Daniel Hupalo1, Christopher W Forsberg2, Jack Goldberg2,3, William S Kremen4,5, Michael J Lyons6, Anthony R Soltis1, Coralie Viollet1, Robert J Ursano7, Murray B Stein4, Carol E Franz4, Yan V Sun8, Viola Vaccarino8, Nicholas L Smith2,3, Clifton L Dalgard1,9, Matthew D Wilkerson1,9, Harvey B Pollard1,9. 1. The American Genome Center, Collaborative Health Initiative Research Program, and Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA. 2. Seattle Epidemiologic Research and Information Center, Office of Research and Development, U.S. Department of Veteran Affairs, Seattle, WA, USA. 3. Department of Epidemiology, University of Washington, Seattle, WA, USA. 4. Department of Psychiatry and of Family Medicine & Public Health, University of California, La Jolla, CA, USA. 5. VA San Diego Center of Excellence for Stress and Mental Health, San Diego, CA, USA. 6. Department of Psychological & Brain Sciences, Boston University, Boston, MA, USA. 7. Department of Psychiatry, Uniformed Services University, Bethesda, MD, USA. 8. Department of Epidemiology, Emory University, Atlanta, GA, USA. 9. Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD, USA.
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 (PAdjusted = 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 (PAdjusted = 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.
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 (PAdjusted = 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 (PAdjusted = 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.
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