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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.

SUBMITTER: Polimanti R

PROVIDER: S-EPMC5589475 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.

Polimanti R R Kaufman J J Zhao H H Kranzler H R HR Ursano R J RJ Kessler R C RC Gelernter J J Stein M B MB

Molecular psychiatry 20170307 1

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 app ...[more]

PMID: 28265120

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Project description:BackgroundThe American College of Surgeons mandates universal screening for alcohol misuse and delivery of an intervention for those screening positive as a requirement for certification as a level 1 trauma center. Though this requirement has been mandated for over a decade, its implementation has been challenging. Our research team completed an implementation study supporting seven pediatric trauma centers' compliance with the requirement by developing and implementing an institutional alcohol Screening, Brief Intervention and Referral to Treatment (SBIRT) policy for adolescent trauma patients. A mixed-methods approach indicated that SBIRT adoption rates increased at all sites; however, providers' fidelity to the SBIRT intervention was variable, and providers reported a number of barriers to SBIRT implementation. The goal of this study is to conduct a fully powered type III hybrid effectiveness-implementation trial to test the effectiveness of a comprehensive implementation strategy in increasing the implementation of SBIRT for alcohol and other drug use (AOD) in pediatric trauma centers.MethodsOur implementation strategy is based on the Science to Service Laboratory (SSL), an approach developed by the SAMHSA-funded Addiction Technology Transfer Centers that consists of three core elements (i.e., didactic training + performance feedback + leadership coaching). Utilizing a stepped wedge design, a national cohort of 10 pediatric trauma centers will receive the SSL implementation strategy. At six distinct time points, each of the 10 sites will provide data from 30 electronic medical records (n = 1800 in total). A subset of adolescents will also report on fidelity of intervention delivery and linkage to care (i.e., continued AOD discussion and/or treatment with a primary care provider) 1 month after hospital discharge. In addition, nurses, social workers, and leaders will report on organizational readiness for implementation at four distinct time points.DiscussionThis protocol proposes a unique opportunity to examine whether a comprehensive implementation strategy can improve the fidelity of SBIRT delivery across a national cohort of pediatric trauma centers. With injured adolescents, this could optimize the detection and intervention of AOD use and improve adolescent health.Trial registrationClinicaltrials.gov NCT03297060 .

Project description:Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in CNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

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A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.

Publications

A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus.

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