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Meta-Analysis
, 23 (9), 1911-1919

Genome-wide Association Study Across European and African American Ancestries Identifies a SNP in DNMT3B Contributing to Nicotine Dependence

Affiliations
Meta-Analysis

Genome-wide Association Study Across European and African American Ancestries Identifies a SNP in DNMT3B Contributing to Nicotine Dependence

D B Hancock et al. Mol Psychiatry.

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.

Conflict of interest statement

Conflicts of Interest

Dr. Bierut and the spouse of Dr. Saccone are listed as inventors on U.S. Patent 8,080,371,”Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. Authors listed with the affiliation deCODE Genetics/AMGEN are employees of deCODE genetics/AMGEN. Although unrelated to this research, Dr. Kranzler has been a consultant or advisory board member for Lundbeck and Indivior and is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. Dr. Kaprio has consulted for Pfizer in 2012–2014 on nicotine dependence.

Figures

Figure 1
Figure 1. Manhattan plot of SNP and indel associations with nicotine dependence from GWAS meta-analysis across 15 studies (total N=38,602 European/European Americans and African Americans)
The –log10 meta-analysis p-values are plotted by chromosomal position of SNPs (depicted as circles) and indels (depicted as triangles). The genome-wide statistical significance threshold (P<5×10−8) is shown as a solid black line.
Figure 2
Figure 2. Novel DNMT3B SNP associations with nicotine dependence from GWAS meta-analysis of EUR and AA studies
SNP and indel associations are shown across DNMT3B and its 100kb flanking region (NCBI build 37 positions presented). r2 values between the top SNP rs910083 and all other SNPs are shown in reference to 1000 Genomes panels: (A) European (EUR) and (B) African (AFR). Indels with missing r2 values are indicated in grey. The p-value threshold of 5×10−8 is marked by the solid black line.
Figure 2
Figure 2. Novel DNMT3B SNP associations with nicotine dependence from GWAS meta-analysis of EUR and AA studies
SNP and indel associations are shown across DNMT3B and its 100kb flanking region (NCBI build 37 positions presented). r2 values between the top SNP rs910083 and all other SNPs are shown in reference to 1000 Genomes panels: (A) European (EUR) and (B) African (AFR). Indels with missing r2 values are indicated in grey. The p-value threshold of 5×10−8 is marked by the solid black line.
Figure 3
Figure 3. Normalized DNMT3B gene expression levels as a function of rs910083 genotype in cerebellum from the Genotype-Tissue Expression (GTEx) project
The box lines mark the first quartile, median, and third quartile; and the whiskers are marked by the highest and lowest data points within the 1.5 × inter-quartile range (third – first quartile) to show outliers that fall outside of these boundaries.

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