Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

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Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

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Title: Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease
Author: Hutchinson, John N.; Raj, Towfique; Fagerness, Jes; Stahl, Eli; Viloria, Fernando T.; Gimelbrant, Alexander; Seddon, Johanna; Daly, Mark; Chess, Andrew; Plenge, Robert

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Citation: Hutchinson, 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.
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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.
Published Version: doi:10.1371/journal.pone.0098464
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049588/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406549
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