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

• Published in: Molecular psychiatry 2016-05, Vol.21 (5), p.594-600
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 45/23; 631/208; 692/53; 692/699/476/5; Addictions; Adolescent; Adult; Age; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal - etiology; Aortic Aneurysm, Abdominal - genetics; Aortic aneurysms; Behavioral Sciences; Biochemistry & Molecular Biology; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Biological Psychology; Chronic obstructive pulmonary disease; dependence; Drug dependence; fagerstrom test; Female; Gene frequency; Gene mutation; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease; genome-wide association; Genomes; Health aspects; Health behavior; heavy smoking; Hospitals; Humans; Iceland; Identification and classification; Immediate Communication; Lung cancer; Lung diseases; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Male; Medicine; Medicine & Public Health; Middle Aged; Missense mutation; Mutation; Mutation, Missense; Neurologi; Neurology; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Nicotine; nicotinic acetylcholine-receptors; Nucleotide sequence; Oncology; Peripheral Arterial Disease - etiology; Peripheral Arterial Disease - genetics; pharmacological chaperone; Pharmacotherapy; Psychiatry; Psykiatri; Public health; Pulmonary Disease, Chronic Obstructive - etiology; Pulmonary Disease, Chronic Obstructive - genetics; Receptors, Nicotinic - genetics; sequence variants; smokers; Smoking; Smoking - genetics; susceptibility locus; Thoracic surgery; Tobacco Use Disorder - complications; Tobacco Use Disorder - genetics; Vascular diseases; White People - genetics; Young Adult
• ISSN: 1359-4184; 1476-5578; 1476-5578
• 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 α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.