Combined Whole Methylome and Genomewide Association Study Implicates CNTN4 in Alcohol Use.

Alcohol Clin Exp Res
Authors
Keywords
Abstract

BACKGROUND: Methylome-wide association (MWAS) studies present a new way to advance the search for biological correlates for alcohol use. A challenge with methylation studies of alcohol involves the causal direction of significant methylation-alcohol associations. One way to address this issue is to combine MWAS data with genomewide association study (GWAS) data.

METHODS: Here, we combined MWAS and GWAS results for alcohol use from 619 individuals. Our MWAS data were generated by next-generation sequencing of the methylated genomic DNA fraction, producing over 60 million reads per subject to interrogate methylation levels at ~27 million autosomal CpG sites in the human genome. Our GWAS included 5,571,786 single nucleotide polymorphisms (SNPs) imputed with 1000 Genomes.

RESULTS: When combining the MWAS and GWAS data, our top finding was a region in an intron of CNTN4 (p = 2.55 × 10(-8) ), located between chr3: 2,555,403 and 2,555,524, encompassing SNPs rs1382874 and rs1382875. This finding was then replicated in an independent sample of 730 individuals. We used bisulfite pyrosequencing to measure methylation and found significant association with regular alcohol use in the same direction as the MWAS (p = 0.021). Rs1382874 and rs1382875 were genotyped and found to be associated in the same direction as the GWAS (p = 0.008 and p = 0.009). After integrating the MWAS and GWAS findings from the replication sample, we replicated our combined analysis finding (p = 0.0017) in CNTN4.

CONCLUSIONS: Through combining methylation and SNP data, we have identified CNTN4 as a risk factor for regular alcohol use.

Year of Publication
2015
Journal
Alcohol Clin Exp Res
Volume
39
Issue
8
Pages
1396-405
Date Published
2015 Aug
ISSN
1530-0277
URL
DOI
10.1111/acer.12790
PubMed ID
26146898
PubMed Central ID
PMC4515164
Links
Grant list
RC2MH089996 / MH / NIMH NIH HHS / United States
RC2 MH089996 / MH / NIMH NIH HHS / United States
K01 AA021266 / AA / NIAAA NIH HHS / United States
1R01MH097283 / MH / NIMH NIH HHS / United States
K01AA021266 / AA / NIAAA NIH HHS / United States
R01 MH097283 / MH / NIMH NIH HHS / United States