Anna R Docherty1, Andrey A Shabalin1, Emily DiBlasi1, Eric Monson1, Niamh Mullins1, Daniel E Adkins1, Silviu-Alin Bacanu1, Amanda V Bakian1, Sheila Crowell1, Danli Chen1, Todd M Darlington1, William B Callor1, Erik D Christensen1, Douglas Gray1, Brooks Keeshin1, Michael Klein1, John S Anderson1, Leslie Jerominski1, Caroline Hayward1, David J Porteous1, Andrew McIntosh1, Qingqin Li1, Hilary Coon1. 1. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City (Docherty, Shabalin, DiBlasi, Monson, Adkins, Bakian, Crowell, Chen, Darlington, Gray, Anderson, Jerominski, Coon); Huntsman Mental Health Institute, University of Utah School of Medicine, Salt Lake City (Docherty); Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond (Docherty, Bacanu); Department of Genetics and Genomic Sciences, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York (Mullins); Department of Psychology, University of Utah, Salt Lake City (Crowell); Utah State Office of the Medical Examiner, Utah Department of Health, Salt Lake City (Callor, Christensen); Mental Illness Research, Education, and Clinical Center, Veterans Integrated Service Network 19, George E. Whalen Department of Veterans Affairs Medical Center, Salt Lake City (Gray); Department of Pediatrics, University of Utah School of Medicine, Salt Lake City (Keeshin); Health Sciences Center Core Research Facility, University of Utah, Salt Lake City (Klein); Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, U.K. (Hayward, Porteous, McIntosh); Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, U.K. (Porteous, McIntosh); and Janssen Research and Development, Neuroscience Therapeutic Area, Titusville, N.J. (Li).
Abstract
OBJECTIVE: Death by suicide is a highly preventable yet growing worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizable suicide death cohorts available for analysis. To address this limitation, the authors conducted the first comprehensive genomic analysis of suicide death using previously unpublished genotype data from a large population-ascertained cohort. METHODS: The analysis sample comprised 3,413 population-ascertained case subjects of European ancestry and 14,810 ancestrally matched control subjects. Analytical methods included principal component analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic-relatedness matrix), gene and gene set-enrichment testing, and polygenic score analyses, as well as single-nucleotide polymorphism (SNP) heritability and genetic correlation estimation using linkage disequilibrium score regression. RESULTS: Genome-wide association analysis identified two genome-wide significant loci (involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367). Gene-based analyses implicated 22 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide death heritability was estimated at an h2SNP value of 0.25 (SE=0.04) and a value of 0.16 (SE=0.02) when converted to a liability scale. Notably, suicide polygenic scores were significantly predictive across training and test sets. Polygenic scores for several other psychiatric disorders and psychological traits were also predictive, particularly scores for behavioral disinhibition and major depressive disorder. CONCLUSIONS: Multiple genome-wide significant loci and genes were identified and polygenic score prediction of suicide death case-control status was demonstrated, adjusting for ancestry, in independent training and test sets. Additionally, the suicide death sample was found to have increased genetic risk for behavioral disinhibition, major depressive disorder, depressive symptoms, autism spectrum disorder, psychosis, and alcohol use disorder compared with the control sample.
OBJECTIVE: Death by suicide is a highly preventable yet growing worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizable suicide death cohorts available for analysis. To address this limitation, the authors conducted the first comprehensive genomic analysis of suicide death using previously unpublished genotype data from a large population-ascertained cohort. METHODS: The analysis sample comprised 3,413 population-ascertained case subjects of European ancestry and 14,810 ancestrally matched control subjects. Analytical methods included principal component analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic-relatedness matrix), gene and gene set-enrichment testing, and polygenic score analyses, as well as single-nucleotide polymorphism (SNP) heritability and genetic correlation estimation using linkage disequilibrium score regression. RESULTS: Genome-wide association analysis identified two genome-wide significant loci (involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367). Gene-based analyses implicated 22 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide death heritability was estimated at an h2SNP value of 0.25 (SE=0.04) and a value of 0.16 (SE=0.02) when converted to a liability scale. Notably, suicide polygenic scores were significantly predictive across training and test sets. Polygenic scores for several other psychiatric disorders and psychological traits were also predictive, particularly scores for behavioral disinhibition and major depressive disorder. CONCLUSIONS: Multiple genome-wide significant loci and genes were identified and polygenic score prediction of suicide death case-control status was demonstrated, adjusting for ancestry, in independent training and test sets. Additionally, the suicide death sample was found to have increased genetic risk for behavioral disinhibition, major depressive disorder, depressive symptoms, autism spectrum disorder, psychosis, and alcohol use disorder compared with the control sample.
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