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Mol Psychiatry. 2018 Jan;23(1):154-160. doi: 10.1038/mp.2017.24. Epub 2017 Mar 7.

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

Author information

1
Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
2
Center for Child and Family Traumatic Stress, Kennedy Krieger Institute, Baltimore, MD, USA.
3
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
4
Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.
5
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
6
Department of Psychiatry, University of Pennsylvania School of Medicine and VISN4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
7
Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
8
Department of Health Care Policy, Harvard Medical School, Boston MA, USA.
9
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
10
Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
11
Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
12
VA San Diego Healthcare System, San Diego, CA, USA.

Abstract

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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