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

Autor: Shanbeh Zienolddiny, Unnur Thorsteinsdottir, Thorunn Rafnar, Ian P. Hall, Gyda Bjornsdottir, Eva Rönmark, Thorgeir E. Thorgeirsson, Tomas Gudbjartsson, Lambertus A. Kiemeney, Aage Haugen, A. Sigvaldason, Steinn Jonsson, Hafdis T. Helgadottir, Angeles Panadero, Hronn Hardardottir, Solveig Gretarsdottir, Kari Stefansson, Anna Helgadottir, Daniel F. Gudbjartsson, Gunnar W Reginsson, Wilbur A. Franklin, Thorarinn Tyrfingsson, Helgi J Isaksson, Ingileif Jonsdottir, Gisli Masson, Asger Dirksen, Stefan E Matthiasson, Bo Lundbäck, Jose I. Mayordomo, Thorarinn Gislason, Patrick Sulem, Haseem Ashraf, Stacy Steinberg, Holly J. Wolf, Jesper Holst Pedersen
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Lung Neoplasms
Iceland
Receptors
Nicotinic
Nicotine
Pulmonary Disease
Chronic Obstructive
Missense mutation
Aged
80 and over
COPD
biology
CHRNA5
Smoking
Tobacco Use Disorder
Middle Aged
3. Good health
Psychiatry and Mental health
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15]
Female
Medical Genetics
medicine.drug
Adult
Fagerstrom Test for Nicotine Dependence
medicine.medical_specialty
Adolescent
Mutation
Missense
White People
Peripheral Arterial Disease
Young Adult
03 medical and health sciences
Cellular and Molecular Neuroscience
Internal medicine
medicine
Humans
Genetic Predisposition to Disease
Lung cancer
Molecular Biology
Allele frequency
Genetic Association Studies
Aged
Medicinsk genetik
business.industry
Odds ratio
medicine.disease
030104 developmental biology
Endocrinology
biology.protein
Immediate Communication
business
Neuroscience
Aortic Aneurysm
Abdominal
Zdroj: Molecular Psychiatry, 21, 5, pp. 594-600
Molecular Psychiatry, 21, 594-600
Molecular Psychiatry
Thorgeirsson, T E, Steinberg, S, Reginsson, G W, Bjornsdottir, G, Rafnar, T, Jonsdottir, I, Helgadóttir, Á, 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, Lundb'ck, B, Dirksen, A, Ashraf, H, Pedersen, J J H, Masson, G, Sulem, P, Thorsteinsdottir, U, Gudbjartsson, D F & Stefansson, K 2016, ' A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences ', Molecular Psychiatry, vol. 21, no. 5, pp. 594-600 . https://doi.org/10.1038/mp.2016.13
ISSN: 1359-4184
Popis: Contains fulltext : 172466.pdf (Publisher’s version ) (Open Access) 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 alpha4beta2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
Databáze: OpenAIRE
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