Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Niamh Mullins, Joo Eun Kang, VA Million Veteran Program, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Eating Disorders Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, MVP Suicide Exemplar Workgroup, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei Hsin Su, Hunna J. Watson, Mark Adams, Swapnil AwasthiMichael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Roel A. Ophoff, Daniel J. Smith

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Abstract

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Original languageEnglish
Pages (from-to)313-327
Number of pages15
JournalBiological Psychiatry
Volume91
Issue number3
Early online date8 Sept 2021
DOIs
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding Information:
Statistical analyses were carried out on the NL Genetic Cluster Computer ( http://www.geneticcluster.org ) hosted by SURFsara and the Mount Sinai high performance computing cluster ( http://hpc.mssm.edu ), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880 ). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University , Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM]).

Funding Information:
In the past 3 years, RCK was a consultant for Datastat, Inc., Sage Pharmaceuticals, and Takeda. HRK and JG are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. HRK is a member of an advisory board for Dicerna Pharmaceuticals and of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Dicerna, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. DL is an employee of Janssen Research & Development, LLC, and shareholder in Johnson & Johnson, the parent company of the Janssen companies. DL declares that, except for income received from her primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. MBS has in the past 3 years been a consultant for Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Epivario, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Oxeia Biopharmaceuticals. MBS has stock options in Oxeia Biopharmaceuticals and Epivario. HJG has received travel grants and speaker honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen-Cilag as well as research funding from Fresenius Medical Care. OAA is a consultant for HealthLytix and received speaker’s honorarium from Lundbeck and Sunovion. RAP is employed by and holds shares in BioMarin Pharmaceuticals. MCO and MJO are supported by a collaborative research grant from Takeda Pharmaceuticals. That support did not contribute to the work described in this manuscript. EHG has served in the speakers’ bureau and the advisory board of Takeda (former Shire do Brasil) Pharmaceutical. JAR-Q was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogui, Lundbeck, Almirall, Braingaze, Sincrolab, Medice, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogui, Bial, Medice, and Eli Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. VR was on the speakers’ bureau and/or acted as consultant for Takeda and Rubió in the last 5 years. She also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Rubió, Shire, Takeda, and Lundbeck. MC was on the speakers’ bureau and/or acted as consultant for Janssen-Cilag in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2021 Society of Biological Psychiatry

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