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bioRxiv · 10.1101/2024.05.17.594606

MSA: scalable DNA methylation screening BeadChip for high-throughput trait association studies

Goldberg, D. C.·Cloud, C.·Lee, S. M.·Barnes, B.·Gruber, S.·Kim, E.·Pottekat, A.·Westphal, M.·McAuliffe, L.·Majournie, E.·KalayilManian, M.·Zhu, Q.·Tran, C.·Hansen, M.·Parker, J. B.·Kohli, R. M.·Porecha, R.·Renke, N.·Zhou, W.
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Abstract

Epigenome-wide association studies (EWAS) are transforming our understanding of the interplay between epigenetics and complex human traits and phenotypes. We introduce the Methylation Screening Array (MSA), a new iteration of the Infinium technology for scalable and quantitative screening of trait associations of nuanced ternary-code cytosine modifications in larger, more inclusive, and stratified human populations. MSA integrates EWAS, single-cell, and cell-type-resolved methylome profiles, covering diverse human traits and diseases. Our first MSA applications yield multiple biological insights: we revealed a previously unappreciated role of 5-hydroxymethylcytosine (5hmC) in trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5-methylcytosines (5mCs) in defining tissues and cells epigenetic identities. In-depth analyses highlighted the cell type context of EWAS and GWAS hits. Using this platform, we conducted a comprehensive human 5hmC aging EWAS, discovering tissue-invariant and tissue-specific aging dynamics, including distinct tissue-specific rates of mitotic hyper- and hypomethylation rates. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.

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Goldberg, D. C., Cloud, C., Lee, S. M., Barnes, B., Gruber, S., Kim, E., Pottekat, A., Westphal, M., McAuliffe, L., Majournie, E., KalayilManian, M., Zhu, Q., Tran, C., Hansen, M., Parker, J. B., Kohli, R. M., Porecha, R., Renke, N., Zhou, W.. 2024-05-21. MSA: scalable DNA methylation screening BeadChip for high-throughput trait association studies. https://doi.org/10.1101/2024.05.17.594606

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