Article

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

Department of Statistics, University of Oxford, Oxford, UK.
Nature Genetics (Impact Factor: 29.35). 05/2010; 42(5):436-40. DOI: 10.1038/ng.572
Source: PubMed

ABSTRACT

Smoking is a leading global cause of disease and mortality. 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 x 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.

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Available from: Arne S Schaefer, Mar 16, 2015
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    • "The International Lung Cancer Consortium was established in 2004 and coordinates genotyping activities and ongoing genome-wide association studies (GWAS) [9]. Recent association findings for smokingrelated diseases implicate genetically derived individual differences [10] [11] [12] [13] [14]. "

    Full-text · Dataset · Oct 2013
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    • "The International Lung Cancer Consortium was established in 2004 and coordinates genotyping activities and ongoing genome-wide association studies (GWAS) [9]. Recent association findings for smokingrelated diseases implicate genetically derived individual differences [10] [11] [12] [13] [14]. "
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    • "Initial genome-wide associations in lung cancer robustly implicated SNPs (Table 1) spanning the chromosome 15q25 region encoding the gene cluster of nicotinic receptors, CHRNA3/A5/B4[9-12]. Subsequent multi-investigator consortia analyses confirmed the association of SNPs spanning this region with heavy smoking, nicotine dependence, craving and related endophenotypes [11,13,14]. Saccone et al. [13] conducted a meta-analysis across 34 datasets of European-ancestry participants (Table 1), including a diverse group of 38,617 smokers, and demonstrated that rs16969968, a nonsynonymous coding polymorphism of the CHRNA5 gene, correlated highly significantly with smoking behavior (odds ratio = 1.33, "
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