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

paper Cited Public

Authors: Clark, Shaunna L; McClay, Joseph L; Adkins, Daniel E; Kumar, Gaurav; Aberg, Karolina A; Nerella, Srilaxmi; Xie, Linying; Collins, Ann L; Crowley, James J; Quackenbush, Corey R; Hilliard, Christopher E; Shabalin, Andrey A; Vrieze, Scott I; Peterson, Roseann E; Copeland, William E; Silberg, Judy L; McGue, Matt; Maes, Hermine; Iacono, William G; Sullivan, Patrick F; Costello, Elizabeth J; van den Oord, Edwin J
Year: 2017
Journal: Alcoholism, clinical and experimental research
PMID: 28196272
DOI: 10.1111/acer.13352
PMCID: PMC5378639

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 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10 ; 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.

#	Section	Preview
20	RESULTS — Individual Variants	Examining the top ten variants (Table S3) confirms that none of the common variants were significant…
21	RESULTS — Sets of Variants	The QQ-plot, Figure 2, shows evidence for association as indicated by the points above the…
22	RESULTS — Sets of Variants	Our results confirm the finding from previous studies that the results from SKAT can be biased.…
23	DISCUSSION	We tested variants in 71 candidate loci plausibly associated with AD. Results showed that no single…
24	DISCUSSION	Six of the top variant sets were located in alcohol or aldehyde dehydrogenase genes. These genes…
25	DISCUSSION	Three of the top variant sets involved the dopamine transporter gene, SLC6A3, also known as DAT1,…
26	DISCUSSION	Only two studies have examined the exons of the loci considered here with the goal of identifying…
27	DISCUSSION	Our findings must be interpreted in the context of the potential limitations. One limitation is that…
28	DISCUSSION	In conclusion, we did not find a single, common variant that was significantly associated with AD in…

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

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