title: A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.
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.
authors.affiliation: Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Polimanti
authors.affiliation: Center for Child and Family Traumatic Stress, Kennedy Krieger Institute, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kaufman
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine and VISN4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Ursano
authors.affiliation: Department of Health Care Policy, Harvard Medical School, Boston MA, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Kessler
authors.affiliation: Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.|Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Stein
mesh_terms: D000293:Adolescent; D000328:Adult; D000437:Alcoholism / Q000235:genetics*; D015331:Cohort Studies; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008016:Life Change Events; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569718:PRKG1 protein, human