Rare variant association study of veteran twin whole-genomes links severe depression with a nonsynonymous change in the neuronal gene BHLHE22

• Type of Material: Article
• Authors: Daniel Hupalo, Uniformed Services University, Bethesda; Christopher W Forsberg, U.S. Department of Veteran Affairs, Seattle; Jack Goldberg, U.S. Department of Veteran Affairs, Seattle; William S Kremen, University of California, La Jolla; Michael J Lyons, Boston University; Anthony R Soltis, Uniformed Services University, Bethesda; Coralie Viollet, Uniformed Services University, Bethesda; Robert J Ursano, Uniformed Services University, Bethesda; Murray B Stein, University of California, La Jolla; Carol E Franz, University of California, La Jolla; Yan Sun, Emory University; Viola Vaccarino, Emory University; Nicholas L Smith, U.S. Department of Veteran Affairs; Clifton L Dalgard, Uniformed Services University, Bethesda; Matthew D Wilkerson, Uniformed Services University, Bethesda; Harvey B Pollard, Uniformed Services University, Bethesda
• Language: English
• Date: 2021-11-29
• Publisher: TAYLOR & FRANCIS LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 USC. 105, no copyright protection is available for such works under US Law.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1080/15622975.2021.1980316
• Title of Journal or Parent Work: WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY
• Volume: 23
• Issue: 4
• Start Page: 295
• End Page: 306
• Grant/Funding Information: This work was supported by NHLBI/NIH under grant IAA-AA-HL-14-007 (Pollard); Cooperative Studies Program (CSP) of the United States Department of Veterans Affairs (VA) Office of Research & Development; R01DA004604 (Tsuang); R01AG050595 (Kremen, Lyons, Franz) and R01AG022381 (Kremen); and R01HL68630, R01AG026255, R01HL125246, and R01HL136205 (Vaccarino).
• Keywords: Life Sciences & Biomedicine; rare variant; whole-genome sequencing; Psychiatry; RISK; WIDE ASSOCIATION; GWAS; BHLHe22; Science & Technology; MAJOR DEPRESSION; BHLHB5; REGISTRY; depression; MDD

Abstract

Objectives: Major Depressive Disorder (MDD) is a complex neuropsychiatric disease with known genetic associations, but without known links to rare variation in the human genome. Here we aim to identify rare genetic variants associated with MDD using deep whole-genome sequencing data in an independent population. Methods: We report the sequencing of 1,688 whole genomes in a large sample of male-male Veteran twins. Depression status was classified based on a structured diagnostic interview according to DSM-III-R diagnostic criteria. Searching only rare variants in genomic regions from recent GWAS on MDD, we used the optimised sequence kernel association test and Fisher's Exact test to fine map loci associated with severe depression. Results: Our analysis identified one gene associated with severe depression, basic helix loop helix e22 (P Adjusted = 0.03) via SKAT-O test between unrelated severely depressed cases compared to unrelated non-depressed controls. The same gene BHLHE22 had a non-silent variant rs13279074 (P Adjusted = 0.032) based on a single variant Fisher’s Exact test between unrelated severely depressed cases compared to unrelated non-depressed controls. Conclusion: The gene BHLHE22 shows compelling genetic evidence of directly impacting the severe depression phenotype. Together these results advance understanding of the genetic contribution to major depressive disorder in a new cohort and link a rare variant to severe forms of the disorder.