A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
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.; Rönmark, E.; Lundbäck, B.; Dirksen, A.; Ashraf, H.; Pedersen, J.H.; Masson, G.; Sulem, P.; Thorsteinsdottir, U.; Gudbjartsson, D.F.; Stefansson, K.
IAN HALL firstname.lastname@example.org
Professor of Molecular Medicine
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.
|Journal Article Type||Article|
|Publisher||Nature Publishing Group|
|Peer Reviewed||Peer Reviewed|
|APA6 Citation||Thorgeirsson, T., Steinberg, S., Reginsson, G., Bjornsdottir, G., Rafnar, T., Jonsdottir, I., …Stefansson, K. (in press). A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences. Molecular Psychiatry, 21(5), https://doi.org/10.1038/mp.2016.13|
|Copyright Statement||Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0|
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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