A rare missense mutation in CHRNA4 associates... : Molecular Psychiatry (original) (raw)

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

• T E Thorgeirsson
• S Steinberg
• G W Reginsson
• G Bjornsdottir
• T Rafnar
• I Jonsdottir
• A Helgadottir
• S Gretarsdottir
• H Helgadottir
• S Jonsson
• S E Matthiasson
• T Gislason
• T Tyrfingsson
• T Gudbjartsson
• H J Isaksson
• H Hardardottir
• A Sigvaldason
• L A Kiemeney
• A Haugen
• S Zienolddiny
• H J Wolf
• W A Franklin
• A Panadero
• J I Mayordomo
• I P Hall
• E Rönmark
• B Lundbäck
• A Dirksen
• H Ashraf
• J H Pedersen
• G Masson
• P Sulem
• U Thorsteinsdottir
• D F Gudbjartsson
• K Stefansson

Molecular Psychiatry

21

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5

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:p

594

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600

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May 2016

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| 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 × 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 α_4_β_2_ isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.