Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.


Journal Article

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Full Text

Cited Authors

  • Olfson, E; Saccone, NL; Johnson, EO; Chen, L-S; Culverhouse, R; Doheny, K; Foltz, SM; Fox, L; Gogarten, SM; Hartz, S; Hetrick, K; Laurie, CC; Marosy, B; Amin, N; Arnett, D; Barr, RG; Bartz, TM; Bertelsen, S; Borecki, IB; Brown, MR; Chasman, DI; van Duijn, CM; Feitosa, MF; Fox, ER; Franceschini, N; Franco, OH; Grove, ML; Guo, X; Hofman, A; Kardia, SLR; Morrison, AC; Musani, SK; Psaty, BM; Rao, DC; Reiner, AP; Rice, K; Ridker, PM; Rose, LM; Schick, UM; Schwander, K; Uitterlinden, AG; Vojinovic, D; Wang, J-C; Ware, EB; Wilson, G; Yao, J; Zhao, W; Breslau, N; Hatsukami, D; Stitzel, JA; Rice, J; Goate, A; Bierut, LJ

Published Date

  • May 2016

Published In

Volume / Issue

  • 21 / 5

Start / End Page

  • 601 - 607

PubMed ID

  • 26239294

Pubmed Central ID

  • 26239294

Electronic International Standard Serial Number (EISSN)

  • 1476-5578

International Standard Serial Number (ISSN)

  • 1359-4184

Digital Object Identifier (DOI)

  • 10.1038/mp.2015.105


  • eng