@article{ab38b434168c4cb48f151136f764b538,
title = "Phenome-wide analyses identify an association between the parent-of-origin effects dependent methylome and the rate of aging in humans",
abstract = "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.",
keywords = "Atypical parent-of-origin efect, Aging, DNAmTL acceleration, Maternal smoking exposure, Lifestyle, Intelligence",
author = "Chenhao Gao and Carmen Amador and Rosie Walker and Archie Campbell and Rebecca Madden and Adams, {Mark James} and Xiaomeng Bai and Ying Liu and Miaoxin Li and Caroline Hayward and Porteous, {David John} and Xueyi Shen and Evans, {Kathryn Louise} and Haley, {Chris S} and McIntosh, {Andrew M} and Pau Navarro and Yanni Zeng",
note = "Funding Information: We want to acknowledge support from Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility (Edinburgh, Scotland) for genotyping of the GS samples. We are grateful to all the families who took part, the general practitioners, and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses. Funding Information: YZ is supported by National Key Research & Development Program of China (STI2030-Major Projects, No. 2021ZD0202000) and the General Program of National Natural Science Foundation of China (81971270). AMM is supported by NIH award R01MH124873 and by UKRI award MR/W014386/1. CA, CH, CSH, and PN want to acknowledge support from the MRC Human Genetics Unit program grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10), and grant MC_PC_U127592696. Generation Scotland has received core funding from the Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 and the Scottish Funding Council HR03006. Genotyping of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the UK MRC and the Wellcome Trust (Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). The DNA methylation (DNAm) profiling and analysis was supported by Wellcome Investigator Award 220857/Z/20/Z and Grant 104036/Z/14/Z (PI: AM McIntosh) and through funding from NARSAD (Ref: 27404; awardee: Dr DM Howard) and the Royal College of Physicians of Edinburgh (Sim Fellowship; Awardee: Dr HC Whalley). Funding Information: We want to acknowledge support from Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility (Edinburgh, Scotland) for genotyping of the GS samples. We are grateful to all the families who took part, the general practitioners, and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses. The review history is available as Additional File 3. Veronique van den Berghe was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = may,
day = "15",
doi = "10.1186/s13059-023-02953-6",
language = "English",
volume = "24",
pages = "1--28",
journal = "Genome Biology",
issn = "1465-6906",
publisher = "BioMed Central",
}