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Marital Status, Alcohol Dependence, and GABRA2: Evidence for Gene-Environment Correlation and Interaction

Danielle M. Dick, Arpana Agrawal, Marc A. Schuckit, Laura Bierut, Anthony Hinrichs, Louis Fox, Joseph Mullaney, C. Robert Cloninger, Victor Hesselbrock, John I. Nurnberger, Jr., Laura Almasy, Tatiana Foroud, Bernice Porjesz, Howard Edenberg, Henri Begleiter

Objective: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence. Method: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of ~900 individuals from control families to test the generalizability of results. Results: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status. Conclusions: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of “environmental” risk factors. (J. Stud. Alcohol 67: 185-194, 2006)