Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes

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Abstract
Altered DNA methylation in addiction-related genes may modify the susceptibility to alcohol or drug dependence (AD or ND). We profiled peripheral blood DNA methylation levels of 384 CpGs in promoter regions of 82 addiction-related genes in 256 African Americans (AAs) (117 cases with AD-ND codependence and 139 controls) and 196 European Americans (103 cases with AD-ND codependence and 93 controls) using Illumina’s GoldenGate DNA methylation array assays. AD-ND codependence-associated DNA methylation changes were analyzed using linear mixed-effects models with consideration of batch effects and covariates age, sex, and ancestry proportions. Seventy CpGs (in 41 genes) showed nominally significant associations (P < 0.05) with AD-ND codependence in both AAs and EAs. One CpG (HTR2Bcg27531267) was hypomethylated in AA cases (P = 7.2 × 10−5), while 17 CpGs in 16 genes (includingHTR2Bcg27531267) were hypermethylated in EA cases (5.6 × 10−9 ≤ P ≤ 9.5 × 10−5). Nevertheless, 13 single nucleotide polymorphisms (SNPs) nearbyHTR2Bcg27531267 and the interaction of these SNPs and cg27531267 did not show significant effects on AD-ND codependence in either AAs or EAs. Our study demonstrated that DNA methylation changes in addiction-related genes could be potential biomarkers for AD-ND co-dependence. Future studies need to explore whether DNA methylation alterations influence the risk of AD-ND codependence or the other way around.

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