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

Autor: Kimbrel NA; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA. Nathan.Kimbrel@va.gov.; VA Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, NC, USA. Nathan.Kimbrel@va.gov.; VA Health Services Research and Development Center of Innovation to Accelerate Discovery and Practice Transformation, Durham, NC, USA. Nathan.Kimbrel@va.gov.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA. Nathan.Kimbrel@va.gov., Ashley-Koch AE; Duke Molecular Physiology Institute, Durham, NC, USA.; Department of Medicine, Duke University Health System, Durham, NC, USA., Qin XJ; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA.; Duke Molecular Physiology Institute, Durham, NC, USA., Lindquist JH; VA Health Services Research and Development Center of Innovation to Accelerate Discovery and Practice Transformation, Durham, NC, USA., Garrett ME; Duke Molecular Physiology Institute, Durham, NC, USA., Dennis MF; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA., Hair LP; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA., Huffman JE; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA., Jacobson DA; Biosciences, Oak Ridge National Laboratory, Oak Ridge, TN, USA.; Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee Knoxville, Knoxville, TN, USA.; Department of Psychology, NeuroNet Research Center, University of Tennessee Knoxville, Knoxville, TN, USA., Madduri RK; Consortium for Advanced Science and Engineering, The University of Chicago, Chicago, IL, USA.; Data Science and Learning Division, Argonne National Laboratory, Lemont, IL, USA., Trafton JA; Program Evaluation and Resource Center, Office of Mental Health and Suicide Prevention, VA Palo Alto Health Care System, Menlo Park, CA, USA., Coon H; Department of Psychiatry, Huntsman Mental Health Institute, University of Utah School of Medicine, Salt Lake City, UT, US.; Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, US., Docherty AR; Department of Psychiatry, Huntsman Mental Health Institute, University of Utah School of Medicine, Salt Lake City, UT, US.; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, US., Kang J; Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, US., Mullins N; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, US.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, US., Ruderfer DM; Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, US.; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, US.; Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, US., Harvey PD; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.; Research Service Bruce W. Carter VA Medical Center, Miami, FL, USA., McMahon BH; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA., Oslin DW; VISN 4 Mental Illness Research, Education, and Clinical Center, Center of Excellence, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Hauser ER; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA.; Duke Molecular Physiology Institute, Durham, NC, USA., Hauser MA; Duke Molecular Physiology Institute, Durham, NC, USA.; Department of Medicine, Duke University Health System, Durham, NC, USA., Beckham JC; Durham Veterans Affairs (VA) Health Care System, Durham, NC, USA.; VA Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, NC, USA.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Apr; Vol. 27 (4), pp. 2264-2272. Date of Electronic Publication: 2022 Mar 28.
DOI: 10.1038/s41380-022-01472-3
Abstrakt: 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.
(© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
Databáze: MEDLINE
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