Qiu Jiting, Zhang Yuwen
Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Mol Neurosci. 2025 Apr 26;75(2):58. doi: 10.1007/s12031-025-02347-2.
Multiple sclerosis (MS) is a chronic autoimmune disease with complex etiologies, including genetic factors. Sex hormones have been implicated in MS pathogenesis, but the underlying genetic mechanisms remain unclear.This study employed a multi-omics Mendelian randomization (MR) approach to evaluate the causal associations between sex hormone-related genes and MS. We utilized summary data from genome-wide association studies (GWAS) and blood-based methylation quantitative trait loci (mQTLs), expression QTL (eQTLs), and proteomic QTL (pQTLs). The analysis employed the summary data-based MR (SMR) method and the HEIDI test for pleiotropy. Colocalization analysis identified shared genetic determinants, validated in UK Biobank and FinnGen R10 cohort. Our study identified a total of 30 mQTLs and 15 eQTLs that confirmed the causal associations between sex hormone-related genes and MS by SMR and colocalization analyses. Notably, the methylation site cg19286687 of the DES gene was positively associated with MS risk. Similarly, DES expression was positively associated with MS risk in eQTL data. Integration of mQTL and eQTL data revealed a positive regulatory association between cg19286687 and DES expression, suggesting that low methylation level of cg19286687 may inhibit DES expression, potentially contributing to MS risk reduction. This multi-omics MR study suggests a potential causal association between sex hormone-related genes and MS. The findings highlight the importance of DES and its methylation the pathogenesis of MS, offering new ideas on disease mechanisms.
多发性硬化症（MS）是一种病因复杂的慢性自身免疫性疾病，包括遗传因素。性激素与MS发病机制有关，但其潜在的遗传机制仍不清楚。本研究采用多组学孟德尔随机化（MR）方法来评估性激素相关基因与MS之间的因果关联。我们利用了全基因组关联研究（GWAS）以及基于血液的甲基化定量性状位点（mQTLs）、表达数量性状基因座（eQTLs）和蛋白质组定量性状基因座（pQTLs）的汇总数据。分析采用了基于汇总数据的MR（SMR）方法和用于多效性的HEIDI检验。共定位分析确定了共享的遗传决定因素，并在英国生物银行和芬兰基因R10队列中得到验证。我们的研究通过SMR和共定位分析共确定了30个mQTLs和15个eQTLs，证实了性激素相关基因与MS之间的因果关联。值得注意的是，DES基因的甲基化位点cg19286687与MS风险呈正相关。同样，在eQTL数据中，DES表达与MS风险呈正相关。mQTL和eQTL数据的整合揭示了cg19286687与DES表达之间的正调控关联，表明cg19286687的低甲基化水平可能抑制DES表达，这可能有助于降低MS风险。这项多组学MR研究表明性激素相关基因与MS之间存在潜在的因果关联。研究结果突出了DES及其甲基化在MS发病机制中的重要性，为疾病机制提供了新的思路。
