Liu Hongwei, Zhang Hanqing, Yin Zhaoxu, Hou Miaomiao
Department of Neurology, Taiyuan Central Hospital, Taiyuan, Shanxi Province, China.
Department of Neurology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Epigenetics Chromatin. 2025 Jan 30;18(1):7. doi: 10.1186/s13072-025-00567-9.
The DNA methylation-based epigenetic clocks are increasingly recognized for their precision in predicting aging and its health implications. Although prior research has identified connections between accelerated epigenetic aging and multiple sclerosis, the chronological and causative aspects of these relationships are yet to be elucidated. Our research seeks to clarify these potential causal links through a bidirectional Mendelian randomization study.
This analysis employed statistics approaches from genome-wide association studies related to various epigenetic clocks (GrimAge, HannumAge, PhenoAge, and HorvathAge) and multiple sclerosis, utilizing robust instrumental variables from the Edinburgh DataShare (n = 34,710) and the International Multiple Sclerosis Genetics Consortium (including 24,091 controls and 14,498 cases). We applied the inverse-variance weighted approach as our main method for Mendelian randomization, with additional sensitivity analyses to explore underlying heterogeneity and pleiotropy.
Using summary-based Mendelian randomization, we found that HannumAge was associated with multiple sclerosis (OR = 1.071, 95%CI:1.006-1.140, p = 0.033, by inverse-variance weighted). The results suggest that an increase in epigenetic age acceleration of HannumAge promotes the risk of multiple sclerosis. In reverse Mendelian randomization analysis, no evidence of a clear causal association of multiple sclerosis on epigenetic age acceleration was identified.
Our Mendelian randomization analysis revealed that epigenetic age acceleration of HannumAge was causally associated with multiple sclerosis, and provided novel insights for further mechanistic and clinical studies of epigenetic age acceleration-mediated multiple sclerosis.
基于DNA甲基化的表观遗传时钟在预测衰老及其对健康的影响方面的准确性越来越受到认可。尽管先前的研究已经确定了表观遗传加速衰老与多发性硬化症之间的联系，但这些关系的时间顺序和因果关系仍有待阐明。我们的研究旨在通过双向孟德尔随机化研究来阐明这些潜在的因果联系。
本分析采用了来自全基因组关联研究的统计方法，这些研究涉及各种表观遗传时钟（GrimAge、HannumAge、PhenoAge和HorvathAge）和多发性硬化症，利用了爱丁堡数据共享库（n = 34,710）和国际多发性硬化症遗传学联盟（包括24,091名对照和14,498例病例）中的稳健工具变量。我们应用逆方差加权方法作为孟德尔随机化的主要方法，并进行了额外的敏感性分析，以探索潜在的异质性和多效性。
使用基于汇总数据的孟德尔随机化方法，我们发现HannumAge与多发性硬化症相关（比值比=1.071，95%置信区间：1.006 - 1.140，p = 0.033，采用逆方差加权法）。结果表明，HannumAge表观遗传年龄加速增加会促进多发性硬化症的风险。在反向孟德尔随机化分析中，未发现多发性硬化症与表观遗传年龄加速之间存在明确因果关联的证据。
我们的孟德尔随机化分析表明，HannumAge的表观遗传年龄加速与多发性硬化症存在因果关系，并为进一步开展表观遗传年龄加速介导的多发性硬化症的机制和临床研究提供了新的见解。
