Sex Hormone-Related Pathogenic Genes in Multiple Sclerosis: A Multi-omics Mendelian Randomization Study

Abstract

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.

Keywords: Colocalization; Mendelian randomization; Multi-omics; Multiple sclerosis; Sex hormone-related genes.