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.

中文翻译：

---

横跨欧洲和非裔美国人祖先的全基因组关联研究确定了DNMT3B中的SNP有助于尼古丁依赖性。

吸烟是全世界可预防的死亡的主要原因。尼古丁依赖性降低了戒烟的可能性，是一种可遗传的性状，与尼古丁乙酰胆碱受体基因和其他基因座的序列变体建立了牢固的联系。为了寻找其他基因座，我们进行了尼古丁依赖的全基因组关联研究（GWAS）荟萃分析，在15项研究中总计38,602名吸烟者（28,677名欧洲人/欧洲裔美国人和9925名非裔美国人）。在针对烟碱依赖性的最大的GWAS荟萃分析和任何吸烟表型的最大的跨祖系GWAS荟萃分析中，我们再次确认了众所周知的CHRNA5-CHRNA3-CHRNB4基因，并进一步在DNA中产生了新的关联甲基转移酶基因DNMT3B。^-8（重度与轻度依赖的赔率（OR）= 1.06，95％置信区间（CI）= 1.04-1.07）。该关联在英国生物银行（N = 48931）中得到了独立证实，使用重度吸烟与不吸烟作为替代表型（P = 3.6×10 ^-4，OR = 1.05，95％CI = 1.02-1.08）。在国际肺癌协会中，Rs910083-C还与鳞状细胞肺癌的风险增加相关（N = 60,586，荟萃分析P = 0.0095，OR = 1.05，95％CI = 1.01-1.09）。此外，rs910083-C被认为是与胎儿脑中较高DNMT3B甲基化相关的顺式甲基化定量性状基因座（QTL）变异（N = 166，P = 2.3×10 ^-26）和来自基因型组织表达计划（N = 103，P = 3.0×10 ^-6）和独立的Brain eQTL年鉴（N = 134，P = 0.028）的成年小脑中较高DNMT3B表达的顺式表达QTL变异体）。这种新颖的DNMT3B顺式作用QTL变体突显了基因调控的大脑对尼古丁依赖，重度吸烟和随之而来的肺癌风险的重要性。