Rare missense variants in CHRNB4 are associated with reduced risk of nicotine dependence

Gabe Haller, Todd Druley, Francesco L. Vallania, Robi D. Mitra, Ping Li, Gustav Akk, Joe Henry Steinbach, Naomi Breslau, Eric Johnson, Dorothy Hatsukami, Jerry Stitzel, Laura J. Bierut, Alison M. Goate

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Genome-wide association studies have identified common variation in the CHRNA5-CHRNA3-CHRNB4 and CHRNA6-CHRNB3 gene clusters that contribute to nicotine dependence. However, the role of rare variation in risk for nicotine dependence in these nicotinic receptor genes has not been studied. We undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes in African American and European American nicotine-dependent smokers and smokers without symptoms of dependence. Carrier status of individuals harboring rare missense variants at conserved sites in each of these genes was then compared in cases and controls to test for an association with nicotine dependence. Missense variants at conserved residues in CHRNB4 are associated with lower risk for nicotine dependence in African Americans and European Americans (AA P = 0.0025, odds-ratio (OR) = 0.31, 95% confidence-interval (CI) = 0.31-0.72; EA P = 0.023, OR = 0.69, 95% CI = 0.50-0.95). Furthermore, these individuals were found to smoke fewer cigarettes per day than non-carriers (AA P = 6.6 × 10 -5, EA P = 0.021). Given the possibility of stochastic differences in rare allele frequencies between groups replication of this association is necessary to confirm these findings. The functional effects of the two CHRNB4 variants contributing most to this association (T375I and T91I) and a missense variant in CHRNA3 (R37H) in strong linkage disequilibrium with T91I were examined in vitro. The minor allele of each polymorphism increased cellular response to nicotine (T375I P = 0.01, T91I P = 0.02, R37H P = 0.003), but the largest effect on in vitro receptor activity was seen in the presence of both CHRNB4 T91I and CHRNA3 R37H (P = 2 × 10 -6).

Original languageEnglish (US)
Article numberddr498
Pages (from-to)647-655
Number of pages9
JournalHuman molecular genetics
Issue number3
StatePublished - Feb 2012

Bibliographical note

Funding Information:
The COGEND project is a collaborative research group and part of the National Institute on Drug Abuse (NIDA) Genetics Consortium. Subject collection was supported by NIH grant P01 CA89392 (L.J.B.). Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C. Electrophysiological studies supported by NIH grant R21 DA26918 (G.A.).

Funding Information:
In memory of Theodore Reich, founding Principal Investigator of COGEND, we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. Lead investigators directing data collection are L.B., N.B., D.H. and E.J. The authors thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.


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