rs55853698

This cross-population meta-analysis of 32,587 smokers (14,786 European ancestry, 6,889 Asian, 10,912 African American) identified rs16969968 as the only genetic variant in the chromosome 15q25 nicotinic receptor region consistently associated with heavy smoking across all three populations (OR=1.33, 95% CI=1.25-1.42, p=1.1×10⁻¹⁷). Additional variants showed consistent association in European and Asian populations but not African Americans, suggesting rs16969968 is likely a functional causal variant.

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 population-based study examined natural selection on nicotinic receptor gene clusters (CHRNB3-A6 on chromosome 8 and CHRNA5-A3-B4 on chromosome 15) using 1000 Genomes data from three populations. Using Tajima's D and integrated haplotype score (iHS) tests, the authors found strong evidence for positive selection in the CHRNB3-A6 region and moderate evidence in CHRNA5-A3-B4. These regions harbor variants previously associated with nicotine dependence (rs16969968, rs1451240) and cocaine dependence. To understand the target of selection, the authors tested variants in COGA subjects (N=492) for association with cognitive phenotypes (WAIS tests) and found one significant association: rs7017612 with WAIS Digit Symbol score (β=0.43, p=0.003), suggesting memory and learning may be the driving force behind selection.