A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

作者：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; Ronmark E; Lundback B; Dirksen A; Ashraf H; Pedersen J H; Masson G; Sulem P

来源：Molecular Psychiatry, 2016, 21(5): 594-600.

DOI：10.1038/mp.2016.13

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 x 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 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 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 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

• 出版日期2016-5
• 单位河北医科大学