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

Show full item record



Permalink

http://hdl.handle.net/10138/272981

Citation

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 . https://doi.org/10.1038/mp.2017.193

Title: Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence
Author: 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.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2018-09
Language: eng
Number of pages: 9
Belongs to series: Molecular Psychiatry
ISSN: 1359-4184
URI: http://hdl.handle.net/10138/272981
Abstract: 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 x 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 x 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 x 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 x 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.
Subject: DNA METHYLTRANSFERASES DNMT3A
CEREBRAL-BLOOD-FLOW
LUNG-CANCER
SMOKING-CESSATION
CIGARETTE-SMOKING
SEQUENCE VARIANTS
GENE-EXPRESSION
FAGERSTROM TEST
BRAIN
RISK
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3124 Neurology and psychiatry
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Genome_wide_ass ... s_European_and_African.pdf 1.588Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record