Exploring allele specific methylation in drug dependence susceptibility

Drug dependence is a neuropsychiatric condition that involves genetic, epigenetic and environmental factors. Allele-specific methylation (ASM) is a common and stable epigenetic mechanism that involves genetic variants correlating with differential levels of methylation at CpG sites. We selected 182 single-nucleotide polymorphisms (SNPs) described to influence cis ASM in human brain regions to evaluate their possible contribution to drug dependence susceptibility. We performed a case-control association study in a discovery sample of 578 drugdependent patients (including 428 cocaine-dependent subjects) and 656 controls from Spain, and then, we followed-up the significant associations in an independent sample of 1119 cases (including 589 cocainedependent subjects) and 1092 controls. In the discovery sample, we identified five nominal associations, one of them replicated in the follow-up sample (rs6020251). The pooled analysis revealed an association between drug dependence and rs6020251 but also rs11585570, both overcoming the Bonferroni correction for multiple testing. We performed the same analysis considering only cocaine-dependent patients and obtained similar results. The rs6020251 variant correlates with differential methylation levels of cg17974185 and lies in the first intron of the CTNNBL1 gene, in a genomic region with multiple histone marks related to enhancer and promoter regions in brain. Rs11585570 is an eQTL in brain and blood for the SCP2 and ECHDC2 genes and correlates with differential methylation of cg27535305 and cg13461509, located in the promoter regions of both genes. To conclude, using an approach that combines genetic and epigenetic data, we highlighted the CTNNBL1, SCP2 and ECHDC2 genes as potential contributors to drug dependence susceptibility.