Browsing by Author "Brooks, Andy"

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    Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence
    (Oxford University Press, 2014-02-01) Haller, Gabe; Kapoor, Manav; Budde, John; Xuei, Xiaoling; Edenberg, Howard; Nurnberger, John; Kramer, John; Brooks, Andy; Tischfield, Jay; Almasy, Laura; Agrawal, Arpana; Bucholz, Kathleen; Rice, John; Saccone, Nancy; Bierut, Laura; Goate, Alison; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10−4) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10−4) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276
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    Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy
    (Nature Publishing Group, 2014-03-28) Sadler, Brooke; Haller, Gabe; Agrawal, Arpana; Culverhouse, Rob; Bucholz, Kathleen; Brooks, Andy; Tischfield, Jay; Johnson, Eric O.; Edenberg, Howard; Schuckit, Marc; Saccone, Nancy; Bierut, Laura; Goate, Alison; Department of Biochemistry & Molecular Biology, IU School of Medicine
    In the U.S.A., cocaine is the second most abused illicit drug. Variants within the CHRNB3-A6 gene cluster have been associated with cigarette consumption in several GWAS. These receptors represent intriguing candidates for the study of cocaine dependence because nicotinic receptors are thought to be involved in generalized addiction pathways. Using genotypic data from a GWAS of the Study of Addiction: Genetics and Environment (SAGE) dataset, we tested for association of CHRNB3-A6 SNPs with DSM-5 cocaine use disorder. Multiple SNPs in the region were significantly associated with increased risk of cocaine use disorder. Inclusion of the most significant SNP as a covariate in a linear regression model provided evidence for an additional independent signal within this locus for cocaine use disorder. These results suggest that the CHRNB3-A6 locus contains multiple variants affecting risk for vulnerability to cocaine and nicotine dependence as well as bipolar disorder, suggesting that they have pleiotropic effects.