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

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

doi:10.1038/nbt.2487

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

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

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579 Scopus citations

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 language	English (US)
Pages (from-to)	142-147
Number of pages	6
Journal	Nature biotechnology
Volume	31
Issue number	2
DOIs	https://doi.org/10.1038/nbt.2487
State	Published - Feb 2013

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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Liu, Y., Aryee, M. J., Padyukov, L., Fallin, M. D., Hesselberg, E., Runarsson, A., Reinius, L., Acevedo, N., Taub, M., Ronninger, M., Shchetynsky, K., Scheynius, A., Kere, J., Alfredsson, L., Klareskog, L., Ekström, T. J., & Feinberg, A. P. (2013). Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature biotechnology, 31(2), 142-147. https://doi.org/10.1038/nbt.2487

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, 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

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

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.",

author = "Yun Liu and Aryee, {Martin J.} and Leonid Padyukov and Fallin, {M. Daniele} and Espen Hesselberg and Arni Runarsson and Lovisa Reinius and Nathalie Acevedo and Margaret Taub and Marcus Ronninger and Klementy Shchetynsky and Annika Scheynius and Juha Kere and Lars Alfredsson and Lars Klareskog and Ekstr{\"o}m, {Tomas J.} and Feinberg, {Andrew P.}",

note = "Funding Information: We thank M. Rosenblum for helpful discussions on the application of statistical mediation methodology. We thank R.A. Irizarry for his contributions to the concepts in this work, his statistical insights on batch effects and helpful comments. We thank E.A. Houseman for codes used for estimating cell proportions. We also thank the EIRA study group18for contributing invaluable clinical information and biological samples. This work was supported by the US National Institutes of Health Centers of Excellence in Genomic Science, 5P50HG003233 to A.P.F., and by the Swedish Research Council, the Swedish Combine project, the Swedish Strategic Foundations, the AFA Insurance and the European Research Council (ERC).",

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AU - Aryee, Martin J.

AU - Padyukov, Leonid

AU - Fallin, M. Daniele

AU - Hesselberg, Espen

AU - Runarsson, Arni

AU - Reinius, Lovisa

AU - Acevedo, Nathalie

AU - Taub, Margaret

AU - Ronninger, Marcus

AU - Shchetynsky, Klementy

AU - Scheynius, Annika

AU - Kere, Juha

AU - Alfredsson, Lars

AU - Klareskog, Lars

AU - Ekström, Tomas J.

AU - Feinberg, Andrew P.

N1 - Funding Information: We thank M. Rosenblum for helpful discussions on the application of statistical mediation methodology. We thank R.A. Irizarry for his contributions to the concepts in this work, his statistical insights on batch effects and helpful comments. We thank E.A. Houseman for codes used for estimating cell proportions. We also thank the EIRA study group18for contributing invaluable clinical information and biological samples. This work was supported by the US National Institutes of Health Centers of Excellence in Genomic Science, 5P50HG003233 to A.P.F., and by the Swedish Research Council, the Swedish Combine project, the Swedish Strategic Foundations, the AFA Insurance and the European Research Council (ERC).

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N2 - 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.

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

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