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

Yun Liu, Martin J. Aryee, Leonid Padyukov, Daniele Daniele Fallin, Espen Hesselberg, Arni Runarsson, Lovisa Reinius, Nathalie Acevedo, Margaret Anne Taub, Marcus Ronninger, Klementy Shchetynsky, Annika Scheynius, Juha Kere, Lars Alfredsson, Lars Klareskog, Tomas J. Ekström, Andrew P Feinberg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)142-147
Number of pages6
JournalNature Biotechnology
Volume31
Issue number2
DOIs
StatePublished - Feb 2013

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DNA Methylation
Rheumatoid Arthritis
Methylation
Association reactions
Epigenomics
Major Histocompatibility Complex
Antibodies
Monocytes
DNA
Blood
Genes
Genotype
Genome
Proteins

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Biotechnology
  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering

Cite this

Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. / Liu, Yun; Aryee, Martin J.; Padyukov, Leonid; Fallin, Daniele Daniele; Hesselberg, Espen; Runarsson, Arni; Reinius, Lovisa; Acevedo, Nathalie; Taub, Margaret Anne; Ronninger, Marcus; Shchetynsky, Klementy; Scheynius, Annika; Kere, Juha; Alfredsson, Lars; Klareskog, Lars; Ekström, Tomas J.; Feinberg, Andrew P.

In: Nature Biotechnology, Vol. 31, No. 2, 02.2013, p. 142-147.

Research output: Contribution to journalArticle

Liu, Y, Aryee, MJ, Padyukov, L, Fallin, DD, Hesselberg, E, Runarsson, A, Reinius, L, Acevedo, N, Taub, MA, Ronninger, M, Shchetynsky, K, Scheynius, A, Kere, J, Alfredsson, L, Klareskog, L, Ekström, TJ & Feinberg, AP 2013, 'Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis', Nature Biotechnology, vol. 31, no. 2, pp. 142-147. https://doi.org/10.1038/nbt.2487
Liu, Yun ; Aryee, Martin J. ; Padyukov, Leonid ; Fallin, Daniele Daniele ; Hesselberg, Espen ; Runarsson, Arni ; Reinius, Lovisa ; Acevedo, Nathalie ; Taub, Margaret Anne ; Ronninger, Marcus ; Shchetynsky, Klementy ; Scheynius, Annika ; Kere, Juha ; Alfredsson, Lars ; Klareskog, Lars ; Ekström, Tomas J. ; Feinberg, Andrew P. / Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. In: Nature Biotechnology. 2013 ; Vol. 31, No. 2. pp. 142-147.
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