GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, 27709, USA.
Department of Psychiatry, Washington University, St. Louis, MO, 63130, USA.
Nat Commun. 2020 Nov 3;11(1):5562. doi: 10.1038/s41467-020-19265-z.
Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.
吸烟是可预防的发病率和死亡率的主要原因。遗传变异导致起始、规律吸烟、尼古丁依赖和戒烟。我们在 58000 名欧洲或非洲血统的吸烟者中进行了基于 Fagerström 尼古丁依赖测试（FTND）的全基因组关联研究。我们观察到五个全基因组显著的位点，包括以前未报道的 MAGI2/GNAI1（rs2714700）和 TENM2（rs1862416）位点，以及将已报道的其他吸烟特征扩展到尼古丁依赖的位点。使用英国生物银行（N=33791）的吸烟量指数，rs2714700 始终与该指数相关；rs1862416 与该指数无关，可能反映了吸烟量指数未捕捉到的尼古丁依赖特征。这两个变体都影响附近的基因表达（rs2714700/MAGI2-AS3 在海马体中；rs1862416/TENM2 在肺部），跨越与尼古丁依赖相关的变体的基因表达在小脑中有富集。尼古丁依赖（基于 SNP 的遗传率为 8.6%）与 18 种其他吸烟特征（r=0.40-1.09）和合并症有遗传相关性。我们的研究结果突出了尼古丁依赖的特定位点，强调了 FTND 作为一种综合表型，扩展了吸烟的遗传知识。
