Genetic variation in the exome : associations with alcohol and tobacco co-use

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Shared genetic factors represent one mechanism underlying alcohol and tobacco co-use and dependence, although common genetic variants identified by molecular genetics studies tend to confer only small disease risk. Rare variants--particularly those in protein-coding regions of the genome--are posited to contribute to disease risk, as well. Therefore, the current study examined genetic variation in protein-coding regions (i.e., the exome) for associations with alcohol and tobacco co-use and dependence. Participants from the UCSF Family Alcoholism Study (N = 1,862) were genotyped using an exome-focused genotyping array, and assessed for DSM-IV diagnoses of alcohol and tobacco dependence, as well as quantitative consumption measures. Analyses included single variant, gene-based, and pathway-based tests of association. A frameshift mutation (rs373285038) in the EPC2 gene was significantly associated with alcohol dependence, as well as EPC2 and the NuA4/Tip60 HAT complex A in the gene and pathway-based tests, respectively. The findings also replicated previous single variant associations from studies of substance use and dependence, including variants in CHRNA3 and CHRNA5 with cigarettes per day. Several of the most highly significant variants and genes demonstrated associations across phenotypes, suggesting that shared genetic factors may underlie risk for increased levels of alcohol and tobacco use. This study provides evidence of the role of rare variation in alcohol and tobacco co-use, as well as the underlying genetic architecture of these traits