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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Polimanti R,Kaufman J,Zhao H,Kranzler HR,Ursano RJ,Kessler RC,Gelernter J,Stein MB

doi

10.1038/mp.2017.24

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

154-160

issue

1

eissn

1359-4184

issn

1476-5578

pii

mp201724

journal_volume

23

pub_type

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