A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus
Kranzler, Henry R.
Ursano, Robert J.
Stein, Murray B.
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CitationPolimanti, Renato, Joan Kaufman, Hongyu Zhao, Henry R. Kranzler, Robert J. Ursano, Ronald C. Kessler, Joel Gelernter, and Murray B. Stein. 2017. “A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.” Molecular psychiatry :10.1038/mp.2017.24. doi:10.1038/mp.2017.24. http://dx.doi.org/10.1038/mp.2017.24.
AbstractTraumatic 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 (ASTARRS, N=16,361) and the Yale-Penn (N=8,084) 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 ASTARRS 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 cGMP-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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