Thorgeirsson, T.E. and Steinberg, S. and Reginsson, G.W. and Bjornsdottir, G. and Rafnar, T. and Jonsdottir, I. and Helgadottir, A. and Gretarsdottir, S. and Helgadottir, H. and Jonsson, S. and Matthiasson, S.E. and Gislason, T. and Tyrfingsson, T. and Gudbjartsson, T. and Isaksson, H.J. and Hardardottir, H. and Sigvaldason, A. and Kiemeney, L.A. and Haugen, A. and Zienolddiny, S. and Wolf, H.J. and Franklin, W.A. and Panadero, A. and Mayordomo, J.I. and Hall, I.P. and Rönmark, E. and Lundbäck, B. and Dirksen, A. and Ashraf, H. and Pedersen, J.H. and Masson, G. and Sulem, P. and Thorsteinsdottir, U. and Gudbjartsson, D.F. and Stefansson, K.
(2016)
A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.
Molecular Psychiatry, 21
(5).
pp. 594-600.
ISSN 1359-4184
Abstract
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 × 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 × 10−4), chronic obstructive pulmonary disease (COPD;P= 9.3 × 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 × 10−4), COPD (OR = 3.22,P= 2.9 × 10−4), PAD (OR = 3.47,P= 9.2 × 10−3) and AAA (OR = 6.44, P= 6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P= 6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7).
Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
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