Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever c... Mehr ...

Verfasser: Hancock, D. B.
Guo, Y.
Reginsson, G. W.
Gaddis, N. C.
Lutz, S. M.
Sherva, R.
Loukola, A.
Minica, C. C.
Markunas, C. A.
Han, Y.
Young, K. A.
Gudbjartsson, D. F.
Gu, F.
McNeil, D. W.
Qaiser, B.
Glasheen, C.
Olson, S.
Landi, M. T.
Madden, P. A.F.
Farrer, L. A.
Vink, J.
Saccone, N. L.
Neale, M. C.
Kranzler, H. R.
McKay, J.
Hung, R. J.
Amos, C. I.
Marazita, M. L.
Boomsma, D. I.
Baker, T. B.
Gelernter, J.
Kaprio, J.
Caporaso, N. E.
Thorgeirsson, T. E.
Hokanson, J. E.
Bierut, L. J.
Stefansson, K.
Johnson, E. O.
Dokumenttyp: Artikel
Erscheinungsdatum: 2018
Reihe/Periodikum: Hancock , D B , Guo , Y , Reginsson , G W , Gaddis , N C , Lutz , S M , Sherva , R , Loukola , A , Minica , C C , Markunas , C A , Han , Y , Young , K A , Gudbjartsson , D F , Gu , F , McNeil , D W , Qaiser , B , Glasheen , C , Olson , S , Landi , M T , Madden , P A F , Farrer , L A , Vink , J , Saccone , N L , Neale , M C , Kranzler , H R , McKay , J , Hung , R J , Amos , C I , Marazita , M L , Boomsma , D I , Baker , T B , Gelernter , J , Kaprio , J , Caporaso , N E , Thorgeirsson , T E , Hokanson , J E , Bierut , L J , Stefansson , K & Johnson , E O 2018 , ' Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence ' , Molecular Psychiatry , vol. 23 , no. 9 , pp. 1911–1919 . https://doi.org/10.1038/mp.2017.193
Schlagwörter: Journal Article / /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_ / name=Netherlands Twin Register (NTR) / /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being / name=SDG 3 - Good Health and Well-being
Sprache: Englisch
Permalink: https://search.fid-benelux.de/Record/base-29214023
Datenquelle: BASE; Originalkatalog
Powered By: BASE
Link(s) : https://research.vu.nl/en/publications/74b77807-4971-4bf7-99f1-e9947f82780b

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77%) was associated with increased risk of nicotine dependence at P=3.7 × 10 −8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10 −4 , OR=1.05, and 95% CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10 −26 ) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10 −6 ) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.