A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus

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Traumatic life experiences are associated with alcohol use problems, an association that is likely to be moderated by genetic predisposition. To understand these interactions, we conducted a gene-by-environment genome-wide interaction study (GEWIS) of alcohol use problems in two independent samples, the Army STARRS (STARRS, N=16 361) and the Yale-Penn (N=8084) cohorts. Because the two cohorts were assessed using different instruments, we derived separate dimensional alcohol misuse scales and applied a proxy-phenotype study design. In African-American subjects, we identified an interaction of PRKG1 rs1729578 with trauma exposure in the STARRS cohort and replicated its interaction with trauma exposure in the Yale-Penn cohort (discovery-replication meta-analysis: z=5.64, P=1.69 × 10−8). PRKG1 encodes cyclic GMP-dependent protein kinase 1, which is involved in learning, memory and circadian rhythm regulation. Considering the loci identified in stage-1 that showed same effect directions in stage-2, the gene ontology (GO) enrichment analysis showed several significant results, including calcium-activated potassium channels (GO:0016286; P=2.30 × 10−5), cognition (GO:0050890; P=1.90 × 10−6), locomotion (GO:0040011; P=6.70 × 10−5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10−5). To our knowledge, this is the largest GEWIS performed in psychiatric genetics, and the first GEWIS examining risk for alcohol misuse. Our results add to a growing body of literature highlighting the dynamic impact of experience on individual genetic risk.

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This study was funded by National Institutes of Health grants R21 AA024404, RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA012870, the VISN1 and VISN4 MIRECCs. We would like to thank an anonymous reviewer for the findings of the KEGG-pathway enrichment analysis. Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009-2015) with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). Subsequently, STARRS-LS was sponsored and funded by the Department of Defense (USUHS grant number HU0001-15-2-0004). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, or the Department of the Army, or the Department of Defense. The Army STARRS Team consists of Co-Principal Investigators: Robert J. Ursano, MD (Uniformed Services University of the Health Sciences) and Murray B. Stein, MD, MPH (University of California San Diego and VA San Diego Healthcare System); Site Principal Investigators: Steven Heeringa, PhD (University of Michigan), James Wagner, PhD (University of Michigan) and Ronald C. Kessler, PhD (Harvard Medical School); Army liaison/consultant: Kenneth Cox, MD, MPH (USAPHC (Provisional)); Biomarker Working Group Chair: Murray B. Stein, MD, MPH (University of California San Diego and VA San Diego Healthcare System); Biomarker Working Group: Susan Borja, PhD (NIMH); Tianxi Cai, ScD (Harvard School of Public Health); Chia-Yen Chen, ScD (Harvard Medical School); Joel Gelernter, MD (Yale University); Sonia Jain, PhD (University of California San Diego); Kevin Jensen, PhD (Yale University); Kristen Jepsen, PhD (University of California San Diego); Ronald C. Kessler, PhD (Harvard Medical School); Douglas Meinecke, PhD (NIMH); Colter Mitchell, PhD (University of Michigan); Caroline Nievergelt, PhD (University of California San Diego); Rema Raman, PhD (University of California San Diego); Jordan W. Smoller, MD, ScD (Harvard Medical School); Michael L. Thomas, PhD (University of California San Diego); Robert J. Ursano, MD (Uniformed Services University of the Health Sciences); Christina L. Wassel, PhD (University of Pittsburgh); Erin Ware, PhD (University of Michigan); Lei Zhang, MD (Uniformed Services University of the Health Sciences); Biomarker Working Group Consultants: Karestan Koenen, PhD (Columbia University); Ronen Segman, MD (Hadassah University Hospital, Israel); Stephan Ripke, MD (Harvard Medical School); Nadia Solovieff, PhD (Harvard Medical School); Other team members: Pablo A. Aliaga, MA (Uniformed Services University of the Health Sciences); COL David M. Benedek, MD (Uniformed Services University of the Health Sciences); Laura Campbell-Sills, PhD (University of California San Diego); Carol S. Fullerton, PhD (Uniformed Services University of the Health Sciences); Nancy Gebler, MA (University of Michigan); Robert K. Gifford, PhD (Uniformed Services University of the Health Sciences); Paul E. Hurwitz, MPH (Uniformed Services University of the Health Sciences); Sonia Jain, PhD (University of California San Diego); Tzu-Cheg Kao, PhD (Uniformed Services University of the Health Sciences); Lisa Lewandowski-Romps, PhD (University of Michigan); Holly Herberman Mash, PhD (Uniformed Services University of the Health Sciences); James E. McCarroll, PhD, MPH (Uniformed Services University of the Health Sciences); James A. Naifeh, PhD (Uniformed Services University of the Health Sciences); Tsz Hin Hinz Ng, MPH (Uniformed Services University of the Health Sciences); Matthew K. Nock, PhD (Harvard University); Nancy A. Sampson, BA (Harvard Medical School); CDR Patcho Santiago, MD, MPH (Uniformed Services University of the Health Sciences); LTC Gary H. Wynn, MD (Uniformed Services University of the Health Sciences); and Alan M. Zaslavsky, PhD (Harvard Medical School).

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Correspondence to M B Stein.

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Competing interests

In the past 3 years, Dr Stein has been a consultant for Actelion Pharmaceuticals, Healthcare Management Technologies, Janssen, Neurocrine, Pfizer, Resilience Therapeutics, Tonix Pharmaceuticals and Oxeia Biopharmaceuticals. Dr Kaufman has provided consultation to Pfizer and Merck Pharmaceutical Company to train investigators to assess bipolar disorder in youth. Dr Kranzler has been an advisory board member, consultant or CME speaker for Indivior, Lundbeck and Otsuka. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Pfizer and XenoPort. In the past 3 years, Dr Kessler received support for his epidemiological studies from Sanofi Aventis; was a consultant for Johnson & Johnson Wellness and Prevention, Shire, Takeda; and served on an advisory board for the Johnson & Johnson Services Inc. Lake Nona Life Project. Kessler is a co-owner of DataStat, Inc., a market research firm that carries out healthcare research. The remaining authors declare no conflict of interest.

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