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

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 with 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 toward 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.

SUBMITTER: Chundru VK

PROVIDER: S-EPMC10196672 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Chundru V Kartik VK Marioni Riccardo E RE Prendergast James G D JGD Lin Tian T Beveridge Allan J AJ Martin Nicholas G NG Montgomery Grant W GW Hume David A DA Deary Ian J IJ Visscher Peter M PM Wray Naomi R NR McRae Allan F AF

Human molecular genetics 20230501 11

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 with complex traits. Here, we investigate DNAm in healthy ageing populations-the Lothian Birth Cohorts of 1921 and 1936-and identify both transien ...[more]

PMID: 36790133

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

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

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