Hutchinson, JohnRaj, TowfiqueFagerness, JesStahl, EliViloria, Fernando T.Gimelbrant, AlexanderSeddon, JohannaDaly, MarkChess, AndrewPlenge, Robert2014-07-072014Hutchinson, John N., Towfique Raj, Jes Fagerness, Eli Stahl, Fernando T. Viloria, Alexander Gimelbrant, Johanna Seddon, Mark Daly, Andrew Chess, and Robert Plenge. 2014. “Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease.” PLoS ONE 9 (6): e98464. doi:10.1371/journal.pone.0098464. http://dx.doi.org/10.1371/journal.pone.0098464.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406549We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results.en-USBiology and life sciencesBiochemistryDNADNA modificationComputational BiologyGenome AnalysisGenome-Wide Association StudiesGeneticsGene ExpressionGene RegulationGenomicsFunctional GenomicsHuman GeneticsGenetic Association StudiesEpigeneticsGenetics of DiseaseImmunologyClinical ImmunologyAutoimmune DiseasesGenetics of the Immune SystemMedicine and Health SciencesJournal Article2014-07-0710.1371/journal.pone.0098464