Saccone Nancy L, Saccone Scott F, Hinrichs Anthony L, Stitzel Jerry A, Duan Weimin, Pergadia Michele L, Agrawal Arpana, Breslau Naomi, Grucza Richard A, Hatsukami Dorothy, Johnson Eric O, Madden Pamela A F, Swan Gary E, Wang Jen C, Goate Alison M, Rice John P, Bierut Laura J
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):453-66. doi: 10.1002/ajmg.b.30828.
Tobacco smoking continues to be a leading cause of preventable death. Recent research has underscored the important role of specific cholinergic nicotinic receptor subunit (CHRN) genes in risk for nicotine dependence and smoking. To detect and characterize the influence of genetic variation on vulnerability to nicotine dependence, we analyzed 226 SNPs covering the complete family of 16 CHRN genes, which encode the nicotinic acetylcholine receptor (nAChR) subunits, in a sample of 1,050 nicotine-dependent cases and 879 non-dependent controls of European descent. This expanded SNP coverage has extended and refined the findings of our previous large-scale genome-wide association and candidate gene study. After correcting for the multiple tests across this gene family, we found significant association for two distinct loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster, one locus in the CHRNB3-CHRNA6 gene cluster, and a fourth, novel locus in the CHRND-CHRNG gene cluster. The two distinct loci in CHRNA5-CHRNA3-CHRNB4 are represented by the non-synonymous SNP rs16969968 in CHRNA5 and by rs578776 in CHRNA3, respectively, and joint analyses show that the associations at these two SNPs are statistically independent. Nominally significant single-SNP association was detected in CHRNA4 and CHRNB1. In summary, this is the most comprehensive study of the CHRN genes for involvement with nicotine dependence to date. Our analysis reveals significant evidence for at least four distinct loci in the nicotinic receptor subunit genes that each influence the transition from smoking to nicotine dependence and may inform the development of improved smoking cessation treatments and prevention initiatives.
吸烟仍然是可预防死亡的主要原因。最近的研究强调了特定胆碱能烟碱受体亚基（CHRN）基因在尼古丁依赖和吸烟风险中的重要作用。为了检测和表征基因变异对尼古丁依赖易感性的影响，我们在1050例欧洲血统的尼古丁依赖病例和879例非依赖对照样本中，分析了覆盖16个CHRN基因完整家族的226个单核苷酸多态性（SNP），这些基因编码烟碱型乙酰胆碱受体（nAChR）亚基。这种扩大的SNP覆盖范围扩展并完善了我们之前大规模全基因组关联和候选基因研究的结果。在对该基因家族的多次检测进行校正后，我们发现CHRNA5-CHRNA3-CHRNB4基因簇中有两个不同的位点、CHRNB3-CHRNA6基因簇中有一个位点以及CHRND-CHRNG基因簇中有第四个新位点存在显著关联。CHRNA5-CHRNA3-CHRNB4中的两个不同位点分别由CHRNA5中的非同义SNP rs169699经968和CHRNA3中的rs578776代表，联合分析表明这两个SNP的关联在统计学上是独立的。在CHRNA4和CHRNB1中检测到名义上显著的单SNP关联。总之，这是迄今为止对CHRN基因与尼古丁依赖关系最全面的研究。我们的分析揭示了烟碱受体亚基基因中至少四个不同位点的显著证据，每个位点都影响从吸烟到尼古丁依赖的转变，并可能为改进戒烟治疗和预防措施的开发提供信息。
