rs8034191

This mediation analysis study of 3,424 COPD cases and 1,872 controls examined direct and indirect genetic effects of known COPD susceptibility loci. The AGPHD1/CHRNA3 variants (rs1051730, rs8034191) showed ~30% of their total effect on COPD mediated by pack-years smoking (OR 1.256-1.305), while IREB2 (rs13180) showed no significant smoking-mediated effect, suggesting independent pathways. FAM13A (rs7671167) and HHIP (rs13118928) demonstrated direct effects on COPD independent of smoking.

This PhD thesis comprehensively explores associations between the CHRNA5-A3-B4 nicotinic acetylcholine receptor gene cluster and smoking-related behaviors. Using systematic review/meta-analysis, genetic epidemiology, laboratory-based techniques, and genome-wide meta-analysis, the study found compelling evidence for a small, robust association between rs16969968/rs1051730 and daily cigarette consumption with a per-allele effect of approximately one cigarette per day (beta≈1.0). A genome-wide meta-analysis of cotinine levels in 2,139 current smokers identified multiple variants in the CHRNA5 region strongly associated with tobacco exposure. However, no association was observed with smoking initiation in a prospectively-assessed cohort.

This paper applies a bias correction method for odds ratio estimates from GWAS discovery data, demonstrating that the 'winner's curse' affects initial effect size estimates. The authors applied conditional maximum likelihood estimation to correct bias in GWAS findings from multiple complex diseases (breast cancer, colorectal cancer, lung cancer, prostate cancer, type I and II diabetes) and show that bias-adjusted odds ratios are substantially more consistent with subsequent replication studies, with selection-adjusted confidence intervals providing better uncertainty quantification than uncorrected estimates.

This comprehensive association study of 226 SNPs across all 16 nicotinic receptor subunit (CHRN) genes identified four distinct genetic loci significantly associated with nicotine dependence in 1050 cases and 879 controls of European descent. The two most significant associations were rs16969968 (CHRNA5, non-synonymous, p=0.00013, OR=1.30) and rs578776 (CHRNA3, p=0.00011, OR=1.34) in the CHRNA5-CHRNA3-CHRNB4 cluster; one locus in the CHRNB3-CHRNA6 cluster tagged by rs13277254 (p=0.00010); and a novel locus in the CHRND-CHRNG cluster tagged by rs12466358 (p=0.00027). Joint analyses confirmed statistical independence of the two CHRNA5-CHRNA3-CHRNB4 signals.