A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.
paper
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- Authors
- Thorgeirsson, T E; Steinberg, S; Reginsson, G W; Bjornsdottir, G; Rafnar, T; Jonsdottir, I; Helgadottir, A; Gretarsdottir, S; Helgadottir, H; Jonsson, S; Matthiasson, S E; Gislason, T; Tyrfingsson, T; Gudbjartsson, T; Isaksson, H J; Hardardottir, H; Sigvaldason, A; Kiemeney, L A; Haugen, A; Zienolddiny, S; Wolf, H J; Franklin, W A; Panadero, A; Mayordomo, J I; Hall, I P; RΓΆnmark, E; LundbΓ€ck, B; Dirksen, A; Ashraf, H; Pedersen, J H; Masson, G; Sulem, P; Thorsteinsdottir, U; Gudbjartsson, D F; Stefansson, K
- Year
- 2016
- Journal
- Molecular psychiatry
- PMID
- 26952864
- DOI
- 10.1038/mp.2016.13
- PMCID
- PMC5414061
Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 Γ 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 Γ 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 Γ 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 Γ 10(-4)), COPD (OR=3.22, P=2.9 Γ 10(-4)), PAD (OR=3.47, P=9.2 Γ 10(-3)) and AAA (OR=6.44, P=6.3 Γ 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 Γ 10(-5)), particularly for early-onset cases (P=2.1 Γ 10(-7)). Our results are in agreement with functional studies showing that the human Ξ±4Ξ²2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
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