Drug addiction is a neuropsychiatric disorder where long-lasting changes in gene expression within particular regions of the brain play an important role. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving stable changes in gene expression in several tissues, including the brain. Allele-specific methylation (ASM) is a common epigenetic mechanism consisting on SNPs that correlate with differential levels of methylation at CpG sites. The aim of our study is to assess the possible contribution of ASM in different brain regions to drug dependence susceptibility.
We performed a SNP selection based on two previous studies that reported thousands of ASM SNPs in different brain regions of post-mortem human samples. By combining both studies, we obtained a total of 43,132 SNPs CpG pairs that include 33,944 SNPs and 5,036 CpG islands. From those, we obtained a sub-list of 184 SNPs using the following selection criteria: cis associations between SNPs and CpG sites, correlation (R2) of DNA methylation with gene expression ≥0.5 and selection of only one SNP per CpG site, the one showing the best correlation (R2). Subsequently, we evaluated the possible contribution of these SNPs to drug dependence predisposition through a case-control association study in a sample of 577 drug-dependent patients and 655 sex-matched controls from Spain, and then we followed-up the significant associations in an independent sample of 1,192 cases and 1,256 sex-matched controls.
In the discovery sample, we obtained five associations (p<0.05) under the additive model after correcting by age. One of them was replicated in the follow-up sample.
To conclude, we detected a potential association between drug dependence and a SNP that correlates with differential levels of methylation at one CpG site. Both the SNP and the CpG site are located in the first intron of a gene encoding an integral protein of the spliceosome. Further research is needed to understand its potential role in the susceptibility to drug dependence.
Title: M114 – EXPLORING ALLELE SPECIFIC METHYLATION (ASM) IN DRUG DEPENDENCE SUSCEPTIBILITY
Authors: Laura Pineda-Cirera, Judit Cabana-Domínguez, Carlos Roncero, Laia Rodriguez-Cintas, Lara Grau-Lópe, R. Felipe Palma-Álvarez, Constanza Daigre, Josep Antoni Ramos-Quiroga, Marta Ribases, Miguel Casas, Bru Cormand, Noèlia Fernàndez-Castillo