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

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Multiple sclerosis (MS) is a chronic autoimmune disease with complex genetic underpinnings.
• The role of sex hormones in MS pathogenesis is recognized, but specific genetic mechanisms are not well understood.

Purpose of the Study:

• To investigate the causal relationship between sex hormone-related genes and MS using a multi-omics approach.
• To identify specific genetic variants and regulatory mechanisms linking sex hormones to MS.

Main Methods:

• Utilized multi-omics Mendelian randomization (MR) with summary data from GWAS, mQTLs, eQTLs, and pQTLs.
• Employed SMR and HEIDI methods for association and pleiotropy testing.
• Performed colocalization analysis and validated findings in independent cohorts (UK Biobank, FinnGen R10).

Main Results:

• Identified 30 mQTLs and 15 eQTLs demonstrating causal associations between sex hormone genes and MS.
• Found a positive association between DES gene methylation site cg19286687 and MS risk.
• Observed a positive association between DES gene expression and MS risk, with evidence of shared genetic regulation.

Conclusions:

• The study suggests a potential causal link between sex hormone-related genes and MS pathogenesis.
• Highlights the significance of the DES gene and its methylation patterns in MS development.
• Provides novel insights into the molecular mechanisms underlying MS.