Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
MRC Integrative Epidemiology Unit University of Bristol, Bristol, UK.
Genome Biol. 2021 Jun 29;22(1):194. doi: 10.1186/s13059-021-02398-9.
Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.
Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.
This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
从 DNA 甲基化数据中得出的生物衰老估算值具有遗传性，与发病率和死亡率相关。因此，确定人群中这些指标变化的遗传和环境因素已成为该领域的主要目标。
利用来自 4 万多人的 DNA 甲基化和 SNP 数据，我们通过对四个表观遗传时钟和粒细胞比例及纤溶酶原激活物抑制剂 1 水平的表观遗传替代标志物的全基因组关联研究（GWAS）荟萃分析，确定了 137 个全基因组显著位点，其中 113 个是新的。我们发现与 Horvath 时钟和编码与脂质代谢和免疫功能相关的基因转录本表达相关的遗传位点存在共享。值得注意的是，这些位点与报告的调节构成时钟 CpG 甲基化水平的位点无关。GrimAge 加速的多基因评分与肥胖相关特征、教育程度、父母寿命和 C-反应蛋白水平有很强的关联。
本研究阐明了表观遗传衰老的遗传结构及其与生活方式因素和长寿的共同遗传贡献。
