SU1 - EXPLORING GENETIC VARIATION THAT INFLUENCES BRAIN METHYLATION IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

Abstract

Background Allele-Specific Methylation (ASM) is a common epigenetic mechanism that involves SNPs correlating with differential levels of methylation at CpG sites. Epigenetic changes play a crucial role in driving lasting changes in gene expression in several tissues, including the brain. As alteration of DNA methylation levels has recently been linked to ADHD symptoms, our aim is to explore the contribution of ASM to ADHD through a case-control association study using different GWAS datasets. Methods We performed a primary SNP selection based on two previous studies that identified ASM variants in different brain regions of post-mortem human samples. Subsequently, from those variants we selected a total of 3,896 SNPs following these criteria: associations in cis between the SNP and methylation at a CpG site, correlation of methylation levels with gene expression (R2) ≥ 0.2, tagSNPs for each CpG site (LD; r2≥0.85). These candidates were inspected in summary statistics data from the first GWAS meta-analysis of adult and childhood ADHD, performed by iPSYCH and the Psychiatric Genomics Consortium (PGC) in 20,183 cases and 35,191 controls. We applied False Discovery Rate (FDR) correction for multiple testing (5% FDR, corrected P≤ 6.78e-05) to determine the top hits. These signals were followed-up to retrieve (i) SNPs located within the same CpG site and thereafter (ii) SNPs in high linkage disequilibrium with the associated SNPs (using the same FDR threshold). Impact of the variants on gene expression levels were further explored in the GTEx database. Results The case-control association study identified eight tagSNPs surviving FDR, which correlate with differential methylation of six CpG sites. Top hits were followed-up to retrieve other SNPs that correlate with methylation of the same CpG sites, making a total of 39 candidate SNPs. The six CpG sites are located in the promoter regions of five genes, not previously related to ADHD. Notably, the risk SNPs associated with three of the genes are eQTLs for those genes in various brain tissues, including the cerebellar hemisphere and the cerebellum. Discussion We have directed existing knowledge of ASM to evaluate its possible contribution to ADHD both at genetic and epigenetic levels. We followed a systematic approach by employing cis-acting ASM variants to pinpoint candidate genes for ADHD. Interestingly, several of the identified variants are eQTLs for genes that are expressed in brain. Our aim is now to further investigate the role of these genes in the development of the ADHD phenotype.