A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences - PubMed (original) (raw)

. 2016 May;21(5):594-600.

doi: 10.1038/mp.2016.13. Epub 2016 Mar 8.

S Steinberg 1, G W Reginsson 1, G Bjornsdottir 1, T Rafnar 1, I Jonsdottir 1 2, A Helgadottir 1, S Gretarsdottir 1, H Helgadottir 1, S Jonsson 2 3, S E Matthiasson 4, T Gislason 2 3, T Tyrfingsson 5, T Gudbjartsson 2 6, H J Isaksson 7, H Hardardottir 3, A Sigvaldason 3, L A Kiemeney 8 9, A Haugen 10, S Zienolddiny 10, H J Wolf 11, W A Franklin 12, A Panadero 13, J I Mayordomo 14, I P Hall 15, E Rönmark 16 17, B Lundbäck 16 18, A Dirksen 19, H Ashraf 19 20, J H Pedersen 21, G Masson 1, P Sulem 1, U Thorsteinsdottir 1, D F Gudbjartsson 1, K Stefansson 1 2

Affiliations

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

T E Thorgeirsson et al. Mol Psychiatry. 2016 May.

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.

PubMed Disclaimer

Conflict of interest statement

Authors whose affiliations are listed as deCODE/Amgen are employees of deCODE/Amgen. The remaining authors declare no conflict of interest.

References

    1. WHO Report on the Global Tobacco Epidemic, 2008: The MPOWER package, WHO, Geneva (2008). Available at: http://www.who.int/tobacco/mpower/mpower_report_full_2008.pdf Accessed February 15, 2016.
    1. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 2008; 452: 638–642. - PMC - PubMed
    1. Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F et al. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet 2010; 42: 448–453. - PMC - PubMed
    1. Hancock DB, Reginsson GW, Gaddis NC, Chen X, Saccone NL, Lutz SM et al. Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence. Transl Psychiatry 2015; 5: e651. - PMC - PubMed
    1. Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 2008; 13: 368–373. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources