Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program

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.

[1]  Philip D. Harvey,et al.  A Genome-Wide Association Study of Suicide Attempts in the Million Veterans Program Identifies Evidence of Pan-Ancestry and Ancestry-Specific Risk Loci , 2022, Molecular Psychiatry.

[2]  Hunna J. Watson,et al.  Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors , 2020, medRxiv.

[3]  B. Harlow,et al.  The influence of diagnosed mental health conditions and symptoms of depression and/or anxiety on suicide ideation, plan, and attempt among college students: findings from the Healthy Minds Study, 2018-2019. , 2021, Journal of affective disorders.

[4]  R. Kessler,et al.  Predictors of Suicide Attempt Within 30 Days After First Medically Documented Suicidal Ideation in U.S. Army Soldiers. , 2021, The American journal of psychiatry.

[5]  Philip D. Harvey,et al.  Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression , 2021, Molecular Psychiatry.

[6]  Rongxin Geng,et al.  BCL7A as a novel prognostic biomarker for glioma patients , 2021, Journal of Translational Medicine.

[7]  S. Curtin,et al.  Suicide Mortality in the United States, 1999-2019. , 2021, NCHS data brief.

[8]  S. Maguen,et al.  Gender Differences in Lifetime Prevalence and Onset Timing of Suicidal Ideation and Suicide Attempt Among Post-9/11 Veterans and Nonveterans. , 2021, Medical care.

[9]  Hongyu Zhao,et al.  Genome-wide association analyses of posttraumatic stress disorder and its symptom subdomains in the Million Veteran Program , 2021, Nature Genetics.

[10]  Charles R. Figley,et al.  Risk and protective factors associated with mental health among female military veterans: results from the veterans’ health study , 2019, BMC Women's Health.

[11]  M. Voracek,et al.  Suicide mortality in the United States following the suicides of Kate Spade and Anthony Bourdain , 2020, The Australian and New Zealand journal of psychiatry.

[12]  K. Kendler,et al.  The Sources of Parent-Child Transmission of Risk for Suicide Attempt and Deaths by Suicide in Swedish National Samples. , 2020, The American journal of psychiatry.

[13]  M. Hotopf,et al.  Genetic aetiology of self-harm ideation and behaviour , 2020, Scientific Reports.

[14]  David R. Gagnon,et al.  Standardized Architecture for a Mega-Biobank Phenomic Library: The Million Veteran Program (MVP). , 2020, AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science.

[15]  Grant D. Huang,et al.  Genotyping Array Design and Data Quality Control in the Million Veteran Program. , 2020, American journal of human genetics.

[16]  P. Sullivan,et al.  Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program. , 2020, The American journal of psychiatry.

[17]  A. Rajkumar,et al.  Systematic review of genetic association studies in people with Lewy body dementia , 2020, International journal of geriatric psychiatry.

[18]  Christopher R. Erbes,et al.  International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci , 2019, Nature Communications.

[19]  Julie A. Lynch,et al.  Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in Genome-wide Association Studies. , 2019, American journal of human genetics.

[20]  M. Blum,et al.  Making the most of Clumping and Thresholding for polygenic scores , 2019, bioRxiv.

[21]  J. Pell,et al.  Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide , 2019, EBioMedicine.

[22]  Brielin C. Brown,et al.  Comparative genetic architectures of schizophrenia in East Asian and European populations , 2018, Nature Genetics.

[23]  V. Vacic,et al.  Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways , 2019, Nature Genetics.

[24]  M. Hauser,et al.  A genome-wide association study of suicide attempts and suicidal ideation in U.S. military veterans , 2018, Psychiatry Research.

[25]  Kirsten H. Dillon,et al.  Examination of the indirect effects of combat exposure on suicidal behavior in veterans. , 2018, Journal of affective disorders.

[26]  Mitchell J. Machiela,et al.  LDassoc: an online tool for interactively exploring genome-wide association study results and prioritizing variants for functional investigation , 2018, Bioinform..

[27]  Warren W. Kretzschmar,et al.  Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression , 2017, Nature Genetics.

[28]  Gerome Breen,et al.  Psychiatric Genomics: An Update and an Agenda , 2017, bioRxiv.

[29]  D. Posthuma,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[30]  J. Bettinger,et al.  Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations. , 2017, Alcoholism, clinical and experimental research.

[31]  Melissa J. Green,et al.  Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder , 2017, bioRxiv.

[32]  P. Visscher,et al.  Causal associations between risk factors and common diseases inferred from GWAS summary data , 2017, bioRxiv.

[33]  E. Nestler,et al.  DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218 , 2017, Biological Psychiatry.

[34]  Evan M. Kleiman,et al.  Risk Factors for Suicidal Thoughts and Behaviors: A Meta-Analysis of 50 Years of Research , 2017, Psychological bulletin.

[35]  C. Tovilla-Zárate,et al.  The role of C957T, TaqI and Ser311Cys polymorphisms of the DRD2 gene in schizophrenia: systematic review and meta-analysis , 2016, Behavioral and Brain Functions.

[36]  C. Hoffmire,et al.  VA Suicide Prevention Applications Network , 2016, Public health reports.

[37]  Andres Metspalu,et al.  Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci , 2016, PLoS genetics.

[38]  S. Southwick,et al.  Nature and determinants of suicidal ideation among U.S. veterans: Results from the national health and resilience in veterans study. , 2016, Journal of affective disorders.

[39]  S. Redline,et al.  Common variants in DRD2 are associated with sleep duration: the CARe consortium. , 2016, Human molecular genetics.

[40]  Mitchell J. Machiela,et al.  LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants , 2015, Bioinform..

[41]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[42]  M. Hauser,et al.  Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans. , 2015, Journal of affective disorders.

[43]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[44]  Joris M. Mooij,et al.  MAGMA: Generalized Gene-Set Analysis of GWAS Data , 2015, PLoS Comput. Biol..

[45]  Jianhua Fu,et al.  Association between ANKK1 (rs1800497) polymorphism of DRD2 gene and attention deficit hyperactivity disorder: A meta-analysis , 2015, Neuroscience Letters.

[46]  Jack Euesden,et al.  PRSice: Polygenic Risk Score software , 2014, Bioinform..

[47]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[48]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[49]  E. Elbogen,et al.  The factor structure of psychiatric comorbidity among Iraq/Afghanistan-era veterans and its relationship to violence, incarceration, suicide attempts, and suicidality , 2014, Psychiatry Research.

[50]  B. Kolb,et al.  dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients , 2013, Translational Psychiatry.

[51]  Lianfeng Zhang,et al.  Cardiotrophin-1 (CTF1) ameliorates glucose-uptake defects and improves memory and learning deficits in a transgenic mouse model of Alzheimer's disease , 2013, Pharmacology Biochemistry and Behavior.

[52]  D. Rujescu,et al.  A comprehensive family-based replication study of schizophrenia genes. , 2013, JAMA psychiatry.

[53]  F. Holsboer,et al.  Genome-Wide Association Study of Antidepressant Treatment-Emergent Suicidal Ideation , 2012, Neuropsychopharmacology.

[54]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[55]  Wolfgang Viechtbauer,et al.  Conducting Meta-Analyses in R with the metafor Package , 2010 .

[56]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[57]  M. Valenstein,et al.  Comorbid anxiety as a suicide risk factor among depressed veterans , 2009, Depression and anxiety.

[58]  Jianxin Shi,et al.  Common variants on chromosome 6p22.1 are associated with schizophrenia , 2009, Nature.

[59]  A. Ashley-Koch,et al.  SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[60]  K. Bucholz,et al.  A twin study of genetic and environmental influences on suicidality in men , 2002, Psychological Medicine.

[61]  D. Brent,et al.  Suicidal behavior runs in families. A controlled family study of adolescent suicide victims. , 1996, Archives of general psychiatry.

[62]  E. Major,et al.  Expression of multiple classes of the nuclear factor-1 family in the developing human brain: differential expression of two classes of NF-1 genes. , 1996, Journal of neurovirology.