Abstract:
: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.
journal_name
Nat Biotechnoljournal_title
Nature biotechnologyauthors
Liu Y,Aryee MJ,Padyukov L,Fallin MD,Hesselberg E,Runarsson A,Reinius L,Acevedo N,Taub M,Ronninger M,Shchetynsky K,Scheynius A,Kere J,Alfredsson L,Klareskog L,Ekström TJ,Feinberg APdoi
10.1038/nbt.2487subject
Has Abstractpub_date
2013-02-01 00:00:00pages
142-7issue
2eissn
1087-0156issn
1546-1696pii
nbt.2487journal_volume
31pub_type
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