title: Allele-specific methylation occurs at genetic variants associated with complex disease.
abstract: We 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.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: John N
authors.initials: JN
authors.lastname: Hutchinson
authors.affiliation: Broad Institute, Cambridge, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jes
authors.initials: J
authors.lastname: Fagerness
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.affiliation: Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Fernando T
authors.initials: FT
authors.lastname: Viloria
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gimelbrant
authors.affiliation: Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Johanna
authors.initials: J
authors.lastname: Seddon
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Daly
authors.affiliation: Department of Developmental and Regenerative Biology, Fishberg Department of Neuroscience, Department of Genetics and Genomic Sciences, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chess
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Plenge
mesh_terms: D000483:Alleles; D019175:DNA Methylation; D004194:Disease / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype