rs588765

This methodological paper presents an approach to interpret joint SNP analysis results by determining whether two apparently distinct genetic signals could actually be produced by a single underlying causal variant. The authors applied this method to joint analysis of rs16969968 and rs588765 in CHRNA5 for nicotine dependence (COGEND sample, n=2053), finding no evidence that a single third SNP could fully explain the observed associations. The method demonstrates that causal variants need not be highly correlated with observed signals nor have large effect sizes to produce joint SNP results.

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 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.