发表机构
Wiess School of Natural Sciences, Rice University（莱斯大学韦斯自然科学学院）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
GIA框架结合AlphaGenome，将表观遗传时钟CpG映射至meQTLs，发现时钟位点显著富集遗传调控，并识别出FHL2的rs10190186变异影响染色质可及性，揭示种系变异对衰老时钟的潜在影响。
AI 中文摘要
表观遗传时钟通过选定CpG位点的DNA甲基化来估计年龄和衰老相关表型，但这些输入在多大程度上受种系遗传变异的影响尚不清楚。由于许多CpG位点的甲基化受遗传调控，时钟估计中的部分个体间差异可能反映遗传差异，而非单纯的衰老相关变化。在此，我们开发了GIA（种系知情衰老）框架，该框架将来自13个已发表表观遗传时钟的CpG位点映射至血液甲基化数量性状位点（meQTLs），并使用AlphaGenome对相关遗传变异进行评分。我们发现，与匹配的未使用Illumina 450k探针相比，时钟CpG位点在血液meQTLs中显著富集（62.7%对39.6%；比值比2.57），且这一现象跨多个时钟家族，表明年龄信息性甲基化位点受种系遗传变异强烈影响。按预测染色质效应排序，我们识别出rs10190186，一个位于FHL2的顺式作用变异，预测可增加血液染色质可及性（ATAC +1.00；DNase +1.64）及FHL2 RNA表达（+0.30）。该位点揭示了遗传变异如何塑造表观遗传时钟反复使用的甲基化特征，从而激励直接测试此类变异是否改变基线时钟估计或纵向衰老轨迹。
英文摘要
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.
