Methylome-wide association of DNA methylation for alcohol consumption in a community population

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Xu K, Zhang X, Hu Y, Sinha R
The purpose of this study is to profile CpG methylation in whole genome among social alcohol drinkers and to examine a methylome-wide association for alcohol consumption. A follow-up experiment was also conducted to assess alcohol consumption in a laboratory setting that assessed alcohol motivation using the alcohol taste task after stress, alcohol cue or neutral cue exposure. Four hundred forty individuals were recruited from a community to conduct a methylome-wide association study (MWAS) for alcohol consumption. We used self-reported average and maximum weekly quantity-frequency measure to assess alcohol use (Usual-quantity-Cahalan). DNA methylation in blood was measured using Illumina HumanMethylation Beadchip 450K. After data filtering and quality control, 437,787,512 probes were used for MWAS of alcohol consumption. Generalized linear model was performed, adjusting for age, gender, race, smoking status, and 6 cell types. Gene enrichment analysis was performed using Molecular Signatures Database 3.0 (MSigDB). Significant p was set at false discover rate (FDR)=0.05. The follow-up experiment in an independent sample of socially drinking subjects (N=63) was analyzed to replicate the candidate probes located on CpG island (CGI). Fifty-one probes were reached MWAS significant (p< 0.05 FDR adjusted), including 7 probes at CGIs. Forty-six out of 51 probes were negatively associated with alcohol consumption. The significant probes were located on 40 genes including genes involving calcium channel function, CNCNA1C (cg11830694 FDR=0.0007) and TRPM1 (cg05858304, FDR=0.0001). We found the calcium ion binding pathway was 1.96 fold enriched in the group of binge/heavy alcohol consumption (FDR=7.3 x 10-7). Our results suggest that alcohol consumption significantly modifies DNA methylation level in peripheral blood cells. We observed overall hypomethylation for greater alcohol consumption among social drinkers. The findings also further suggest the important role of calcium channel function in alcohol consumption.