TY - JOUR
T1 - A genome-wide gene-by-Trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus
AU - Polimanti, R.
AU - Kaufman, J.
AU - Zhao, H.
AU - Kranzler, H. R.
AU - Ursano, R. J.
AU - Kessler, R. C.
AU - Gelernter, J.
AU - Stein, M. B.
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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 â8). 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 â5), cognition (GO:0050890; P=1.90 × 10 â6), locomotion (GO:0040011; P=6.70 × 10 â5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10 â5). 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.
AB - 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 â8). 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 â5), cognition (GO:0050890; P=1.90 × 10 â6), locomotion (GO:0040011; P=6.70 × 10 â5) and Stat3 protein regulation (GO:0042517; P=6.4 × 10 â5). 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.
UR - http://www.scopus.com/inward/record.url?scp=85014543268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014543268&partnerID=8YFLogxK
U2 - 10.1038/mp.2017.24
DO - 10.1038/mp.2017.24
M3 - Article
C2 - 28265120
AN - SCOPUS:85014543268
SN - 1359-4184
VL - 23
SP - 154
EP - 160
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 1
ER -