Rare genetic variants underlie outlying levels of DNA methylation and gene-expression

Chundru, V. K. et al. (2023) Rare genetic variants underlie outlying levels of DNA methylation and gene-expression. Human Molecular Genetics, 32(11), pp. 1912-1921. (doi: 10.1093/hmg/ddad028) (PMID:36790133) (PMCID:PMC10196672)

Abstract

Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared to complex traits. Here, we investigate DNAm in healthy ageing populations—the Lothian Birth Cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic single nucleotide polymorphisms (SNPs) within 1 kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels towards the tails of the population distribution. This study demonstrates the role of rare SNPs in the phenotypic variation of DNAm, and the effect of extreme levels of DNAm on gene expression.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Beveridge, Dr Allan
• Authors: Chundru, V. K., Marioni, R. E., Pendergast, J. G.D., Lin, T., Beveridge, A. J., Martin, N. G., Montgomery, G. W., Hume, D. A., Deary, I. J., Visscher, P. M., Wray, N. R., and McRae, A. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Human Molecular Genetics
• Publisher: Oxford University Press
• ISSN: 0964-6906
• ISSN (Online): 1460-2083
• Published Online: 15 February 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Human Molecular Genetics 32(11):1912-1921
• Publisher Policy: Reproduced under a Creative Commons License