Uncommon Protein-Coding Variants Associated With Suicide Attempt in a Diverse Sample of U.S. Army Soldiers

Matthew D Wilkerson; Daniel Hupalo; Joshua C Gray; Xijun Zhang; Jiawei Wang; Matthew J Girgenti; Camille Alba; Gauthaman Sukumar; Nathaniel M Lott; James A Naifeh; Pablo Aliaga; Ronald C Kessler; Clesson Turner; Harvey B Pollard; Clifton L Dalgard; Robert J Ursano; Murray B Stein

doi:10.1016/j.biopsych.2023.12.008

Uncommon Protein-Coding Variants Associated With Suicide Attempt in a Diverse Sample of U.S. Army Soldiers

Biol Psychiatry. 2023 Dec 21:S0006-3223(23)01783-3. doi: 10.1016/j.biopsych.2023.12.008. Online ahead of print.

Authors

Matthew D Wilkerson¹, Daniel Hupalo², Joshua C Gray³, Xijun Zhang², Jiawei Wang⁴, Matthew J Girgenti⁴, Camille Alba², Gauthaman Sukumar², Nathaniel M Lott⁵, James A Naifeh⁶, Pablo Aliaga⁶, Ronald C Kessler⁷, Clesson Turner⁸, Harvey B Pollard⁹, Clifton L Dalgard¹, Robert J Ursano⁶, Murray B Stein¹⁰

Affiliations

¹ Center for Military Precision Health, Uniformed Services University, Bethesda, Maryland; Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, Maryland.
² Center for Military Precision Health, Uniformed Services University, Bethesda, Maryland.
³ Department of Medical and Clinical Psychology, Uniformed Services University, Bethesda, Maryland.
⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
⁵ Department of Microbiology and Immunology, Uniformed Services University, Bethesda, Maryland.
⁶ Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University, Bethesda, Maryland.
⁷ Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.
⁸ Department of Pediatrics, Uniformed Services University, Bethesda, Maryland.
⁹ Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, Maryland.
¹⁰ Department of Psychiatry, University of California San Diego, La Jolla, California; Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, California; VA San Diego Healthcare System, San Diego, California. Electronic address: mstein@health.ucsd.edu.

PMID: 38141912
DOI: 10.1016/j.biopsych.2023.12.008

Abstract

Background: Suicide is a societal and public health concern of global scale. Identifying genetic risk factors for suicide attempt can characterize underlying biology and enable early interventions to prevent deaths. Recent studies have described common genetic variants for suicide-related behaviors. Here, we advance this search for genetic risk by analyzing the association between suicide attempt and uncommon variation exome-wide in a large, ancestrally diverse sample.

Methods: We sequenced whole genomes of 13,584 soldiers from the Army STARRS (Army Study to Assess Risk and Resilience in Servicemembers), including 979 individuals with a history of suicide attempt. Uncommon, nonsilent protein-coding variants were analyzed exome-wide for association with suicide attempt using gene-collapsed and single-variant analyses.

Results: We identified 19 genes with variants enriched in individuals with history of suicide attempt, either through gene-collapsed or single-variant analysis (Bonferroni p_adjusted < .05). These genes were CIB2, MLF1, HERC1, YWHAE, RCN2, VWA5B1, ATAD3A, NACA, EP400, ZNF585A, LYST, RC3H2, PSD3, STARD9, SGMS1, ACTR6, RGS7BP, DIRAS2, and KRTAP10-1. Most genes had variants across multiple genomic ancestry groups. Seventeen of these genes were expressed in healthy brain tissue, with 9 genes expressed at the highest levels in the brain versus other tissues. Brains from individuals deceased from suicide aberrantly expressed RGS7BP (p_adjusted = .035) in addition to nominally significant genes including YWHAE and ACTR6, all of which have reported associations with other mental disorders.

Conclusions: These results advance the molecular characterization of suicide attempt behavior and support the utility of whole-genome sequencing for complementing the findings of genome-wide association studies in suicide research.

Keywords: Exome; Genetics; Genomics; Military; Suicide; Whole-genome sequencing.

Published by Elsevier Inc.