| Title: | Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence |
| Journal: | Molecular Psychiatry |
| Published: | 3 Oct 2017 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/28972577/ |
| DOI: | https://doi.org/10.1038/mp.2017.193 |
| URL: | https://research.vu.nl/files/108250713/Genomewide_association_study_across_European_and_AfricanAmerican_ancestries_identifies_a_SNP_in_DNMT3B_contributing_to_nicotine_dependence.pdf |
Publication 8487
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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 × 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.</p>
38 Authors
- D B Hancock
- Y Guo
- G W Reginsson
- N C Gaddis
- S M Lutz
- R Sherva
- A Loukola
- C C Minica
- C A Markunas
- Y Han
- K A Young
- D F Gudbjartsson
- F Gu
- D W McNeil
- B Qaiser
- C Glasheen
- S Olson
- M T Landi
- P A F Madden
- L A Farrer
- J Vink
- N L Saccone
- M C Neale
- H R Kranzler
- J McKay
- R J Hung
- C I Amos
- M L Marazita
- D I Boomsma
- T B Baker
- J Gelernter
- J Kaprio
- N E Caporaso
- T E Thorgeirsson
- J E Hokanson
- L J Bierut
- K Stefansson
- E O Johnson
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