
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.26.608843
preprint
1
Article
Common DNA sequence variation influences epigenetic aging in African populations
Meeks Gillian L. http://orcid.org/0000-0002-8436-6514

Scelza Brooke http://orcid.org/0000-0001-5875-8875

Asnake Hana M.
Prall Sean http://orcid.org/0000-0001-5719-6460

Patin Etienne http://orcid.org/0000-0002-9911-4459

Froment Alain http://orcid.org/0000-0001-5448-9698

Fagny Maud http://orcid.org/0000-0002-7740-2521

Quintana-Murci Lluis http://orcid.org/0000-0003-2429-6320

Henn Brenna M. http://orcid.org/0000-0003-4998-287X

Gopalan Shyamalika http://orcid.org/0000-0002-2608-8472

26 8 2024
2024.08.26.608843https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.26.608843
nihpp-2024.08.26.608843.pdf
Abstract

Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ‡Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.
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