Piotr Pawel Jaholkowski

• Kopal, Jakub; Bakken, N. R.; Parekh, Pravesh; Shadrin, Alexey; Jaholkowski, Piotr Pawel & Ystaas, L. A. R. [Vis alle 14 forfattere av denne artikkelen] (2026). Early-childhood temperament trajectories map onto transdiagnostic psychiatric risk. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03881-0. 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.

• Hysaj, Elgeta; Jaholkowski, Piotr Pawel; Shadrin, Alexey; Bergstedt, Jacob; Lu, Yi & Bertone-Johnson, Elizabeth [Vis alle 17 forfattere av denne artikkelen] (2026). A Genome-Wide Association Study of Premenstrual Symptoms in Two Nordic Populations. Biological Psychiatry: Global Open Science. 6(5), s. 1–11. doi: 10.1016/j.bpsgos.2026.100784. Fulltekst i vitenarkiv
• Parekh, Pravesh; Parker, Nadine; Pecheva, Diliana; Frei, Evgeniia; Vaudel, Marc & Smith, Diana M. [Vis alle 26 forfattere av denne artikkelen] (2026). FEMA-Long: Modeling unstructured covariances for discovery of time-dependent effects in large-scale longitudinal datasets. PLoS Genetics. ISSN 1553-7390. 22(6). doi: 10.1371/journal.pgen.1012184. Fulltekst i vitenarkiv Vis sammendrag

  While linear mixed-effects (LME) models are common for analyzing longitudinal data, most users rely on random intercepts or simple stationary covariance, due to unavailability of computationally tractable solutions. Here, we extend the Fast and Efficient Mixed-Effects Algorithm (FEMA) and present FEMA-Long, a computationally tractable approach to flexibly modeling longitudinal covariance suitable for high-dimensional data. FEMA-Long can: i) model unstructured covariance, ii) model covariates as smooth functions using splines, iii) discover time-dependent effects of covariates with spline interactions, and iv) use these flexible longitudinal modeling strategies to perform longitudinal genome-wide association studies and discover time-dependent genetic effects, in a computationally scalable manner, suitable for high-dimensional data. Through extensive simulations, we show that estimates from FEMA-Long are accurate, while being up to several thousand times faster and with minimal carbon footprint. To show the utility of FEMA-Long for discovering novel biological signal, using data from the Norwegian Mother, Father and Child Cohort Study (MoBa), we performed a longitudinal genome-wide association study with non-linear SNP-by-time interaction on length, weight, and BMI of 68,273 infants with up to six measurements in the first year of life. We found dynamic patterns of random effects including time-varying heritability and genetic correlations, as well as several genetic variants showing time-dependent effects, highlighting the applicability of FEMA-Long to enable novel discoveries.

• 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
• Tesli, Natalia; Jaholkowski, Piotr Pawel; Rokicki, Jaroslav; Jangmo, Andreas; Ziaka, Laoura & Shadrin, Alexey [Vis alle 9 forfattere av denne artikkelen] (2026). Adolescents at the crossroads: genetic associations between psychotic symptoms and antisocial traits | European Child & Adolescent Psychiatry | Springer Nature Link. European Child and Adolescent Psychiatry. ISSN 1018-8827. doi: 10.1007/s00787-026-03153-w. Fulltekst i vitenarkiv Vis sammendrag

  Antisocial behaviour in youth has serious consequences at individual and societal level. Adolescence is also a critical period for the emergence of prodromal psychosis symptoms. Their co-occurrence may aggravate aggression and lead to severe adverse outcomes. Common genetic risk for psychosis, antisocial behaviour, and substance use has been suggested, but the putatively shared genetic architecture is unknown, and evidence in youth is limited. Here we examined whether common genetic liability indexed by polygenic risk scores (PRSs) relates to these complex traits in the Norwegian Mother, Father and Child Cohort Study (MoBa; n = 18960). Antisocial psychopathology was operationalised as three complementary dimensions: conduct-disorder (CD) traits, oppositional-defiant disorder (ODD) traits, and psychopathy traits. We first quantified phenotypic correlations between psychotic-like experiences (PLEs) and the antisocial dimensions. We then evaluated PRS-phenotype associations (single-PRS and joint multivariable models) using PRSs for antisocial behaviour (PRSASB) and schizophrenia (PRSSCZ), in addition to PRS for alcohol use disorder (PRSAUD). We found phenotypic correlations between antisocial traits and PLEs (rs=0.13–0.34, p < 0.0001). This overlap was reflected at the genetic level, as we found associations between PRSASB and PLEs (p = 0.0004). The associations between PRSSCZ and antisocial traits were present for CD (p = 0.005) and ODD (p = 0.003) traits. Both PLEs and antisocial traits were associated with PRSAUD. Patterns persisted in mutually adjusted models. These findings indicate cross-trait associations between polygenic liability for SCZ, ASB, AUD and adolescent PLEs and antisocial dimensions in the general youth population, consistent with partially shared common genetic influences. Future studies should further delineate underlying biological mechanisms.

• 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
• 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.

• Parker, Nadine; Koch, Elise; Shadrin, Alexey; Fuhrer, Julian; Hindley, Guy F. L. & Stinson, Sara Elizabeth [Vis alle 15 forfattere av denne artikkelen] (2026). Leveraging the genetics of psychiatric disorders to prioritize potential drug targets and compounds. Neuropsychopharmacology. ISSN 0893-133X. doi: 10.1038/s41386-026-02380-8. Fulltekst i vitenarkiv
• 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.

• Rokicki, Jaroslav; Campbell, Megan L.; Meer, Dennis van der; Sartorius, Alina Marie; Tesli, Natalia & Jaholkowski, Piotr Pawel [Vis alle 11 forfattere av denne artikkelen] (2025). Brain-based gene expression and corresponding behavioural relevance of risk genes for broad antisocial behaviour. NeuroImage. ISSN 1053-8119. 311. doi: 10.1016/j.neuroimage.2025.121198. Fulltekst i vitenarkiv
• Lu, Zheng An; Ploner, Alexander; Jaholkowski, Piotr Pawel; Shadrin, Alexey; Brew, Bronwyn K. & Andreassen, Ole [Vis alle 7 forfattere av denne artikkelen] (2025). Genetic overlap of severe psychiatric disorders with lung function and asthma suggests shared biological mechanisms. Brain, Behavior, and Immunity. ISSN 0889-1591. 129, s. 305–317. doi: 10.1016/j.bbi.2025.06.003. Fulltekst i vitenarkiv Vis sammendrag

  Background Severe psychiatric disorders are frequently comorbid with lung function decline and asthma. Despite their considerable heritability, the genetic relationships between them are unclear. Methods We investigated the shared genetic architecture for three severe psychiatric disorders (schizophrenia, bipolar disorder, and anorexia nervosa) with lung function and asthma using results from genome-wide association studies. We performed MiXeR analyses to quantify their genetic overlap. A conditional/conjunctional false discovery rate (cond/conjFDR) approach was employed to detect shared genomic loci. Gene-based enrichment analyses were adopted to explore the shared biological mechanisms. Transcriptome analysis results were incorporated to prioritize biologically plausible shared genes in relevant tissues. Findings MiXeR analyses demonstrated consistent moderate polygenic overlap (∼400 to 800 shared variants) across all pairs of psychiatric and respiratory phenotypes. The cond/conjFDR analyses found that lung function shared 227 loci with SCZ, 83 loci with BIP and 13 loci with AN, whereas asthma shared 132 loci with SCZ, 25 loci with BIP and 2 loci with AN, among which there were 268 novel loci for psychiatric disorders and 244 novel loci for the respiratory phenotypes. Gene-based enrichment analyses demonstrated that genes shared with psychiatric disorders for lung function were enriched for less specific non-immune GO terms (i.e. muscle organ development, mitochondrial matrix and cellular response to ion zinc), whereas genes shared with asthma were mostly enriched for GO term categories involving immune mechanisms (i.e. lymphocyte activation, immune response, metabolism, protein metabolism and regulation of JAK-STAT cascade), indicating divergent shared etiology. A total of 55 shared genes were prioritized as biologically plausible in tissues including brain, lung, whole blood and adrenal gland. Interpretation This study elucidates a complex shared genetic architecture for three severe psychiatric disorders with lung function and asthma and implicates overlapping immune and non-immune mechanisms. Our findings present novel evidence and putative mechanisms for a lung-brain axis underlying psychiatric disorders and lung diseases, which may inspire the development of novel treatments.

• Frei, Evgeniia; Filiz, Tahir Tekin; Frei, Oleksandr; Loughnan, Robert; Jaholkowski, Piotr Pawel & Parker, Nadine [Vis alle 12 forfattere av denne artikkelen] (2025). Genome-wide analysis of screen behaviors among adolescents identifies novel loci and overlap with educational attainment and mental disorders. Scientific Reports. 15(1). doi: 10.1038/s41598-025-17450-y. Fulltekst i vitenarkiv
• Frei, Evgeniia; Frei, Oleksandr; Jaholkowski, Piotr Pawel; Parker, Nadine; Parekh, Pravesh & Shadrin, Alexey [Vis alle 12 forfattere av denne artikkelen] (2025). The phenotypic and genetic relationship between adolescent mental health and time spent on social media, gaming, and TV. Psychiatry Research. ISSN 0165-1781. 353. doi: 10.1016/j.psychres.2025.116761. Fulltekst i vitenarkiv
• 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 .

• Haftorn, Kristine Løkås; Rudsari, Hamid Khoshfekr; Jaholkowski, Piotr Pawel; Dåstøl, Vilde Øverlien; Hestetun, Sigrid Valen & Andreassen, Ole [Vis alle 8 forfattere av denne artikkelen] (2025). Nonlinearity and sex differences in the performance of a polygenic risk score for juvenile idiopathic arthritis. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1531390. Fulltekst i vitenarkiv Vis sammendrag

  Background: Juvenile idiopathic arthritis (JIA) is an immune-mediated pediatric disease believed to result from a complex interplay of genetic and environmental factors. Genome-wide association studies have enabled calculation of polygenic risk scores (PRS) for JIA. Understanding how the PRS associates with JIA and whether it performs similarly across sexes is essential for its utility in future studies. Methods: We studied the relationship between a PRS developed from a previously published genome-wide association study of JIA and JIA in children from the Norwegian Mother, Father and Child Cohort Study (MoBa; total n = 57,630; JIA cases = 238). Generalized linear models (GLM) and generalized additive models (GAM) were used in logistic regression to assess the association. Furthermore, we investigated whether the relationship between PRS and JIA differed by sex by applying GAM models with interaction terms. Results: PRS was significantly associated with JIA using both GLM (p< 2e-16) and GAM (p< 2e-16) models, and our results indicated a nonlinear relationship between PRS and JIA (effective degrees of freedom, EDF = 1.96). We found a significant interaction between sex and JIA PRS in relation to JIA (p = 0.017), and indications of a stronger and more logit-nonlinear relationship in females (EDF = 1.82) versus males (EDF = 1.06). Conclusion: The relationship between PRS and JIA was slightly logit-nonlinear for females and logit-linear for males. The PRS for JIA can likely be used either as a continuous or discrete variable in analyses, but sex-stratification is recommended for future studies.

• Bauer, Anna E.; Jaholkowski, Piotr Pawel; Lu, Yi; Guintivano, Jerry; Hannigan, Laurie John & Corfield, Elizabeth Claire [Vis alle 14 forfattere av denne artikkelen] (2025). Identification and validation of postpartum depression subtypes: a population-based cohort study. EClinicalMedicine. 89, s. 103540–103540. doi: 10.1016/j.eclinm.2025.103540. Fulltekst i vitenarkiv Vis sammendrag

  Background Postpartum depression (PPD) affects 18% of postpartum women globally. PPD is a heterogeneous condition with diverse presentations, which may differ in underlying etiology, potential outcomes, and optimal treatment. This study aimed to identify and validate PPD subtypes using comprehensive phenotypic and genetic data from a large, nationwide cohort. Methods In this population-based cohort study, we used data from the Norwegian Mother, Father, and Child Cohort Study and Medical Birth Registry of Norway (MoBa), and applied unsupervised clustering (Uniform Manifold Approximation and Projection [UMAP] + Density-Based Spatial Clustering of Applications with Noise [DBSCAN]) to identify PPD subtypes among 7859 women with PPD (training set n = 5239). All pregnant women in Norway were eligible to enroll in MoBa between Jun 1, 1999 and Dec 31, 2008. Among women with their first recorded pregnancies in MoBa, they were considered to have clinically significant PPD if they scored ≥8 on the 6-item version of the Edinburgh Postnatal Depression Scale (EPDS) (equivalent to ≥11 on the full EPDS) administered at six months after birth. Input variables included psychiatric symptom severity, psychiatric history, trauma history, pain, and substance use. We then characterized clusters and tested associations with perinatal-relevant auxiliary variables and polygenic scores (PGS) for eight psychiatric and neurodevelopmental conditions. Findings were validated in a reserved test set (n = 2620). Findings Nine clusters were identified in the training set (n = 5239), with seven replicating in the independent test set (n = 2620). Clusters were differentiated by symptom severity, onset timing, trauma history, and pain during pregnancy. In the training set, the cluster with the most severe symptoms was characterized by depression + trauma and comprised 28% [1483/5239] of training sample. This cluster showed marked socioeconomic adversity and elevated genetic risk for psychiatric conditions compared to other clusters (ADHD PGS OR 1.19, 95% CI 1.12–1.28; major depression PGS OR 1.15, 95% CI 1.07–1.23; PTSD PGS OR 1.09, 95% CI 1.02–1.17). In the test set, this cluster also comprised 28% [729/2620] and showed consistent associations with ADHD (OR 1.23, 95% CI 1.12–1.35), major depression (OR 1.09, 95% CI 0.99–1.20), and PTSD (OR 1.17, 95% CI 1.06–1.29). Conversely, the mild PPD cluster (10% [498/5239] of training sample) showed a protective profile (ADHD PGS OR 0.81, 95% CI 0.73–0.90; major depression PGS OR 0.85, 95% CI 0.77–0.94). In the test set, it represented 10% (263/2620), with consistent protective associations for ADHD (OR 0.84, 95% CI 0.72–0.96) and major depression (OR 0.77, 95% CI 0.67–0.89). Two early-onset clusters demonstrated distinct profiles despite similar symptom severity. The cluster characterized as early-onset PPD + pain (6% of training set [310/5239] and 7% of test set [178/2620]) had the highest prevalence of somatic conditions, including migraines (19% [58/310] training; 15% [26/178] test), nausea (47% [144/310] training; 53% [94/178] test), prenatal hospitalization (41% [128/310] training; 35% [62/178] test), and birth by caesarean section (10% [31/310] training; 8% [14/178] test), whereas the cluster characterized as early-onset PPD + anger (6% [307/5239] of training sample; 6% [158/2620] of test sample) showed many fewer physical health burdens. The clusters in the training and testing set had moderate to high concordance (ARI = 0.76 [95% CI 0.74, 0.77], FMI = 0.79 [95% CI 0.77, 0.81]).

• Bergstedt, Jacob; Kõiv, Kadri; Jangmo, Andreas; Haram, Marit; Jaholkowski, Piotr Pawel & Treur, Jorien L. [Vis alle 21 forfattere av denne artikkelen] (2025). Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases. medRxiv. doi: 10.1101/2025.03.11.25323757. Fulltekst i vitenarkiv Vis sammendrag

  Abstract IMPORTANCE Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN, SETTING, AND PARTICIPANTS Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking. Key Points Question Is genetic liability to specific psychiatric disorders associated with an increased risk of clinically diagnosed cardiometabolic diseases even after adjusting for cross-disorder psychiatric pleiotropy, body mass index, and smoking status? Findings In this study of cohorts in Sweden, Estonia, and Norway, genetic liability to major depressive disorder (MDD) showed stronger associations with cardiometabolic disease (CMD) compared to other psychiatric disorders. Genetic liability to anxiety disorder and PTSD showed associations with CMD that were attenuated when adjusting for cross-disorder psychiatric pleiotropy. Genetic liability to ADHD showed strong associations with obesity and type 2 diabetes that were strongly attenuated when adjusting for body mass index, and smoking status. Genetic liability to schizophrenia showed inverse associations with CMD. Meaning These findings suggest that MDD has a distinctive genetic relationship with CMD compared to other psychiatric disorders and that the well-established phenotypic association between schizophrenia and CMD is not related to genetic factors.

• 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.

• Haram, Marit; Jangmo, Andreas; Jaholkowski, Piotr Pawel; Pasman, Joëlle; Meijsen, Joeri & Shorter, John R. [Vis alle 15 forfattere av denne artikkelen] (2025). Associations of polygenic risk scores for major depression and depression severity: an investigation of 105 623 individuals with 16 years follow-up. Molecular Psychiatry. ISSN 1359-4184. s. 1–8. doi: 10.1038/s41380-025-03243-2. Fulltekst i vitenarkiv Vis sammendrag

  Genetic risk could be informative for identifying individuals at risk of depression with severe outcomes. With the novel approach of combined health care registries and self-report measures related to depression, the authors aimed to identify the impact of polygenic risk scores (PRS) for major depression on self report measures and a diagnosis of depression across diagnostic thresholds. The study sample comprised participants from the Norwegian Mother, Father and Child Cohort Study with linked information of depression diagnoses during 2006–2022 from health registries. Linear and logistic models were used to estimate the associations between PRS for major depression and self-reported measures related to depression (Symptom Checklist- 5, Satisfaction With Life Scale, Rosenberg Self-Esteem Scale), and a diagnosis of depression. Analyses were performed in groups stratified by level of depression severity defined by registrations in primary and specialist health care. Among the 105 623 individuals included in the study, mean (SD) age was 33.9 (5.3) and 58.5% were female. The associations between PRS for major depression and Rosenberg Self-Esteem Scale were more prominent in individuals with a history of inpatient status compared to outpatient status (β = 0.095, cluster robust 95% CI 0.029–0.162; P  = 0.005) and status of primary care (β = 0.098, cluster robust 95% CI 0.035–0.160; P  = 0.002). PRS for major depression were associated with a diagnosis of depression in all groups of depression severity, with highest effect sizes for more severe types (history of inpatient status: OR = 1.85, cluster robust 95% CI 1.75–1.94; P  < 0.01). The results provide new knowledge of how PRS for major depression vary with depression severity.

• Al-Soufi, Laila; Hindley, Guy; Rødevand, Linn; Shadrin, Alexey; Jaholkowski, Piotr Pawel & Fominykh, Vera [Vis alle 10 forfattere av denne artikkelen] (2025). Polygenic overlap of substance use behaviors and disorders with externalizing and internalizing problems independent of genetic correlations. Psychological Medicine. ISSN 0033-2917. 55. doi: 10.1017/S0033291725000108. Fulltekst i vitenarkiv Vis sammendrag

  Background: Externalizing and internalizing pathways may lead to the development of substance use behaviors (SUBs) and substance use disorders (SUDs), which are all heritable phenotypes. Genetic correlation studies have indicated differences in the genetic susceptibility between SUBs and SUDs. We investigated whether these substance use phenotypes are differently related to externalizing and internalizing problems at a genetic level. Methods: We analyzed data from genome-wide association studies (GWAS) of four SUBs and SUDs, five externalizing traits, and five internalizing traits using the bivariate causal mixture model (MiXeR) to estimate genetic overlap beyond genetic correlation. Results: Two distinct patterns were found. SUBs demonstrated high genetic overlap but low genetic correlation of shared variants with internalizing traits, suggesting a pattern of mixed effect directions of shared genetic variants. Conversely, SUDs and externalizing traits exhibited considerable genetic overlap with moderate to high positive genetic correlation of shared variants, suggesting concordant effect direction of shared risk variants. Conclusions: These results highlight the importance of the externalizing pathway in SUDs as well as the limited role of the internalizing pathway in SUBs. As MiXeR is not intended for the identification of specific genes, further studies are needed to reveal the underlying shared mechanisms of these traits.

• 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.

• Birkenæs, Viktoria; Parekh, Pravesh; Hegemann, Laura Elizabeth; Bakken, Nora Refsum; Frei, Evgeniia & Jaholkowski, Piotr Pawel [Vis alle 13 forfattere av denne artikkelen] (2025). Youth psychotic experiences: psychometric evaluation and diagnostic associations of the CAPE-16 in adolescents from the Norwegian Mother, Mather and Child Cohort. Journal of Child Psychology and Psychiatry. ISSN 0021-9630. 67(1), s. 27–40. doi: 10.1111/jcpp.70007. Fulltekst i vitenarkiv Vis sammendrag

  Background: Adolescent self-reported psychotic experiences are associated with mental illness and could help guide prevention strategies. Youth report substantially more experiences than adults. However, with large societal changes like the digital revolution and COVID-19 pandemic, existing questionnaires may no longer accurately capture youth experiences. We aimed to determine the ability of the CAPE-16 questionnaire in capturing psychotic experiences across contexts (biological sex and COVID-19 response) and generations, thereby validating important psychometric aspects of the tool in modern adolescents. Methods: We used data from the Norwegian Mother, Father and Child Study (MoBa), a population-based pregnancy cohort. Adolescents responded to the CAPE-16 questionnaire (n = 18,835). For a comparison between age groups, we included adult men from the parent generation who responded to the CAPE-9 (n = 28,793). We investigated the psychometric properties of CAPE-16 through confirmatory factor analyses, measurement invariance testing across biological sex, response before/during the COVID-19 pandemic, and generations (adolescents and fathers), and examined subscale and item-level associations with subsequent registry-based psychiatric diagnoses (average time between CAPE and last registry update: 3.68 ± 1.34 years). Results: Out of 18,835 adolescents, 33.2% reported lifetime psychotic experiences. We confirmed a three-factor structure (paranoia, bizarre thoughts, and hallucinations) and good subscale reliability (ω = .86 and .90). CAPE-16 scores were stable across biological sex and pandemic status. CAPE-9 response patterns were non-invariant across adolescents and adult men, with an item related to digital technology particularly prone to bias. CAPE-16 subscales were associated with subsequent psychiatric diagnoses, especially psychotic disorders. Conclusions: CAPE-16 is a reliable measure of psychotic experiences across sex and a major societal stressor in adolescents. More frequent and distressing experiences increase the risk of subsequent psychiatric diagnoses. Different response patterns between adults and adolescents for items related to digital technology suggest differences in interpretation. Hence, certain items may benefit from revisions.

• Dåstøl, Vilde Øverlien; Haftorn, Kristine Løkås; Rudsari, Hamid Khoshfekr; Jaholkowski, Piotr Pawel; Størdal, Ketil & Håberg, Siri Eldevik [Vis alle 12 forfattere av denne artikkelen] (2025). Maternal seafood intake, dietary contaminant exposure, and risk of juvenile idiopathic arthritis: exploring gene-environment interactions. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1523990. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: Juvenile idiopathic arthritis (JIA) originates from a complex interplay between genetic and environmental factors. We investigated the association between seafood intake and dietary contaminant exposure during pregnancy and JIA risk, to identify sex differences and gene-environment interactions. Methods: We used the Norwegian Mother, Father, and Child Cohort Study (MoBa), a population-based prospective pregnancy cohort (1999–2008). JIA patients were identified through the Norwegian Patient Registry, with remaining mother-child pairs serving as controls. We assessed maternal seafood intake and dietary contaminants typically found in seafood using a food frequency questionnaire completed during pregnancy, mainly comparing high (≥90th percentile, P90) vs low (<P90) intake. Multivariable logistic regression calculated adjusted odds ratios (aOR), including sex-stratification analyses. A polygenic risk score (PRS) for JIA was used in a subsample to assess gene-environment interactions. Results: We identified 217 JIA patients and 71,884 controls. High vs low maternal intake of lean/semi-oily fish was associated with JIA (aOR 1.51, 95% CI 1.02-2.22), especially among boys (aOR 2.13, 95% CI 1.21-3.75). A significant gene-environment interaction was observed between total fish intake and PRS, with high fish intake associated with JIA primarily in those with low PRS (p<0.03). We found no associations between high vs low exposure to other types of seafood or environmental contaminants and JIA. Conclusions: We found a modestly increased risk of JIA associated with high intake of lean/semi-oily fish during pregnancy, not explained by estimated exposure to dietary contaminants. Our data suggest a more pronounced association in children with a lower genetic predisposition for JIA.

• 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.

• Hestetun, Sigrid Valen; Rudsari, Hamid Khoshfekr; Jaholkowski, Piotr Pawel; Shadrin, Alexey; Haftorn, Kristine Løkås & Andersen, Svend [Vis alle 13 forfattere av denne artikkelen] (2024). Incidence and Genetic Risk of Juvenile Idiopathic Arthritis in Norway by Latitude. Arthritis & Rheumatology. ISSN 2326-5191. 77(4), s. 458–467. doi: 10.1002/art.43040. Fulltekst i vitenarkiv Vis sammendrag

  Objective: We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographic regions of Norway and whether potential regional incidence differences are explained by environmental or genetic factors across regions. Methods: We conducted a register-based cohort study including all Norwegian children born from 2004 to 2019, with follow-up throughout 2020. The JIA diagnosis, defined by at least two International Classification of Diseases, Tenth Revision codes for JIA, was validated against medical records. The incidence rate (IR) and hazard ratio (HR) for JIA were estimated for all Norway and for the North, Mid, and South regions. In a subsample from the Norwegian Mother, Father, and Child Cohort Study (MoBa), the genetic risk for JIA was assessed in the three regions. Results: After median 9.1 (range 0.3-16.0) years of follow-up, we identified 1,184 patients with JIA and 910,058 controls. The IR for JIA/100,000 person-years was 14.4 in all of Norway, 25.9 in the North region, 17.9 in the Mid region, and 12.5 in the South region. The HR (95% confidence interval [CI]) of JIA in the North region was 2.07 (1.77-2.43) and in the Mid region HR 1.43 (95% CI 1.23-1.67) compared with the South region. Adjustments for perinatal factors, socioeconomic status, and early antibiotic exposure did not change our estimates substantially. In MoBa (238 patients with JIA, 57,392 controls), the association between JIA and region of birth was no longer significant when adjusting for genetic factors. Conclusion: We found a higher incidence of JIA with increasing latitude without evidence for available environmental factors explaining the observed gradient. In contrast, genetic factors modified the association, but further studies are warranted.

• 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.

• 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.

• 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
• Bączyńska, E.; Zaręba-Kozioł, M.; Ruszczycki, B.; Krzystyniak, A.; Wójtowicz, T. & Bijata, K. [Vis alle 26 forfattere av denne artikkelen] (2024). Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. Neurobiology of Stress. 33. doi: 10.1016/j.ynstr.2024.100683. Fulltekst i vitenarkiv Vis sammendrag

  Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subregion of the hippocampus.

• Bakken, Nora Refsum; Parker, Nadine; Hannigan, Laurie John; Hagen, Espen; Parekh, Pravesh & Shadrin, Alexey [Vis alle 15 forfattere av denne artikkelen] (2024). Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders. Journal of Child Psychology and Psychiatry. ISSN 0021-9630. 66(3), s. 350–365. doi: 10.1111/jcpp.14063. Fulltekst i vitenarkiv Vis sammendrag

  Background Symptoms related to mood and anxiety disorders (emotional disorders) often present in childhood and adolescence. Some of the genetic liability for mental disorders, and emotional and behavioral difficulties seems to be shared. Yet, it is unclear how genetic liability for emotional disorders and related traits influence trajectories of childhood behavioral and emotional difficulties, and if specific developmental patterns are associated with higher genetic liability for these disorders. Methods This study uses data from a genotyped sample of children (n = 54,839) from the Norwegian Mother, Father, and Child Cohort Study (MoBa). We use latent growth models (1.5–5 years) and latent profile analyses (1.5–8 years) to quantify childhood trajectories and profiles of emotional and behavioral difficulties and diagnoses. We examine associations between these trajectories and profiles with polygenic scores for bipolar disorder (PGSBD), anxiety (PGSANX), depression (PGSDEP), and neuroticism (PGSNEUR). Results Associations between PGSDEP, PGSANX, and PGSNEUR, and emotional and behavioral difficulties in childhood were more persistent than age-specific across early childhood (1.5–5 years). Higher PGSANX and PGSDEP were associated with steeper increases in behavioral difficulties across early childhood. Latent profile analyses identified five profiles with different associations with emotional disorder diagnosis. All PGS were associated with the probability of classification into profiles characterized by some form of difficulties (vs. a normative reference profile), but only PGSBD was uniquely associated with a single developmental profile. Conclusions Genetic risk for mood disorders and related traits contribute to both a higher baseline level of, and a more rapid increase in, emotional and behavioral difficulties across early and middle childhood, with some indications for disorder-specific profiles. Our findings may inform research on developmental pathways to emotional disorders and the improvement of initiatives for early identification and targeted intervention.

• 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
• Hiller, John Kim; Jangmo, Andreas; Tesli, Martin Steen; Jaholkowski, Piotr Pawel; Hoseth, Eva Zsuzsanna & Steen, Nils Eiel [Vis alle 7 forfattere av denne artikkelen] (2023). Lipid Biomarker Research in Bipolar Disorder: A Scoping Review of Trends, Challenges, and Future Directions. Biological Psychiatry: Global Open Science. 3(4), s. 594–604. doi: 10.1016/j.bpsgos.2023.07.004. Fulltekst i vitenarkiv Vis sammendrag

  Bipolar disorder (BD) is a disabling disorder with heterogeneous symptom profiles and trajectories. Like many other neuropsychiatric disorders, clinical decision making related to diagnoses and choice of treatment is based on clinical assessments alone, and risk prediction for treatment success or resistance at an individual level remains sparse. An enormous effort to add biological markers to this risk prediction is ongoing. The role of lipids in normal brain functioning is well established, and several hypotheses about the role of lipids in the pathogenesis of neuropsychiatric disorders, including BD, have been made. The frequent comorbidity between neuropsychiatric disorders and cardiovascular disease, the genetic overlap of risk genes for severe mental disorders and genes involved in lipid regulation, and the lipid-altering effects of antipsychotics and mood stabilizers indicate that lipids could hold promise as biomarkers for neuropsychiatric disorders, including BD. To date, reviews of lipid biomarkers in schizophrenia and major depression have noted caveats for future investigations, while reviews of lipid biomarker research in BD is missing. In the current scoping review, we present a comprehensive overview of trends in previous research on lipid biomarkers in BD. The current literature varies greatly in the phenotypes investigated and study designs, leading to divergent findings. Small sample size; potential confounders related to physical activity, nutritional status, and medication use; and cross-sectional designs were frequently reported limitations. Future research may benefit from pivoting toward utilization of newer laboratory techniques such as lipidomics, but consistent use of study methods across cohorts is also needed.

• 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.

• 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.

• Birkenæs, Viktoria; Bakken, Nora Refsum; Frei, Evgeniia; Jaholkowski, Piotr Pawel; Smeland, Olav Bjerkehagen & Woldeyohannes, Markos Tesfaye [Vis alle 15 forfattere av denne artikkelen] (2023). Psychometric Properties and Diagnostic Associations of the Short-Form Community Assessment of Psychic Experiences in a Population-Based Sample of 29 021 Adult Men. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), s. 1229–1238. doi: 10.1093/schbul/sbad074. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background and Hypothesis Around 5%–7% of the adult population are estimated to have lifetime psychotic experiences (PEs), which are associated with psychosis risk. PEs assessed with Community Assessment of Psychic Experiences (CAPE) are associated with psychosis but also non-psychotic disorders, which could be partly explained by CAPE indirectly capturing emotional symptoms. We investigated the psychometric properties of a shorter version, CAPE-9, and whether CAPE-9 scores are associated with lifetime psychotic or non-psychotic mental disorders after controlling for current anxiety and depressive symptoms. Design CAPE-9 questionnaire data were obtained from 29 021 men (42.4 ± 5.6 yrs.) from the Norwegian Mother, Father, and Child Cohort Study. We investigated CAPE-9 reliability and factor structure. Logistic regression was used to test effects of current anxiety and depressive symptoms (SCL-12) on associations between CAPE-9 scores and psychiatric diagnoses. Results CAPE-9 fit a previously reported 3-factor structure and showed good reliability. Twenty-six percent reported at least one lifetime PE. CAPE-9 scores were significantly associated with most psychiatric disorders (schizophrenia, depression, bipolar disorder, substance abuse, anxiety, trauma-related disorders, and ADHD). After controlling for concurrent emotional symptoms, only associations with schizophrenia (OR = 1.29; 95% CI = 1.18–1.38) and trauma-related disorders (OR = 1.09; CI = 1.02–1.15) remained significant. Conclusions CAPE-9 showed good psychometric properties in this large population-based adult male sample, and PEs were more clearly associated with psychotic disorders after controlling for current emotional symptoms. These results support the use of the short CAPE-9 as a cost-effective tool for informing public health initiatives and advancing our understanding of the dimensionality of psychosis.

• Tesli, Natalia; Jaholkowski, Piotr Pawel; Jaholkowski, Piotr Pawel; Haukvik, Unn Kristin Hansen; Jangmo, Andreas & Haram, Marit [Vis alle 16 forfattere av denne artikkelen] (2023). Conduct disorder - a comprehensive exploration of comorbidity patterns, genetic and environmental risk factors. Psychiatry Research. ISSN 0165-1781. 331, s. 1–10. doi: 10.1016/j.psychres.2023.115628. Fulltekst i vitenarkiv
• Bakken, Nora R.; Parker, Nadine; Hannigan, Laurie J.; Hagen, Espen; Parekh, Pravesh & Shadrin, Alexey [Vis alle 15 forfattere av denne artikkelen] (2023). Childhood trajectories of emotional and behavioral difficulties are related to polygenic liability for mood and anxiety disorders. medRxiv. doi: 10.1101/2023.11.21.23298804. Fulltekst i vitenarkiv

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• Birkenæs, Viktoria; Shadrin, Alexey; Frei, Evgeniia; Parekh, Pravesh; Jaholkowski, Piotr Pawel & Smeland, Olav Bjerkehagen [Vis alle 9 forfattere av denne artikkelen] (2023). Genome-Wide Analysis of Self-Reported Psychotic Experiences in the Norwegian Mother, Father, and Child study. Fulltekst i vitenarkiv

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