Dataset Information

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

ABSTRACT: Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations.We employed targeted capture of the CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6, and EGLN2\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations.In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2.We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up.

SUBMITTER: Clark SL

PROVIDER: S-EPMC5942610 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

Clark Shaunna L SL McClay Joseph L JL Adkins Daniel E DE Aberg Karolina A KA Kumar Gaurav G Nerella Sri S Xie Linying L Collins Ann L AL Crowley James J JJ Quakenbush Corey R CR Hillard Christopher E CE Gao Guimin G Shabalin Andrey A AA Peterson Roseann E RE Copeland William E WE Silberg Judy L JL Maes Hermine H Sullivan Patrick F PF Costello Elizabeth J EJ van den Oord Edwin J EJ

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 20150817 5

<h4>Introduction</h4>Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the repor ...[more]

PMID: 26283763

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Dataset Information

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

Publications

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

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