A Genome-Wide Gene-By-Trauma Interaction Study of Alcohol Misuse in Two Independent Cohorts Identifies PRKG1 as a Risk Locus

• Activity Number: 498 - Designs and Statistical Methods Used in Genetics and Mental Health for Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)
• Type: Topic Contributed
• Date/Time: Wednesday, July 31, 2019 : 10:30 AM to 12:20 PM
• Sponsor: Mental Health Statistics Section
• Author(s): Renato Polimanti* and Joan Kaufman and Hongyu Zhao and Henry R. Kranzler and Robert J Ursano and Ron Kessler and Joel Gelernter and Murray B. Stein
• Companies: and Johns Hopkins School of Medicine and Yale and University of Pennsylvania School of Medicine and Uniformed Services University of the Health Sciences and Harvard Medical School and Yale University and UCSD
• Keywords: Trauma; Alcohol Abuse; Genetics; Gene-Environment Interaction; Genome-wide Analysis; Army

Abstract

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. 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 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.