GIA: Germline-Informed Aging with AlphaGenome Finds Genetically Regulated CpGs
Abstract
Epigenetic clocks estimate age and aging-related phenotypes from DNA methylation at selected CpG sites, but the extent to which these inputs are influenced by germline genetic variation is unclear. Because methylation at many CpGs is genetically regulated, some between-person variation in clock estimates may reflect inherited genetic differences rather than aging-related change alone. Here we developed GIA (Germline-Informed Aging), a framework that maps CpGs selected from 13 published epigenetic clocks to blood methylation quantitative trait loci (meQTLs) and scores associated genetic variants with AlphaGenome. We show that clock CpGs were enriched for blood meQTLs relative to matched unused Illumina 450k probes (62.7% versus 39.6%; OR 2.57), across multiple clock families, suggesting that age-informative methylation sites are heavily influenced by germline genetic variation. Ranking by predicted chromatin effect isolated rs10190186, a cis-acting variant at FHL2 predicted to increase blood chromatin accessibility (ATAC +1.00; DNase +1.64) and FHL2 RNA (+0.30). This locus illustrates how inherited variation may shape methylation features repeatedly used by epigenetic clocks, motivating direct tests of whether such variants shift baseline clock estimates or longitudinal aging trajectories.
Related
- AlphaGenome informed machine learning for pathogenicity prediction of germline mutations
- A genetically regulated SKAP2 switch modulates human T lymphocyte adhesion and migration.
- Analysis of single nucleotide substitution in CYP21A2 gene using Alphagenome
- Scooby-2: fine-tuning AlphaGenome for single-cell genomic track prediction
- Applying AlphaGenome Variant Impact for SNV Prioritization
BibTeX
@misc{lim2026germlineinformed,
title = {{GIA: Germline-Informed Aging with AlphaGenome Finds Genetically Regulated CpGs}},
author = {Sean Lim},
howpublished = {arXiv},
year = {2026},
month = sep,
doi = {10.48550/arxiv.2609.17801},
eprint = {2609.17801},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2609.17801},
note = {CC0},
}
RIS
TY - UNPB
TI - GIA: Germline-Informed Aging with AlphaGenome Finds Genetically Regulated CpGs
AU - Sean Lim
PY - 2026
DA - 2026/09/15
PB - arXiv
DO - 10.48550/arxiv.2609.17801
UR - https://arxiv.org/abs/2609.17801
AB - Epigenetic clocks estimate age and aging-related phenotypes from DNA methylation at selected CpG sites, but the extent to which these inputs are influenced by germline genetic variation is unclear. Because methylation at many CpGs is genetically regulated, some between-person variation in clock estimates may reflect inherited genetic differences rather than aging-related change alone. Here we developed GIA (Germline-Informed Aging), a framework that maps CpGs selected from 13 published epigenetic clocks to blood methylation quantitative trait loci (meQTLs) and scores associated genetic variants with AlphaGenome. We show that clock CpGs were enriched for blood meQTLs relative to matched unused Illumina 450k probes (62.7% versus 39.6%; OR 2.57), across multiple clock families, suggesting that age-informative methylation sites are heavily influenced by germline genetic variation. Ranking by predicted chromatin effect isolated rs10190186, a cis-acting variant at FHL2 predicted to increase blood chromatin accessibility (ATAC +1.00; DNase +1.64) and FHL2 RNA (+0.30). This locus illustrates how inherited variation may shape methylation features repeatedly used by epigenetic clocks, motivating direct tests of whether such variants shift baseline clock estimates or longitudinal aging trajectories.
ER -