Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis

• Published in: Nature biotechnology Vol. 31; no. 2; pp. 142 - 147
• Main Authors: Liu, Yun, Aryee, Martin J, Padyukov, Leonid, Fallin, M Daniele, Hesselberg, Espen, Runarsson, Arni, Reinius, Lovisa, Acevedo, Nathalie, Taub, Margaret, Ronninger, Marcus, Shchetynsky, Klementy, Scheynius, Annika, Kere, Juha, Alfredsson, Lars, Klareskog, Lars, Ekström, Tomas J, Feinberg, Andrew P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2013; Nature Publishing Group
• Subjects: 631/208/176/1988; 631/208/205/2138; 692/699/1670/498; Agriculture; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Blood; Case-Control Studies; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - genetics; Epigenetic inheritance; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Genomes; Health aspects; Health risk assessment; Heterogeneity; Humans; Life Sciences; Major Histocompatibility Complex - genetics; Medicin och hälsovetenskap; Methylation; Physiological aspects; Polymorphism, Single Nucleotide; Rheumatoid arthritis; Risk Factors; United States; Sweden
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/nbt.2487

Liu et al. use mediation analysis to find changes in DNA methylation that mediate the genetic risk for rheumatoid arthritis. Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody–associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG ( P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.