DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is thus a potential candidate for explaining the many identified SNP associations with diseases and complex traits that are not found in coding regions. We identified and replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n=614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in the subtelomeric 1Mbp of the genome and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5' UTR regions. No association was observed between either the SNPs or DNA methylation sites of trans mQTL and telomere length. LD Score regression was used to partition the heritability for a number of complex traits and diseases into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1x10^-10), ulcerative colitis (p = 2x10^-5), Crohn's disease (p = 6x10^-8) and coronary artery disease (p = 5.5x10^-6) when compared to a random sample of SNPs with matched minor allele frequency. This enrichment is explained by the genomic location of the mQTL SNPs, which are biased towards genic regions of the genome due to the combination of the vast majority being located in cis to the DNA methylation probes and the probes on the array being over-representing genic regions.

Identification of 55,000 Replicated DNA Methylation QTL