Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans

Chenhao Gao, Carmen Amador, Rosie Walker, Archie Campbell, Rebecca Madden, Mark James Adams, Xiaomeng Bai, Ying Liu, Miaoxin Li, Caroline Hayward, David John Porteous, Xueyi Shen, Kathryn Louise Evans, Chris S Haley, Andrew M McIntosh, Pau Navarro, Yanni Zeng

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

BACKGROUND: The variation in the rate at which humans age may be rooted in early events acting through the genomic regions that are influenced by such events and subsequently are related to health phenotypes in later life. The parent-of-origin-effect (POE)-regulated methylome includes regions enriched for genetically controlled imprinting effects (the typical type of POE) and regions influenced by environmental effects associated with parents (the atypical POE). This part of the methylome is heavily influenced by early events, making it a potential route connecting early exposures, the epigenome, and aging. We aim to test the association of POE-CpGs with early and later exposures and subsequently with health-related phenotypes and adult aging.

RESULTS: We perform a phenome-wide association analysis for the POE-influenced methylome using GS:SFHS (N discovery  = 5087, N replication  = 4450). We identify and replicate 92 POE-CpG-phenotype associations. Most of the associations are contributed by the POE-CpGs belonging to the atypical class where the most strongly enriched associations are with aging (DNAmTL acceleration), intelligence, and parental (maternal) smoking exposure phenotypes. A proportion of the atypical POE-CpGs form co-methylation networks (modules) which are associated with these phenotypes, with one of the aging-associated modules displaying increased within-module methylation connectivity with age. The atypical POE-CpGs also display high levels of methylation heterogeneity, fast information loss with age, and a strong correlation with CpGs contained within epigenetic clocks.

CONCLUSIONS: These results identify the association between the atypical POE-influenced methylome and aging and provide new evidence for the "early development of origin" hypothesis for aging in humans.

Original languageEnglish
Article number117
Pages (from-to)1-28
Number of pages28
JournalGenome Biology
Early online date15 May 2023
Publication statusPublished - 15 May 2023

Keywords / Materials (for Non-textual outputs)

  • Atypical parent-of-origin efect
  • Aging
  • DNAmTL acceleration
  • Maternal smoking exposure
  • Lifestyle
  • Intelligence


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