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Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.

Publication ,  Journal Article
Clark, SL; McClay, JL; Adkins, DE; Kumar, G; Aberg, KA; Nerella, S; Xie, L; Collins, AL; Crowley, JJ; Quackenbush, CR; Hilliard, CE; McGue, M ...
Published in: Alcohol Clin Exp Res
April 2017

BACKGROUND: Previous genomewide association studies (GWASs) have identified a number of putative risk loci for alcohol dependence (AD). However, only a few loci have replicated and these replicated variants only explain a small proportion of AD risk. Using an innovative approach, the goal of this study was to generate hypotheses about potentially causal variants for AD that can be explored further through functional studies. METHODS: We employed targeted capture of 71 candidate loci and flanking regions followed by next-generation deep sequencing (mean coverage 78X) in 806 European Americans. Regions included in our targeted capture library were genes identified through published GWAS of alcohol, all human alcohol and aldehyde dehydrogenases, reward system genes including dopaminergic and opioid receptors, prioritized candidate genes based on previous associations, and genes involved in the absorption, distribution, metabolism, and excretion of drugs. We performed single-locus tests to determine if any single variant was associated with AD symptom count. Sets of variants that overlapped with biologically meaningful annotations were tested for association in aggregate. RESULTS: No single, common variant was significantly associated with AD in our study. We did, however, find evidence for association with several variant sets. Two variant sets were significant at the q-value <0.10 level: a genic enhancer for ADHFE1 (p = 1.47 × 10-5 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10-5 ; q = 0.035), an adenosine receptor that belongs to a G-protein-coupled receptor gene family. CONCLUSIONS: To our knowledge, this is the first sequencing study of AD to examine variants in entire genes, including flanking and regulatory regions. We found that in addition to protein coding variant sets, regulatory variant sets may play a role in AD. From these findings, we have generated initial functional hypotheses about how these sets may influence AD.

Duke Scholars

Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

April 2017

Volume

41

Issue

4

Start / End Page

711 / 718

Location

England

Related Subject Headings

  • Young Adult
  • Substance Abuse
  • Sequence Analysis, DNA
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genetic Variation
  • Genetic Association Studies
  • Female
  • Alcoholism
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Clark, S. L., McClay, J. L., Adkins, D. E., Kumar, G., Aberg, K. A., Nerella, S., … van den Oord, E. J. (2017). Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence. Alcohol Clin Exp Res, 41(4), 711–718. https://doi.org/10.1111/acer.13352
Clark, Shaunna L., Joseph L. McClay, Daniel E. Adkins, Gaurav Kumar, Karolina A. Aberg, Srilaxmi Nerella, Linying Xie, et al. “Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.Alcohol Clin Exp Res 41, no. 4 (April 2017): 711–18. https://doi.org/10.1111/acer.13352.
Clark SL, McClay JL, Adkins DE, Kumar G, Aberg KA, Nerella S, et al. Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence. Alcohol Clin Exp Res. 2017 Apr;41(4):711–8.
Clark, Shaunna L., et al. “Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.Alcohol Clin Exp Res, vol. 41, no. 4, Apr. 2017, pp. 711–18. Pubmed, doi:10.1111/acer.13352.
Clark SL, McClay JL, Adkins DE, Kumar G, Aberg KA, Nerella S, Xie L, Collins AL, Crowley JJ, Quackenbush CR, Hilliard CE, Shabalin AA, Vrieze SI, Peterson RE, Copeland WE, Silberg JL, McGue M, Maes H, Iacono WG, Sullivan PF, Costello EJ, van den Oord EJ. Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence. Alcohol Clin Exp Res. 2017 Apr;41(4):711–718.
Journal cover image

Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

April 2017

Volume

41

Issue

4

Start / End Page

711 / 718

Location

England

Related Subject Headings

  • Young Adult
  • Substance Abuse
  • Sequence Analysis, DNA
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genetic Variation
  • Genetic Association Studies
  • Female
  • Alcoholism