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

the VA Million Veteran Program (MVP), the MVP Suicide Exemplar Workgroup, the International Suicide Genetics Consortium

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)2264-2272
Number of pages9
JournalMolecular Psychiatry
Volume27
Issue number4
DOIs
StatePublished - Apr 2022

Funding

This research is based on data from the Million Veteran Program, Office of Research and Development (ORD), Veterans Health Administration (VHA), and was supported by award #I01CX001729 from the Clinical Science Research and Development (CSR&D) Service of VHA ORD. J.C. Beckham was also supported by a Senior Research Career Scientist Award (#lK6BX003777) from CSR&D. Niamh Mullins was supported by a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We also thank and acknowledge MVP, the MVP Suicide Exemplar Workgroup, and the ISGC for their contributions to this manuscript. A complete listing of contributors from the MVP, MVP Suicide Exemplar Workgroup, and ISGC is provided in the Supplementary Materials. This work was also supported in part by the joint U.S. Department of Veterans Affairs and US Department of Energy MVP CHAMPION program. This manuscript has been co-authored by UT-Battelle, LLC under contract no. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a nonexclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan ( http://energy.gov/downloads/doe-public-access-plan , last accessed September 16, 2020). The GWAS summary statistics generated from this study will be available via dbGaP. The dbGaP accession assigned to the Million Veteran Program is phs001672.v1.p. This research is based on data from the Million Veteran Program, Office of Research and Development (ORD), Veterans Health Administration (VHA), and was supported by award #I01CX001729 from the Clinical Science Research and Development (CSR&D) Service of VHA ORD. J.C. Beckham was also supported by a Senior Research Career Scientist Award (#lK6BX003777) from CSR&D. Niamh Mullins was supported by a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We also thank and acknowledge MVP, the MVP Suicide Exemplar Workgroup, and the ISGC for their contributions to this manuscript. A complete listing of contributors from the MVP, MVP Suicide Exemplar Workgroup, and ISGC is provided in the Supplementary Materials. This work was also supported in part by the joint U.S. Department of Veterans Affairs and US Department of Energy MVP CHAMPION program. This manuscript has been co-authored by UT-Battelle, LLC under contract no. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a nonexclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan , last accessed September 16, 2020). The GWAS summary statistics generated from this study will be available via dbGaP. The dbGaP accession assigned to the Million Veteran Program is phs001672.v1.p.

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