Search

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation., Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population., Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023., Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status., Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events., Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%)., Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

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.)

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.

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.)