Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 17 other smoking traits (r_g=0.40-0.95) and co-morbidities. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

中文翻译：

---

扩展尼古丁依赖性的遗传结构及其具有多种特征的共有遗传学：尼古丁依赖性基因组学（iNDiGO）联盟的发现

吸烟是可预防的发病率和死亡率的主要原因。知识正在演变为引发，经常吸烟，尼古丁依赖（ND）和戒烟的基础遗传学。我们使用FagerströmND检验（FTND）对58,000名欧洲或非洲血统的吸烟者进行了全基因组关联研究。确定了五个基因组范围内的重要基因座，包括两个新的基因座MAGI2 / GNAI1（rs2714700）和TENM2（rs1862416），并将报道的其他吸烟性状的基因座扩展到ND。使用英国生物库中的吸烟重度指数（HSI）（N = 33,791），rs2714700一直存在关联，但rs1862416没有关联，可能反映了HSI无法捕获的ND特征。两种变体均为cis-eQTLs（海马MAGI2-AS3为rs2714700，肺部TENM2为rs1862416），小脑中丰富了与ND相关变体的基因表达。基于SNP的ND遗传力为8.6％，并且ND与其他17种吸烟性状具有遗传相关性（_g = 0.40-0.95）和合并症。我们的结果强调FTND是一种复合表型，可扩展吸烟的遗传知识，包括ND特异的基因座。