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The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val(158)Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the Schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene. [ABSTRACT FROM AUTHOR]

Understanding the neurobiological mechanisms involved in psychopathology has been hindered by the limitations of categorical nosologies. The Hierarchical Taxonomy of Psychopathology (HiTOP) is an alternative dimensional system for characterizing psychopathology, derived from quantitative studies of covariation among diagnoses and symptoms. HiTOP provides more promising targets for clinical neuroscience than traditional psychiatric diagnoses and can facilitate cumulative integration of existing research. We systematically reviewed 164 human neuroimaging studies with sample sizes of 194 or greater that have investigated dimensions of psychopathology classified within HiTOP. Replicated results were identified for constructs at five different levels of the hierarchy, including the overarching p-factor, the externalizing superspectrum, the thought disorder and internalizing spectra, the distress subfactor, and the depression symptom dimension. Our review highlights the potential of dimensional clinical neuroscience research and the usefulness of HiTOP while also suggesting limitations of existing work in this relatively young field. We discuss how HiTOP can be integrated synergistically with neuroscience-oriented, transdiagnostic frameworks developed by the National Institutes of Health, including the Research Domain Criteria, Addictions Neuroclinical Assessment, and the National Institute on Drug Abuse's Phenotyping Assessment Battery, and how researchers can use HiTOP to accelerate clinical neuroscience research in humans and other species. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: India currently accounts for a majority of global suicide deaths. Research in European ancestry has established that suicide mortality has a significant genetic component, and suggests that inflammation may play a crucial role in the pathophysiology of suicide. Inflammation is also highly relevant in regions of increased pollution exposure, such as the megacities of India. To address the existing gaps in genetic research on suicide and possible association with inflammatory biomarkers, we examined genetic polymorphism and clinical risk phenotypes in a population-based suicide-death cohort, India., Material and Methods: Genotyping of IL-1β(rs16944) & (rs1143627), IL-4(rs2070874), IL-6(rs1800795) and IL-10(rs1800896) was done in 234 post-mortem suicide-death cases and 256 post-mortem controls ( N  = 490) using PCR RFLP method., Results: Our analyses identified three significant ( p  < 0.001) associations of cytokine variants with suicide death, including IL-1β(rs16944), OR = 0.627; IL-4(rs2070874), OR = 0.524; and IL-6(rs1800795), OR = 2.509. Cases were more likely female and were more likely to have a history of psychiatric illness, though rate of psychiatric illness was low in suicide cases(9%)., Conclusion: Our genetic results are generally consistent with previous research on risk for depression and suicidal behaviour, and both genetic and phenotypic results provide new insights into risk factors that may contribute to suicide in India.

Competing Interests: JG and HRK are named as inventors on PCT patent application #15/878,640, entitled Genotype-guided dosing of opioid agonists, filed Jan 24, 2018 and issued on Jan 26, 2021 as US Patent No. 10 900 082. MB is a paid member of the scientific advisory board for Nucleus Genomics.

Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR) = 1.24, p = 3.88 × 10 -12 ; SZ OR = 1.09, p = 2.44 × 10 -20 ). However, while the effect of mental distress (OR = 1.17, p = 1.02 × 10 -4 ) and risk-taking (OR = 1.52, p = 0.028) on SA was independent of SZ genetic liability, the BD-SA relationship appeared to account for the effect of these risk factors. Similarly, the association with loneliness on SA was null after accounting for the effect of SZ genetic liability. These findings highlight the complex interplay between genetic risk of psychiatric disorders and behavioral traits in the context of SA, suggesting the need for a comprehensive mental health assessment for high-risk individuals., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation., Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394)., Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported., Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations., Competing Interests: Disclosures Ole Andreassen: Consultant to Cortechs.ai and Precision-Health.ai, and received speaker’s honorarium from Lundbeck, Sunovion, Janssen and Otsuka. Murray Stein: MBS has in the past 3 years received consulting income from Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Delix Therapeutics, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, Karuna Therapeutics, Lykos Therapeutics, NeuroTrauma Sciences, Otsuka US, PureTech Health, Sage Therapeutics, Seaport Therapeutics, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He is on the scientific advisory board of the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Philip Harvey: Dr. Harvey consults for a variety of pharmaceutical and device manufacturers on phase 2 and 3 studies of cognition and negative symptoms in SMI. These activities have been reviewed and determined not to be related to the content of this paper. John Mann: Dr. Mann receives royalties for commercial use of the C-SSR S from the Research Foundation of Mental Hygiene and from Columbia University for the Columbia Pathways App. All other listed authors declare no conflicts of interest.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies., Competing Interests: Per Hoffmann receives Salary from the Life & Brain GmbH, Bonn, Germany. James L. Kennedy is a member of the Scientific Advisory Board for Myriad Neuroscience Inc. Ian B. Hickie was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-18). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. Andrew M. Mcintosh has received research support from Eli Lilly, Janssen, and The Sackler Trust. AMM has also received speaker fees from Illumina and Janssen. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He is paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Joel Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082; and is paid for editorial work for the journal “Complex Psychiatry.” Iiris Hovatta received speaker’s honoraria from Lundbeck. Ole A. Andreassen received speaker’s honorarium from Lundbeck and Sunovion, consultant for Cortechs.ai and Precision Health AS. Katharina Domschke has been a member of the Steering Committee Neurosciences, Janssen, Inc. until 2022 and is currently a member of the Board of the German National Society of Psychiatry (DGPPN) and the Neurotorium Editorial Board of the Lundbeck Foundation. Jordan W. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar Tempus Labs. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. Eduard Maron has received research support and has also received speaker fees from Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Indorsia, Neuraxpharm, Servier and Janssen Cilag. Henrik Larsson has served as a speaker for Evolan Pharma, Medici and Shire/Takeda and has received research grants from Shire/Takeda; all outside the submitted work. Gerome Breen is an advisory board member for Compass Pathways. Jürgen Deckert is a member of the board of the German Society of Biological Psychiatry and is on the scientific advisory boards of non-profit organizations and foundations. Volker Arolt worked as an advisor for Sanofi-Adventis Germany. Zach Fuller and Xin Wang are employees of 23andMe and hold stock or stock options in 23andMe. All other authors have no competing interests to declare.

Background: Adolescents with elevated body mass index (BMI) are at an increased risk for depression and body dissatisfaction. Type 2 diabetes (T2D) is an established risk factor for depression. However, shared genetic risk between cardiometabolic conditions and mental health outcomes remains understudied in youth., Methods: The current study examined associations between polygenic risk scores (PRS) for BMI and T2D, and symptoms of depression and body dissatisfaction, in a sample of 827 community adolescents (M age  = 13.63, SD age  = 1.01; 76% girls). BMI, depressive symptoms, and body dissatisfaction were assessed using validated self-report questionnaires., Results: BMI-PRS was associated with phenotypic BMI (β = 0.24, p < 0.001) and body dissatisfaction (β = 0.17, p < 0.001), but not with depressive symptoms. The association between BMI-PRS and body dissatisfaction was significantly mediated by BMI (indirect effect = 0.10, CI [0.07-0.13]). T2D-PRS was not associated with depression or body dissatisfaction., Conclusions: The results suggest phenotypic BMI may largely explain the association between genetic risk for elevated BMI and body dissatisfaction in adolescents. Further research on age-specific genetic effects is needed, as summary statistics from adult discovery samples may have limited utility in youth., Impact: The association between genetic risk for elevated BMI and body dissatisfaction in adolescents may be largely explained by phenotypic BMI, indicating a potential pathway through which genetic predisposition influences body image perception. Furthermore, age-specific genetic research is needed to understand the unique influences on health outcomes during adolescence. By identifying BMI as a potential mediator in the association between genetic risk for elevated BMI and body dissatisfaction, the current findings offer insights that could inform interventions targeting body image concerns and mental health in this population., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Nonfatal suicidality is the most robust predictor of suicide death. However, only ~10% of those who survive an attempt go on to die by suicide. Moreover, ~50% of suicide deaths occur in the absence of prior known attempts, suggesting risks other than nonfatal suicide attempt need to be identified. We studied data from 4,000 population-ascertained suicide deaths and 26,191 population controls to improve understanding of risks leading to suicide death. This study included 2,253 suicide deaths and 3,375 controls with evidence of nonfatal suicidality (SUI&#95;SI/SB and CTL&#95;SI/SB) from diagnostic codes and natural language processing of electronic health records notes. Characteristics of these groups were compared to 1,669 suicides with no prior nonfatal SI/SB (SUI&#95;None) and 22,816 controls with no lifetime suicidality (CTL&#95;None). The SUI&#95;None and CTL&#95;None groups had fewer diagnoses and were older than SUI&#95;SI/SB and CTL&#95;SI/SB. Mental health diagnoses were far less common in both the SUI&#95;None and CTL&#95;None groups; mental health problems were less associated with suicide death than with presence of SI/SB. Physical health diagnoses were conversely more often associated with risk of suicide death than with presence of SI/SB. Pending replication, results indicate highly significant clinical differences among suicide deaths with versus without prior nonfatal SI/SB., Competing Interests: COMPETING INTERESTS All authors of this study declare no competing financial or personal interests relevant to this work.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

This review describes the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychosis-related psychopathology, the psychosis superspectrum. The HiTOP psychosis superspectrum was developed to address shortcomings of traditional diagnoses for psychotic disorders and related conditions including low reliability, arbitrary boundaries between psychopathology and normality, high symptom co-occurrence, and heterogeneity within diagnostic categories. The psychosis superspectrum is a transdiagnostic dimensional model comprising two spectra-psychoticism and detachment-which are in turn broken down into fourteen narrow components, and two auxiliary domains-cognition and functional impairment. The structure of the spectra and their components are shown to parallel the genetic structure of psychosis and related traits. Psychoticism and detachment have distinct patterns of association with urbanicity, migrant and ethnic minority status, childhood adversity, and cannabis use. The superspectrum also provides a useful model for describing the emergence and course of psychosis, as components of the superspectrum are relatively stable over time. Changes in psychoticism predict the onset of psychosis-related psychopathology, whereas changes in detachment and cognition define later course. Implications of the superspectrum for genetic, socio-environmental, and longitudinal research are discussed. A companion review focuses on neurobiology, treatment response, and clinical utility of the superspectrum, and future research directions., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Offspring of depressed mothers have elevated risk of developing depression because they are exposed to greater stress. While generally assumed that youth's increased exposure to stress is due to the environmental effects of living with a depressed parent, youth's genes may influence stress exposure through gene-environment correlations (rGEs). To understand the relationship between risk for depression and stress, we examined the effects of polygenic risk for depression on youth stress exposure., Methods: We examined the relations of a polygenic risk score (PRS) for depression (DEP-PRS), as well as PRSs for 5 other disorders, with youth stress exposure. Data were from a longitudinal study of a community sample of youth and their parents (n = 377) focusing on data collected at youth's aged 12 and 15 assessments., Results: Elevated youth DEP-PRS was robustly associated with increased dependent stress, particularly interpersonal events. Exploratory analyses indicated that findings were driven by major stress and were not moderated by maternal nor paternal history of depression, and of the 5 additional PRSs tested, only elevated genetic liability for bipolar I was associated with increased dependent stress-particularly non-interpersonal events., Limitations: Like other PRS studies, we focused on those of European ancestry thus, generalizability of findings is limited., Conclusion: Polygenic risk contributes to youth experiencing stressful life events which are dependent on their behavior. This rGE appears to be specific to genetic risk for mood disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e-06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide., (© 2023. The Author(s).)

Preventing suicidal thoughts and behaviours (STB) among youth is a global public health priority. STB are known to have a heritable basis, and the development of risk for STB likely arises from complex gene-environment interactions across the life course. Lannoy et al. (Journal of Child Psychology and Psychiatry, 63, 2022 and 1164) describe a study in which polygenic risk for suicide attempt, as well as recent negative life events, were related to recent suicidal ideation in adolescents of about 17 years old. Building on this important work, we highlight several critical areas of focus for research in suicide genetics, including problems of measurement, as well as priorities for better uncovering the specific aetiological pathways to STB., (© 2023 Association for Child and Adolescent Mental Health.)

Background: Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology., Methods: The sample consisted of 4717 unrelated children (mean age = 9.92, s.d. = 0.62; 47.1% female; all European ancestry). Psychopathology was conceptualized hierarchically as empirically derived general factor ( p -factor) and five specific factors: externalizing, internalizing, neurodevelopmental, somatoform, and detachment. Partial correlations explored associations between psychopathology factors and 22 psychopathology-related PRSs. Regressions tested which level of the psychopathology hierarchy was most strongly associated with each PRS., Results: Thirteen PRSs were significantly associated with the general factor, most prominently Chronic Multisite Pain-PRS ( r = 0.098), ADHD-PRS ( r = 0.079), and Depression-PRS ( r = 0.078). After adjusting for the general factor, Depression-PRS, Neuroticism-PRS, PTSD-PRS, Insomnia-PRS, Chronic Back Pain-PRS, and Autism-PRS were not associated with lower order factors. Conversely, several externalizing PRSs, including Adventurousness-PRS and Disinhibition-PRS, remained associated with the externalizing factor (| r | = 0.040-0.058). The ADHD-PRS remained uniquely associated with the neurodevelopmental factor ( r = 062)., Conclusions: PRSs developed to predict vulnerability to emotional difficulties and chronic pain generally captured genetic risk for all forms of childhood psychopathology. PRSs developed to predict vulnerability to externalizing difficulties, e.g. disinhibition, tended to be more specific in predicting behavioral problems. The results may inform translation of existing PRSs to pediatric research and future clinical practice.

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (rG = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; rG = 0.78; p = 1.98e-95) and major depressive disorder (MDD; rG = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Genetic factors contribute to individual differences in the severity of coronavirus disease 2019 (COVID-19). A portion of genetic predisposition can be captured using polygenic risk scores (PRS). Relatively little is known about the associations between PRS and COVID-19 severity or post-acute COVID-19 in community-dwelling individuals., Methods: Participants in this study were 983 World Trade Center responders infected for the first time with SARS-CoV-2 (mean age at infection = 56.06; 93.4% male; 82.7% European ancestry). Seventy-five (7.6%) responders were in the severe COVID-19 category; 306 (31.1%) reported at least one post-acute COVID-19 symptom at 4-week follow-up. Analyses were adjusted for population stratification and demographic covariates., Findings: The asthma PRS was associated with severe COVID-19 category (odds ratio [OR] = 1.61, 95% confidence interval: 1.17-2.21) and more severe COVID-19 symptomatology (β = .09, p = .01), independently of respiratory disease diagnosis. Severe COVID-19 category was also associated with the allergic disease PRS (OR = 1.97, [1.26-3.07]) and the PRS for COVID-19 hospitalization (OR = 1.35, [1.01-1.82]). PRS for coronary artery disease and type II diabetes were not associated with COVID-19 severity., Conclusion: Recently developed polygenic biomarkers for asthma, allergic disease, and COVID-19 hospitalization capture some of the individual differences in severity and clinical course of COVID-19 illness in a community population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Waszczuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The degree to which suicide risk aggregates in US families is unknown. The authors aimed to determine the familial risk of suicide in Utah, and tested whether familial risk varies based on the characteristics of the suicides and their relatives., Methods: A population-based sample of 12 160 suicides from 1904 to 2014 were identified from the Utah Population Database and matched 1:5 to controls based on sex and age using at-risk sampling. All first through third- and fifth-degree relatives of suicide probands and controls were identified ( N = 13 480 122). The familial risk of suicide was estimated based on hazard ratios (HR) from an unsupervised Cox regression model in a unified framework. Moderation by sex of the proband or relative and age of the proband at time of suicide (<25 v. ⩾25 years) was examined., Results: Significantly elevated HRs were observed in first- (HR 3.45; 95% CI 3.12-3.82) through fifth-degree relatives (HR 1.07; 95% CI 1.02-1.12) of suicide probands. Among first-degree relatives of female suicide probands, the HR of suicide was 6.99 (95% CI 3.99-12.25) in mothers, 6.39 in sisters (95% CI 3.78-10.82), and 5.65 (95% CI 3.38-9.44) in daughters. The HR in first-degree relatives of suicide probands under 25 years at death was 4.29 (95% CI 3.49-5.26)., Conclusions: Elevated familial suicide risk in relatives of female and younger suicide probands suggests that there are unique risk groups to which prevention efforts should be directed - namely suicidal young adults and women with a strong family history of suicide.

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown., Objective: To identify novel, replicable genomic risk loci for SITB., Design, Setting, and Participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022., Main Outcome and Measures: SITB., Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry., Conclusions and Relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10 -8 before and p = 4.55 × 10 -8 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 × 10 -8 ), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD., (© 2022. The Author(s).)

Background: There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer's disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown., Objective: In a study of 3,997 WTC responders, polygenic scores for Alzheimer's disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD., Results: Polygenic scores for Alzheimer's disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer's disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors., Conclusion: These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer's disease, as genetic liability for Alzheimer's disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues., (© 2022 Wiley Periodicals LLC.)

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [ 11 C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential (BP ND ) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS both at baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10 -9 ) and 1 (p = 3.69 × 10 -8 ). A strong pan-ancestry signal at the Dopamine Receptor D2 locus (p = 1.77 × 10 -7 ) was also identified and subsequently replicated in a large, independent international civilian cohort (p = 7.97 × 10 -4 ). Additionally, ancestry-specific genome-wide significant loci were also detected in African-Americans, European-Americans, Asian-Americans, and Hispanic-Americans. Pathway analyses suggested over-representation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. These findings confirm that the genetic architecture underlying suicide attempt risk is complex and includes both pan-ancestry and ancestry-specific risk loci. Moreover, pathway analyses suggested many commonly impacted biological pathways that could inform development of improved therapeutics for suicide prevention., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Suicide accounts for >800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with >90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks., (© 2022 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Negative schizotypal traits potentially can be digitally phenotyped using objective vocal analysis. Prior attempts have shown mixed success in this regard, potentially because acoustic analysis has relied on small, constrained feature sets. We employed machine learning to (a) optimize and cross-validate predictive models of self-reported negative schizotypy using a large acoustic feature set, (b) evaluate model performance as a function of sex and speaking task, (c) understand potential mechanisms underlying negative schizotypal traits by evaluating the key acoustic features within these models, and (d) examine model performance in its convergence with clinical symptoms and cognitive functioning. Accuracy was good (> 80%) and was improved by considering speaking task and sex. However, the features identified as most predictive of negative schizotypal traits were generally not considered critical to their conceptual definitions. Implications for validating and implementing digital phenotyping to understand and quantify negative schizotypy are discussed., Competing Interests: Declaration of Conflicting Interests The author(s) declared that there were no conflicts of interest with respect to the authorship or the publication of this article.

Approximately 5% of individuals with schizophrenia die from suicide. However, suicide in psychosis is still poorly characterized, partly due to a lack of adequate population-based clinical or genetic data on suicide death. The Utah Suicide Genetics Research Study (USGRS) provides a large population-based cohort of suicide deaths with medical record and genome-wide data (N = 4380). Examination of this cohort identified medical and genetic risks associated with type of suicide death and investigated the relative contributions of psychotic and affective symptoms to method of suicide. Key differences in method of suicide (common vs. atypical methods) were tested in relation to lifetime psychosis and genome-wide genetic risk for schizophrenia, major depressive disorder, and neuroticism. Consistent with previous studies, psychosis-spectrum disorders were observed to be common in suicide (15% of the cohort). Individuals with psychosis more frequently died from atypical methods, with rates of atypical suicide increasing across the schizophrenia spectrum. Genetic risk for schizophrenia was also associated with atypical suicide, regardless of clinical diagnosis, though this association weakened when filtering individuals with schizophrenia from the analysis. Follow-up examination indicated that high rates of atypical suicide observed in schizophrenia are not likely accounted for by restricted access to firearms. Overall, better accounting for the increased risk of atypical suicide methods in psychosis could lead to improved prevention strategies in a large portion of the suicide risk population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

The Hierarchical Taxonomy of Psychopathology consortium aims to develop a comprehensive self-report measure to assess psychopathology dimensionally. The current research describes the initial conceptualization, development, and item selection for the thought disorder spectrum and related constructs from other spectra. The thought disorder spectrum is defined primarily by the positive and disorganized traits and symptoms of schizophrenia-spectrum disorders. The Thought Disorder Sub-Workgroup identified and defined 16 relevant constructs and wrote 10 to 15 items per each construct. These items were administered, along with detachment and mania items, to undergraduates and people with serious mental illness. Three hundred and sixty-five items across 25 scales were administered. An exploratory factor analysis of the scale scores suggested a two-factor structure corresponding to positive and negative symptoms for two samples. The mania scales loaded with the positive factor, while the detachment scales loaded with the negative factor. Item-level analyses resulted in 19 preliminary scales, including 215 items that cover the range of thought disorder pathology, and will be carried forward for the next phase of data collection/analysis.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication., (© 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Suicide-related behaviors are heterogeneous and transdiagnostic, and may demonstrate varying levels of genetic overlap with different substance use disorders (SUDs). We used linkage disequilibrium score regression, genomic structural equation models, and Mendelian randomization to examine the genetic relationships between several SUDs and suicide-related behaviors. Our analyses incorporated summary statistics from the largest genome-wide association studies (GWAS) of problematic alcohol use, the Fagerström test for nicotine dependence, cannabis use disorder, and opioid use disorder (Ns ranging from 46,213-435,563) and GWAS of ever self-harmed, suicide attempt, and suicide death (Ns ranging from 18,223-117,733). We also accounted for genetic liability to depression (N = 500,199) and risk tolerance (N = 315,894). Suicide-related behaviors were significantly genetically correlated with each other and each SUD, but there was little evidence of causal relationships between the traits. Simultaneously correlating a common SUD factor with each specific suicide indicator while controlling for depression and risk tolerance revealed significant, positive genetic correlations between the SUD factor and suicide-related behaviors (r g  = 0.26-0.45, SE = 0.08-0.09). In the model, depression's association with suicide death (β = 0.42, SE = 0.06) was weaker compared to ever-self harmed and suicide attempt (β = 0.58, SE = 0.05 and β = 0.50, SE = 0.06, respectively). We identify a general level of genetic overlap between SUDs and suicide-related behaviors, which is independent of depression and risk tolerance. Additionally, our findings suggest that genetic and behavioral contributions to suicide death may somewhat differ from nonlethal suicide-related behaviors., (© 2021 Wiley Periodicals LLC.)

Suicidal ideation, suicide attempt (SA) and suicide are significantly heritable phenotypes. However, the extent to which these phenotypes share genetic architecture is unclear. This question is of great relevance to determining key risk factors for suicide, and to alleviate the societal burden of suicidal thoughts and behaviors (STBs). To help address the question of heterogeneity, consortia efforts have recently shifted from a focus on suicide within the context of major psychopathology (e.g. major depressive disorder, schizophrenia) to suicide as an independent entity. Recent molecular studies of suicide risk by members of the Psychiatric Genomics Consortium and the International Suicide Genetics Consortium have identified genome-wide significant loci associated with SA and with suicide death, and have examined these phenotypes within and outside of the context of major psychopathology. This review summarizes important insights from epidemiological and biometrical research on suicide, and discusses key empirical findings from molecular genetic examinations of STBs. Polygenic risk scores for these phenotypes have been observed to be associated with case-control status and other risk phenotypes. In addition, estimated shared genetic covariance with other phenotypes suggests specific medical and psychiatric risks beyond major depressive disorder. Broadly, molecular studies suggest a complexity of suicide etiology that cannot simply be accounted for by depression. Discussion of the state of suicide genetics, a growing field, also includes important ethical and clinical implications of studying the genetic risk of suicide.

Background: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees., Objectives: We aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample., Methods: We used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI., Results: The PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts ( q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes., Conclusions: Our results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Bipolar disorder (BP) suicide death rates are 10-30 times greater than the general population, likely arising from environmental and genetic risk factors. Though suicidal behavior in BP has been investigated, studies have not addressed combined clinical and genetic factors specific to suicide death. To address this gap, a large, harmonized BP cohort was assessed to identify clinical risk factors for suicide death and attempt which then directed testing of underlying polygenic risks. 5901 individuals of European ancestry were assessed: 353 individuals with BP and 2498 without BP who died from suicide (BPS and NBPS, respectively) from a population-derived sample along with a volunteer-derived sample of 799 individuals with BP and a history of suicide attempt (BPSA), 824 individuals with BP and no prior attempts (BPNSA), and 1427 individuals without several common psychiatric illnesses per self-report (C). Clinical and subsequent directed genetic analyses utilized multivariable logistic models accounting for critical covariates and multiple testing. There was overrepresentation of diagnosis of PTSD (OR = 4.9, 95%CI: 3.1-7.6) in BPS versus BPSA, driven by female subjects. PRS assessments showed elevations in BPS including PTSD (OR = 1.3, 95%CI:1.1-1.5, versus C), female-derived ADHD (OR = 1.2, 95%CI:1.1-1.4, versus C), and male insomnia (OR = 1.4, 95%CI: 1.1-1.7, versus BPSA). The results provide support from genetic and clinical standpoints for dysregulated traumatic response particularly increasing risk of suicide death among individuals with BP of Northern European ancestry. Such findings may direct more aggressive treatment and prevention of trauma sequelae within at-risk bipolar individuals.

Purpose: Death from suicide has an estimated heritability of ~50%. Research may soon allow calculation of polygenic risk scores (PRS) for suicide death, which could be marketed directly to consumers. This raises ethical concerns. Understanding how consumers will utilize this information is urgent., Methods: We conducted three focus groups involving suicide attempt survivors ("survivors") and family members of suicide decedents ("family members") to gauge their reactions to this technology. Questions focused on positive and negative implications of PRS results. Qualitative research methods were used to summarize studio results., Results: Eight survivors and 13 family members participated. Both groups postulated benefits of suicide PRS, including prevention and reduced stigma. Their concerns ranged from increased stigma to adverse psychological effects. They suggested that suicide PRS should be accompanied by extensive education and counseling. Participants experienced no adverse effects., Conclusion: Many ethical, legal, and social implications of genetic testing for suicide risk are highly salient to community stakeholders. Our participants hoped that suicide PRS could have significant individual and community-level benefits, but had concerns about effects in several domains, including stigma, access to insurance and employment, and increased anxiety and depression.

Background: Empirical evidence suggests that schizotypy is a useful construct for analyzing and understanding psychotic disorders. However, several issues remain to be resolved., Method: This selective, critical review, addresses some questions and limitations, and discusses future directions of work., Results: First, we present a conceptual outline and discuss the evidence from translational and interdisciplinary studies on schizotypy. Next, we examine and discuss newer analytical and methodological approaches, including network and machine learning approaches. We also discuss newer psychometric identification approaches, such as those using biobehavioral and ambulatory assessment. Next, we review recent cross-cultural studies in schizotypy research. Finally, we identify new challenges and directions and draw conclusions., Conclusions: This selective, critical review suggests that new methods can contribute to the construction of a solid scientific model of schizotypy as a risk construct.