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

Publication ,  Journal Article
Clark, SL; McClay, JL; Adkins, DE; Aberg, KA; Kumar, G; Nerella, S; Xie, L; Collins, AL; Crowley, JJ; Quakenbush, CR; Hillard, CE; Gao, G ...
Published in: Nicotine Tob Res
May 2016

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up.

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Published In

Nicotine Tob Res

DOI

EISSN

1469-994X

Publication Date

May 2016

Volume

18

Issue

5

Start / End Page

626 / 631

Location

England

Related Subject Headings

  • Tobacco Use Disorder
  • Smoking
  • Public Health
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease
  • Gene Frequency
 

Citation

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Clark, S. L., McClay, J. L., Adkins, D. E., Aberg, K. A., Kumar, G., Nerella, S., … van den Oord, E. J. (2016). Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses. Nicotine Tob Res, 18(5), 626–631. https://doi.org/10.1093/ntr/ntv166
Clark, Shaunna L., Joseph L. McClay, Daniel E. Adkins, Karolina A. Aberg, Gaurav Kumar, Sri Nerella, Linying Xie, et al. “Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.Nicotine Tob Res 18, no. 5 (May 2016): 626–31. https://doi.org/10.1093/ntr/ntv166.
Clark SL, McClay JL, Adkins DE, Aberg KA, Kumar G, Nerella S, et al. Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses. Nicotine Tob Res. 2016 May;18(5):626–31.
Clark, Shaunna L., et al. “Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.Nicotine Tob Res, vol. 18, no. 5, May 2016, pp. 626–31. Pubmed, doi:10.1093/ntr/ntv166.
Clark SL, McClay JL, Adkins DE, Aberg KA, Kumar G, Nerella S, Xie L, Collins AL, Crowley JJ, Quakenbush CR, Hillard CE, Gao G, Shabalin AA, Peterson RE, Copeland WE, Silberg JL, Maes H, Sullivan PF, Costello EJ, van den Oord EJ. Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses. Nicotine Tob Res. 2016 May;18(5):626–631.
Journal cover image

Published In

Nicotine Tob Res

DOI

EISSN

1469-994X

Publication Date

May 2016

Volume

18

Issue

5

Start / End Page

626 / 631

Location

England

Related Subject Headings

  • Tobacco Use Disorder
  • Smoking
  • Public Health
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease
  • Gene Frequency