Olfson E, Saccone N L, Johnson E O, Chen L-S, Culverhouse R, Doheny K, Foltz S M, Fox L, Gogarten S M, Hartz S, Hetrick K, Laurie C C, Marosy B, Amin N, Arnett D, Barr R G, Bartz T M, Bertelsen S, Borecki I B, Brown M R, Chasman D I, van Duijn C M, Feitosa M F, Fox E R, Franceschini N, Franco O H, Grove M L, Guo X, Hofman A, Kardia S L R, Morrison A C, Musani S K, Psaty B M, Rao D C, Reiner A P, Rice K, Ridker P M, Rose L M, Schick U M, Schwander K, Uitterlinden A G, Vojinovic D, Wang J-C, Ware E B, Wilson G, Yao J, Zhao W, Breslau N, Hatsukami D, Stitzel J A, Rice J, Goate A, Bierut L J
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
Mol Psychiatry. 2016 May;21(5):601-7. doi: 10.1038/mp.2015.105. Epub 2015 Aug 4.
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.
α5烟碱型受体亚基基因（CHRNA5）中的常见非同义变体rs16969968是欧美人群中尼古丁依赖最强的遗传风险因素，对非裔美国人的风险也有影响。为全面研究CHRNA5的其他编码变异是否影响尼古丁依赖风险，我们对1582例尼古丁依赖者（尼古丁依赖的Fagerström测试评分⩾4）和1238例非依赖者进行了靶向测序，并利用12项外显子芯片数据研究对常见和低频变异进行独立复制验证。使用逻辑回归分析个体常见变异（次要等位基因频率（MAF）⩾0.05）、低频变异集合（0.05>MAF⩾0.005）和罕见变异集合（MAF<0.005）来检验尼古丁依赖情况。对主要结果进行荟萃分析，纳入了12174例重度吸烟者和11290例轻度吸烟者的重复研究。覆盖深度达180×的新一代测序在CHRNA5中鉴定出24个非同义变异和2个移码缺失，在2820名受试者中包括9个新变异。荟萃分析证实了唯一常见变异（rs16969968，欧洲血统：比值比（OR）=1.3，P=3.5×10⁻¹¹；非洲血统：OR=1.3，P=0.01）的风险效应，并表明三个低频变异也导致独立风险（合并项，欧洲血统：OR=1.3，P=0.005；非洲血统：OR=1.4，P=0.0006）。其余22个罕见编码变异与欧美裔主要样本中尼古丁依赖风险增加相关（OR=12.9，P=0.01），在非裔美国人中也呈相同风险趋势（OR=1.5，P=0.37）。我们的结果表明，CHRNA5常见、低频和罕见编码变异均独立与尼古丁依赖风险相关。这些新鉴定出的变异可能影响肺癌等吸烟相关疾病的风险。
