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A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

ABSTRACT: 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.

SUBMITTER: Kimbrel NA

PROVIDER: S-EPMC9910180 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

Kimbrel Nathan A NA Ashley-Koch Allison E AE Qin Xue J XJ Lindquist Jennifer H JH Garrett Melanie E ME Dennis Michelle F MF Hair Lauren P LP Huffman Jennifer E JE Jacobson Daniel A DA Madduri Ravi K RK Trafton Jodie A JA Coon Hilary H Docherty Anna R AR Kang Jooeun J Mullins Niamh N Ruderfer Douglas M DM Harvey Philip D PD McMahon Benjamin H BH Oslin David W DW Hauser Elizabeth R ER Hauser Michael A MA Beckham Jean C JC

Molecular psychiatry 20220328 4

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 behavi ...[more]

PMID: 35347246

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Project description: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.

Project description:BackgroundCalcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS.MethodsWe performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study.ResultsWe identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS (PALMD, TEX41, IL6, LPA, FADS) and 6 were novel (CEP85L, FTO, SLMAP, CELSR2, MECOM, CDAN1). Two novel lead variants were associated in non-White individuals (P<0.05): rs12740374 (CELSR2) in Black and Hispanic individuals and rs1522387 (SLMAP) in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [LPA], rs12740374 [CELSR2]) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the FTO locus. However, the FTO locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis.ConclusionsWe performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.

Project description:ImportancePeople with disability are at heightened risk for suicide ideation, planning, and attempt, with risk growing as the number of disabling limitations increases. Military veterans have higher rates of suicide deaths and disability relative to nonveterans.ObjectiveTo evaluate whether veteran status is associated with greater risk for suicide in those with disability.Design, setting, and participantsThis survey study used cross-sectional self-reported data from US adults who participated in the 2015-2020 National Survey on Drug Use and Health. Data were weighted to represent the population. Data analysis was conducted from July to August 2022.Main outcomes and measuresSuicide ideation, planning, and attempt served as primary outcomes. Disability status (present or absent) and number of disabling limitations (1, 2, or ≥3) served as factors. Veteran status was determined based on self-report (veteran or nonveteran). Multivariable logistic regression examined suicide ideation, planning, and attempt as a function of veteran status and disability variables.ResultsParticipants included 231 099 US veterans and nonveterans, representing 236 551 727 US adults, of whom 20.03% (weighted n = 47 397 876) reported a disabling limitation, 8.92% were veterans (weighted n = 21 111 727; 16.0% aged 35-49 years; 91.0% men; 6.7% Hispanic; 10.9% non-Hispanic Black; and 78.4% non-Hispanic White) and 91.08% were nonveterans (weighted n = 215 440 000; 25.4% aged 35-49 years; 44.0% male; 16.5% Hispanic; 11.7% non-Hispanic Black; and 63.3% non-Hispanic White). Overall, 4.39% reported suicide ideation, planning, or attempt (weighted n = 10 401 065). Among those with no disability, veteran status was associated with higher risk of suicide planning (adjusted odds ratio [AOR], 1.71; 95% CI, 1.17-2.49). Among those with 1 or 2 disabling limitations, being a veteran was associated with a lower risk of suicide planning (AOR, 0.57; 95% CI, 0.34-0.95) and history of attempt (AOR, 0.46; 95% CI, 0.24-0.88).Conclusions and relevanceIn this study of how suicide risk differs as a function of disability and veteran status, risk for death by suicide was lower among veterans with disability relative to nonveterans with disability. Veteran status may mitigate risk for suicide given increased receipt of more disability-related care through the Department of Veterans Affairs. Further research would extend this line of inquiry by examining the cause and type of disability as well as perceptions of disability on self-worth. It is possible that physical wounds of war are protective because of the meaning and value of service to one's country.

Dataset Information

A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

Publications

A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci.

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