Deep sequencing of three loci Implicated in large-scale genome-wide association study smoking meta-analyses

Shaunna L. Clark*, Joseph L. McClay, Daniel E. Adkins, Karolina A. Aberg, Gaurav Kumar, Sri Nerella, Linying Xie, Ann L. Collins, James J. Crowley, Corey R. Quakenbush, Christopher E. Hillard, Guimin Gao, Andrey A. Shabalin, Roseann E. Peterson, William E. Copeland, Judy L. Silberg, Hermine Maes, Patrick F. Sullivan, Elizabeth J. Costello, Edwin J. van den Oord

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)626-631
Number of pages6
JournalNicotine and Tobacco Research
Volume18
Issue number5
DOIs
Publication statusPublished - 1 May 2016
Externally publishedYes

Keywords

  • smoking
  • follow-up
  • gene frequency
  • genome
  • cyp2a6 gene
  • genome-wide
  • association study
  • massively-parallel genome sequencing

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