Guy Frederick Lanyon Hindley

• 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
• 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 .

• 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.

• 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.

• Meer, Dennis van der; Hindley, Guy; Shadrin, Alexey; Smeland, Olav Bjerkehagen; Parker, Nadine & Dale, Anders M. [Vis alle 8 forfattere av denne artikkelen] (2025). Mapping the Genetic Landscape of Psychiatric Disorders With the MiXeR Toolset. Biological Psychiatry. ISSN 0006-3223. 98(6), s. 455–465. doi: 10.1016/j.biopsych.2025.02.886. Fulltekst i vitenarkiv Vis sammendrag

  Psychiatric disorders have complex genetic architectures with substantial genetic overlap across conditions, which may partially explain their high levels of comorbidity. This presents significant challenges to research. Genome-wide association studies (GWASs) have uncovered hundreds of loci associated with single disorders, but the genetic landscape of psychiatric disorders has remained largely obscure. Moving beyond the conventional infinitesimal model, uni-, bi-, and trivariate MiXeR tools, applied to GWAS summary statistics, has enabled us to more comprehensively describe the genetic architecture of complex disorders and traits and their overlap. Furthermore, the GSA-MiXeR tool improves biological interpretation of GWAS findings to better elucidate causal mechanisms. Here, we outline the methodology that underlies the MiXeR tools together with instructions for their optimal use. We review results from studies that have investigated the genetic architecture of psychiatric disorders and their overlap using the MiXeR toolset. These studies have revealed generally high polygenicity and low discoverability among psychiatric disorders, particularly in contrast to somatic disorders. There is also pervasive genetic overlap across psychiatric disorders and behavioral traits, while their overlap with somatic traits is smaller, consistent with differences in polygenicity. Finally, GSA-MiXeR has quantified the contribution of gene sets to the heritability of psychiatric disorders, prioritizing small, biologically coherent gene sets. Together, these findings have implications for our understanding of the complex relationships between psychiatric disorders and related traits. MiXeR tools have provided new insights into the genetic architecture of psychiatric disorders, generating a better understanding of their underlying biological mechanisms and potential for clinical utility.

• 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.

• 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.

• Beck, Dani; Lange, Ann-Marie Glasø de; Gurholt, Tiril Pedersen; Voldsbekk, Irene; Maximov, Ivan & Subramaniapillai, Sivaniya [Vis alle 19 forfattere av denne artikkelen] (2024). Dissecting unique and common variance across body and brain health indicators using age prediction. Human Brain Mapping. ISSN 1065-9471. 45(6). doi: 10.1002/hbm.26685. Fulltekst i vitenarkiv Vis sammendrag

  Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6–82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict ‘body age’. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals.

• Andersson, Patrik; Linge, Jennifer; Gurholt, Tiril Pedersen; Sønderby, Ida Elken; Hindley, Guy & Andreassen, Ole A. [Vis alle 7 forfattere av denne artikkelen] (2024). Poor muscle health and cardiometabolic risks associated with antidepressant treatment. Obesity. ISSN 1930-7381. 32(10), s. 1857–1869. doi: 10.1002/oby.24085. Fulltekst i vitenarkiv
• 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.

• 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
• 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.

• 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
• 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.

• 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.

• 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
• 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.

• 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
• 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.

• 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.

• 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
• Motazedi, Ehsan; Cheng, Weiqiu; Thomassen, Jesper Qvist; Frei, Oleksandr; Rongve, Arvid & Athanasiu, Lavinia [Vis alle 30 forfattere av denne artikkelen] (2022). Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations. Journal of Alzheimer's Disease. ISSN 1387-2877. 88(4), s. 1533–1544. doi: 10.3233/JAD-220174. Fulltekst i vitenarkiv Vis sammendrag

  Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

• Hindley, Guy; Frei, Oleksandr; Shadrin, Alexey; Cheng, Weiqiu; O'Connell, Kevin Sean & Icick, Romain [Vis alle 17 forfattere av denne artikkelen] (2022). Charting the Landscape of Genetic Overlap Between Mental Disorders and Related Traits Beyond Genetic Correlation. American Journal of Psychiatry. ISSN 0002-953X. 179(11), s. 833–843. doi: 10.1176/appi.ajp.21101051. Fulltekst i vitenarkiv
• Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Lin, Aihua & Hindley, Guy [Vis alle 17 forfattere av denne artikkelen] (2022). Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings. Neuropsychopharmacology. ISSN 0893-133X. 47, s. 1883–1891. doi: 10.1038/s41386-022-01401-6. Fulltekst i vitenarkiv
• Cheng, Weiqiu; Frei, Oleksandr; Meer, Dennis van der; Wang, Yunpeng; O`Connell, Kevin & Chu, Yunhan [Vis alle 20 forfattere av denne artikkelen] (2021). Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness. JAMA psychiatry. ISSN 2168-6238. 78(9), s. 1020–1030. doi: 10.1001/jamapsychiatry.2021.1435. Fulltekst i vitenarkiv Vis sammendrag

  Importance Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive. Objective To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci. Design, Setting, and Participants Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021. Main Outcomes and Measures The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci. Results Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified. Conclusions and Relevance This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

• Bahrami, Shahram; Shadrin, Alexey A.; Frei, Oleksandr; O`Connell, Kevin; Bettella, Francesco & Krull, Florian [Vis alle 15 forfattere av denne artikkelen] (2021). Genetic loci shared between major depression and intelligence with mixed directions of effect. Nature Human Behaviour. s. 1–9. doi: 10.1038/s41562-020-01031-2. Fulltekst i vitenarkiv
• O'Connell, Kevin Sean; Frei, Oleksandr; Bahrami, Shahram; Smeland, Olav Bjerkehagen; Bettella, Francesco & Cheng, Weiqiu [Vis alle 16 forfattere av denne artikkelen] (2021). Characterizing the Genetic Overlap Between Psychiatric Disorders and Sleep-Related Phenotypes. Biological Psychiatry. ISSN 0006-3223. 90(9), s. 1–11. doi: 10.1016/j.biopsych.2021.07.007. Fulltekst i vitenarkiv Vis sammendrag

  Background: A range of sleep disturbances are commonly experienced by patients with psychiatric disorders, and genome-wide genetic analyses have shown some significant genetic correlations between these traits. Here, we applied novel statistical genetic methodologies to better characterize the potential shared genetic architecture between sleep-related phenotypes and psychiatric disorders. Methods: Using the MiXeR method, which can estimate polygenic overlap beyond genetic correlation, the shared genetic architecture between major psychiatric disorders (bipolar disorder [N = 51,710], depression [N = 480,359], and schizophrenia [N = 77,096]) and sleep-related phenotypes (chronotype [N = 449,734], insomnia [N = 386,533] and sleep duration [N = 446,118]) were quantified on the basis of genetic summary statistics. Furthermore, the conditional/conjunctional false discovery rate framework was used to identify specific shared loci between these phenotypes, for which positional and functional annotation were conducted with FUMA. Results: Extensive genetic overlap between the sleep-related phenotypes and bipolar disorder (63%–77%), depression (76%–79%), and schizophrenia (64%–79%) was identified, with moderate levels of congruence between most investigated traits (47%–58%). Specific shared loci were identified for all bivariate analyses, and a subset of 70 credible genes were mapped to these shared loci. Conclusions: The current results provide evidence for substantial polygenic overlap between psychiatric disorders and sleep-related phenotypes, beyond genetic correlation (|rg| = 0.02 to 0.42). Moderate congruency within the shared genetic components suggests a complex genetic relationship and potential subgroups with higher or lower genetic concordance. This work provides new insights and understanding of the shared genetic etiology of sleep-related phenotypes and psychiatric disorders and highlights new opportunities and avenues for future investigation.

• Gergel, Tania; Das, Preety; Owen, Gareth; Stephenson, Lucy; Rifkin, Larry & Hindley, Guy Frederick Lanyon [Vis alle 8 forfattere av denne artikkelen] (2021). Reasons for endorsing or rejecting self-binding directives in bipolar disorder: a qualitative study of survey responses from UK service users. The Lancet Psychiatry. ISSN 2215-0374. 8(7), s. 599–609. doi: 10.1016/S2215-0366(21)00115-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Self-binding directives instruct clinicians to overrule treatment refusal during future severe episodes of illness. These directives are promoted as having the potential to increase autonomy for individuals with severe episodic mental illness. Although lived experience is central to their creation, the views of service users on self-binding directives have not been investigated substantially. This study aimed to explore whether reasons for endorsement, ambivalence, or rejection given by service users with bipolar disorder can address concerns regarding self-binding directives, decision-making capacity, and human rights. Methods This qualitative study used data from an internet-based survey distributed to the mailing list of the UK charity Bipolar UK, which contained multiple closed and open questions on advance decision making for patients with bipolar disorder. We included participants who reported that they have been diagnosed with bipolar disorder by a professional (doctor or psychiatrist). In a previous study, quantitative analysis of a closed question about self-binding directives had shown endorsement among a high proportion of participants with bipolar disorder who completed the survey. In this study, we did a thematic analysis of responses from those participants who answered a subsequent open question about reasons for their view. Research was done within a multidisciplinary team, including team members with clinical, legal, and ethical expertise, and lived experience of bipolar disorder. Ideas and methods associated with all these areas of expertise were used in the thematic analysis to gain insight into the thoughts of individuals with bipolar disorder about self-binding directives and associated issues. Findings Between Oct 23, 2017, and Dec 5, 2017, 932 individuals with a self-reported clinical diagnosis of bipolar disorder completed the internet survey, with 565 individuals (154 men, 400 women, 11 transgender or other), predominantly white British, providing free-text answers to the open question. 463 (82%) of the 565 participants endorsed self-binding directives, of whom 411 (89%) describing a determinate shift to distorted thinking and decision making when unwell as their key justification. Responses indicating ambivalence (37 [7%) of the 565 responses) were dominated by logistical concerns about the drafting and implementation of self-binding directives, whereas those who rejected self-binding directives (65 [12%] of the 565 responses) cited logistical concerns, validity of their thinking when unwell, and potential contravention of human rights. Interpretation This study is, to our knowledge, the first large study assessing the reasons why mental health service users might endorse or reject the use of self-binding directives. The findings provide empirical support for introducing self-binding directives into mental health services as well as advance decision-making practice and policy, and might help address enduring ethical concerns surrounding possible implementation of the directive while a person retains decision-making capacity. The opinions expressed here in responses given by multiple service users with bipolar disorder challenge a prominent view within international disability rights debates that involuntary treatment and recognition of impaired mental capacity constitute inherent human rights violations.

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• 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
• Gergel, Tania; Das, Preety; Owen, Gareth; Stephenson, Lucy; Rifkin, Larry & Hindley, Guy (2021). Advance directives reduce friction over involuntary treatment – Authors' reply. The Lancet Psychiatry. ISSN 2215-0374. 8(9), s. 750–751. doi: 10.1016/S2215-0366(21)00290-X. Fulltekst i vitenarkiv

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