Combined Whole Methylome and Genomewide Association Study Implicates CNTN4 in Alcohol Use. (4th July 2015)

• Record Type: Journal Article
• Authors: Clark, Shaunna L.; Aberg, Karolina A.; Nerella, Srilaxmi; Kumar, Gaurav; McClay, Joseph L.; Chen, Wenan; Xie, Linying Y.; Harada, Aki; Shabalin, Andrey A.; Gao, Guimin; Bergen, Sarah E.; Hultman, Christina M.; Magnusson, Patrik K. E.; Sullivan, Patrick F.; van den Oord, Edwin J. C. G.
• Is Part Of: Alcoholism. Volume 39:Number 8(2015:Aug.)
• Page Start: 1396
• Page End: 1405
• Publication Date: 2015-07-04
• Subjects: Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.12790
• Languages: English
• ISSNs: 0145-6008

Abstract

<abstract abstract-type="main" id="acer12790-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="acer12790-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="acer12790-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="acer12790-sec-0003" sec-type="section"> <title>Results</title> <p>When combining the MWAS and GWAS data, our top finding was a region in an intron of <italic>CNTN4</italic> (<italic>p </italic>= 2.55 × 10<sup>−8</sup>), 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 (<italic>p </italic>= 0.021). Rs1382874 and rs1382875 were genotyped and found to be associated in the same direction as the GWAS (<italic>p </italic>= 0.008 and <italic>p </italic>= 0.009). After integrating the MWAS and GWAS findings from the replication sample, we replicated our combined analysis finding (<italic>p </italic>= 0.0017) in <italic>CNTN4</italic>.</p> </sec> <sec id="acer12790-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Through combining methylation and SNP data, we have identified <italic>CNTN4</italic> as a risk factor for regular alcohol use.</p> </sec> </abstract>