A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.
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Authors
Thorgeirsson, T ESteinberg, 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
Issue Date
2016-05
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A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences. 2016, 21 (5):594-600 Mol. PsychiatryAbstract
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.Description
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http://dx.doi.org/ 10.1038/mp.2016.13Rights
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10.1038/mp.2016.13
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