional enrichment. Shared genetic liabilities to psychotic disorders and cannabis phenotypes were explored using causal analyses and polygenic scores, using the Norwegian Thematically Organized Psychosis cohort. Findings Psychotic disorders were more heritable than cannabis phenotypes and more polygenic than cannabis use disorder. We observed positive genome-wide genetic correlations between psychotic disorders and cannabis phenotypes (range 0·22–0·35) with a mixture of positive and negative local genetic correlations. Three to 27 shared loci were identified for the psychotic disorder and cannabis phenotype pairs. Enrichment of mapped genes implicated neuronal and olfactory cells as well as drug–gene targets for nicotine, alcohol, and duloxetine. Psychotic disorders showed a causal effect on cannabis phenotypes, and lifetime cannabis use had a causal effect on bipolar disorder. Of 2181 European participants from the Norwegian Thematically Organized Psychosis cohort applied in polygenic risk score analyses, 1060 (48·6%) were females and 1121 (51·4%) were males (mean age 33·1 years [SD 11·8]). 400 participants had bipolar disorder, 697 had schizophrenia, and 1044 were healthy controls. Within this sample, polygenic scores for cannabis phenotypes predicted psychotic disorders independently and improved prediction beyond the polygenic score for the psychotic disorders. Interpretation A subgroup of individuals might have a high genetic risk of developing a psychotic disorder and using cannabis. This finding supports public health efforts to reduce cannabis use, particularly in individuals at high risk or patients with psychotic disorders. Identified shared loci and their functional implications could facilitate development of novel treatments.

• Wang, Shan; Rhijn, Jon-Ruben van; Akkouh, Ibrahim Ahmed; Kogo, Naoki; Maas, Nadine & Bleeck, Anna [Vis alle 15 forfattere av denne artikkelen] (2022). Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway. Cell reports. 39(5). doi: 10.1016/j.celrep.2022.110790. Fulltekst i vitenarkiv Vis sammendrag

  Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/ Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/- cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.

• Sæther, Linn Sofie; Ueland, Thor; Haatveit, Beathe; Maglanoc, Luigi; Szabo, Attila & Djurovic, Srdjan [Vis alle 15 forfattere av denne artikkelen] (2022). Inflammation and cognition in severe mental illness: patterns of covariation and subgroups. Molecular Psychiatry. ISSN 1359-4184. 8, s. 1284–1292. doi: 10.1038/s41380-022-01924-w. Fulltekst i vitenarkiv Vis sammendrag

  A potential relationship between dysregulation of immune/inflammatory pathways and cognitive impairment has been suggested in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, multivariate relationships between peripheral inflammatory/immune-related markers and cognitive domains are unclear, and many studies do not account for inter-individual variance in both cognitive functioning and inflammatory/immune status. This study aimed to investigate covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains and inflammatory/immune markers. We found that poor verbal learning and psychomotor processing speed was associated with higher levels of interleukin-18 system cytokines and beta defensin 2, reflecting enhanced activation of innate immunity, a pattern augmented in SMI compared to HC. Applying hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition—low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition—high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups differed in IQ, years of education, age, CRP, BMI (all groups), level of functioning, symptoms and defined daily dose (DDD) of antipsychotics (SMI cohort). Our findings suggest a link between cognitive impairment and innate immune dysregulation in a subset of individuals with severe mental illness.

• Werner, Maren Caroline Frogner; Wirgenes, Katrine Verena; Shadrin, Alexey; Lunding, Synve Hoffart; Rødevand, Linn & Hjell, Gabriela [Vis alle 15 forfattere av denne artikkelen] (2022). Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis. Translational Psychiatry. 12(1). doi: 10.1038/s41398-022-01811-6. Fulltekst i vitenarkiv Vis sammendrag

  Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

• Wilson, Madison N.; Thunemann, Martin; Liu, Xin; Lu, Yichen; Puppo, Francesca & Adams, Jason W. [Vis alle 16 forfattere av denne artikkelen] (2022). Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex. Nature Communications. 13. doi: 10.1038/s41467-022-35536-3. Fulltekst i vitenarkiv Vis sammendrag

  Human cortical organoids, three-dimensional neuronal cultures, are emerging as powerful tools to study brain development and dysfunction. However, whether organoids can functionally connect to a sensory network in vivo has yet to be demonstrated. Here, we combine transparent microelectrode arrays and two-photon imaging for longitudinal, multimodal monitoring of human cortical organoids transplanted into the retrosplenial cortex of adult mice. Two-photon imaging shows vascularization of the transplanted organoid. Visual stimuli evoke electrophysiological responses in the organoid, matching the responses from the surrounding cortex. Increases in multi-unit activity (MUA) and gamma power and phase locking of stimulus-evoked MUA with slow oscillations indicate functional integration between the organoid and the host brain. Immunostaining confirms the presence of human-mouse synapses. Implantation of transparent microelectrodes with organoids serves as a versatile in vivo platform for comprehensive evaluation of the development, maturation, and functional integration of human neuronal networks within the mouse brain.

• Jensen, Søren Beck; Sheikh, Mashhood Ahmed; Akkouh, Ibrahim Ahmed; Szabo, Attila; O'Connell, Kevin Sean & Lekva, Tove [Vis alle 23 forfattere av denne artikkelen] (2022). Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness. Schizophrenia Bulletin. ISSN 0586-7614. 49(3), s. 635–645. doi: 10.1093/schbul/sbac191. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

• Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia & Amin, Najaf [Vis alle 407 forfattere av denne artikkelen] (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genetics. ISSN 1061-4036. 54(4), s. 412–436. doi: 10.1038/s41588-022-01024-z. Fulltekst i vitenarkiv Vis sammendrag

  Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

• Jansen, Iris E.; Lee, Sven J. van der; Gomez-Fonseca, Duber; Rojas, Itziar de; Dalmasso, Maria Carolina & Grenier-Boley, Benjamin [Vis alle 50 forfattere av denne artikkelen] (2022). Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathologica. ISSN 0001-6322. 144(5), s. 821–842. doi: 10.1007/s00401-022-02454-z. Fulltekst i vitenarkiv Vis sammendrag

  Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

• Sheikh, Mashhood Ahmed; O'Connell, Kevin Sean; Lekva, Tove; Szabo, Attila; Akkouh, Ibrahim Ahmed & Osete, Jordi Requena [Vis alle 31 forfattere av denne artikkelen] (2022). Systemic cell adhesion molecules in severe mental illness: Potential role of intercellular CAM-1 in linking peripheral and neuroinflammation. Biological Psychiatry. ISSN 0006-3223. 93, s. 187–196. doi: 10.1016/j.biopsych.2022.06.029. Fulltekst i vitenarkiv Vis sammendrag

  Background Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. Methods We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). Results Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ. Conclusions Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

• Bahrami, Shahram; Hindley, Guy Frederick Lanyon; Winsvold, Bendik K S; O'Connell, Kevin Sean; Frei, Oleksandr & Shadrin, Alexey [Vis alle 39 forfattere av denne artikkelen] (2022). Dissecting the shared genetic basis of migraine and mental disorders using novel statistical tools. Brain. ISSN 0006-8950. 145(1), s. 142–153. doi: 10.1093/brain/awab267. Fulltekst i vitenarkiv Vis sammendrag

  Migraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.

• Mullins, Niamh; Kang, JooEun; Campos, Adrian I.; Coleman, Jonathan R.I.; Edwards, Alexis C. & Galfalvy, Hanga [Vis alle 52 forfattere av denne artikkelen] (2022). Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors. Biological Psychiatry. ISSN 0006-3223. 91(3), s. 313–327. doi: 10.1016/j.biopsych.2021.05.029. Fulltekst i vitenarkiv Vis sammendrag

  Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

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• Lambert, Jean Charles; Ramirez, Alfredo; Ruiz, Agustín; Andreassen, Ole; Sims, Rebecca & Hiltunen, Mikko [Vis alle 517 forfattere av denne artikkelen] (2026). Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias. Nature Genetics. ISSN 1061-4036. 58, s. 1214–1225. doi: 10.1038/s41588-026-02583-1. Fulltekst i vitenarkiv Vis sammendrag

  To better characterize the genetic architecture underlying Alzheimer’s disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

• Stefansson, Hreinn; Walters, G. Bragi; Sveinbjornsson, Gardar; Tragante, Vinicius; Einarsson, Gudmundur & Helgason, Hannes [Vis alle 67 forfattere av denne artikkelen] (2024). Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease. New England Journal of Medicine. ISSN 0028-4793. 390(23), s. 2217–2219. doi: 10.1056/NEJMc2314334. Fulltekst i vitenarkiv
• Hindley, Guy; Drange, Ole Kristian; Lin, Aihua; Kutrolli, Gleda; Shadrin, Alexey & Parker, Nadine [Vis alle 20 forfattere av denne artikkelen] (2024). Corrigendum to “Cross-trait genome-wide association analysis of C-reactive protein level and psychiatric disorders” [Psychoneuroendocrinology 157 (2023) 106368] (Psychoneuroendocrinology (2023) 157, (S0306453023003463), (10.1016/j.psyneuen.2023.106368)). Psychoneuroendocrinology. ISSN 0306-4530. doi: 10.1016/j.psyneuen.2024.106980. Fulltekst i vitenarkiv
• Rojas, Itziar de; Moreno-Grau, Sonia; Tesi, Niccolo; Grenier-Boley, Benjamin; Andrade, Victor & Jansen, Iris E. [Vis alle 293 forfattere av denne artikkelen] (2023). Erratum: Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores (Nature communications (2021) 12 1 (3417)). Nature Communications. 14(1), s. 716–716. doi: 10.1038/s41467-023-36192-x. Fulltekst i vitenarkiv

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