Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Molecular psychiatry, 2018-09, Vol.23 (9), p.1911-1919

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (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 , 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 ) 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 ) 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.