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

Department of Statistics, University of Oxford, Oxford, UK.
Nature Genetics (Impact Factor: 29.65). 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]. "
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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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    ABSTRACT: Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The cur-rent study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor al-lele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 -1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 -3.06, p = 0.0022, and 1.07 -2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results sup-port the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.
    Journal of Cancer Therapy 08/2013; 4(8):29-35. DOI:10.4236/jct.2013.48A005
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    • "18 Shared authorships. Received 19 November 2012; revised 23 April 2013; accepted 25 April 2013; accepted article preview online 21 May 2013 the CHRNA5–CHRNA3–CHRNB4 cluster of cholinergic nicotinic receptor subunit genes in both smoking and ND (Saccone et al, 2007; Bierut et al, 2008; Thorgeirsson et al, 2008, 2010; The Tobacco and Genetics Consortium (TAG) (2010); Liu et al, 2010). A recent meta-analysis of 34 data sets of European descent smokers showed that several statistically independent loci in this region are associated with smoking behavior, including signals represented by rs578776 and rs16969968 (Saccone et al, 2010). "
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    ABSTRACT: Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex and personality traits related to addiction. In both samples carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal anterior cingulate cortex but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared to AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the anterior cingulate cortex to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.Neuropsychopharmacology accepted article preview online, 21 May 2013; doi:10.1038/npp.2013.131.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2013; 38(11). DOI:10.1038/npp.2013.131 · 7.83 Impact Factor
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