Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence

Gabe Haller, Manav Kapoor, John Budde, Xiaoling Xuei, Howard Edenberg, John Nurnberger, John Kramer, Andy Brooks, Jay Tischfield, Laura Almasy, Arpana Agrawal, Kathleen Bucholz, John Rice, Nancy Saccone, Laura Bierut, Alison Goate

    Research output: Contribution to journalArticlepeer-review

    26 Scopus citations


    Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol andcocaine dependence.Becauseof the substantial comorbidity, it hasoftenbeenunclear 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 DSMIV 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; H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10-5, β = 2.04) and alcohol dependence symptoms (P =2.6 × 10-4, β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006).Theseare the first results to implicate rare variants inCHRNB3orCHRNA3in risk for alcohol dependence or cocaine dependence.

    Original languageEnglish (US)
    Article numberddt463
    Pages (from-to)810-819
    Number of pages10
    JournalHuman molecular genetics
    Issue number3
    StatePublished - Feb 2014

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)


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