Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Jonathan Marchini and colleagues with the Ox-GSK consortium report a meta-analysis for smoking phenotypes from 20 studies including 41,150 individuals, confirming an association at the CHRNA5 – CHRNA3 locus on 15q25 to smoking quantity. They use imputation based on 1,000 Genomes Project Pilot 1 data to refine the association at this locus. Smoking is a leading global cause of disease and mortality 1 . We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 ( P = 9.45 × 10 −19 ) that includes CHRNA5 , CHRNA3 and CHRNB4 , three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2 ) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5 . Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3 .