rs1150793 (MSH5): Autoimmune Disease Risk Variant

Key takeaways

• This locus in the MSH5 and SAPCD1 region has been identified in cross-trait genome-wide association analyses for shared genetic architecture across rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes.
• A proteogenomics study of over 54,000 UK Biobank participants found protein ratio associations at this region are 7.6-fold enriched in known protein-protein interactions, suggesting this locus reflects biological links between implicated proteins.
• GTEx data from 953 donors shows this variant is associated with reduced expression of LY6G5C across whole blood, spleen, skeletal muscle, and skin.
• The variant is also associated with increased expression of PSORS1C1 in esophageal tissue, while reducing expression of LY6G6C and MPIG6B in that same tissue.

What the research says A large-scale cross-trait genome-wide association study examining the genetic overlap among rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes identified 82 common risk genes, with this region among the implicated shared loci. A proteogenomics analysis using Olink affinity proteomics on over 54,000 UK Biobank samples found that testing ratios between protein pairs identified 4,248 associations with 2,821 protein ratios (rQTLs), increasing the number of discovered loci by 24.7% compared to standard single-protein methods, with rQTLs 7.6-fold enriched in established protein-protein interactions. GTEx tissue expression data from 953 donors links this variant to reduced expression of LY6G5C across multiple immune-relevant tissues and to altered expression of three additional nearby genes in esophageal mucosa GTEx Portal.

Reported associations

• Shared autoimmune disease risk (rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, type 1 diabetes): A cross-trait meta-analysis identified 58 genome-wide significant loci shared between rheumatoid arthritis and multiple sclerosis, 86 shared loci between rheumatoid arthritis and inflammatory bowel disease, and 107 shared loci between rheumatoid arthritis and type 1 diabetes, with 82 common risk genes found across these conditions; Mendelian randomization supported possible causal associations between rheumatoid arthritis and both multiple sclerosis and type 1 diabetes.
• Protein-level genetic signals (UK Biobank proteomics): Proteogenomics analysis identified this locus through protein ratio quantitative trait loci (rQTLs) that are 7.6-fold enriched in established protein-protein interactions, with the ratio-based approach uncovering 24.7% more genetic signals than single-protein GWAS and identifying novel loci of clinical relevance.
• LY6G5C expression (multiple immune-relevant tissues): This variant is associated with reduced expression of LY6G5C in spleen, skin (unexposed suprapubic), skeletal muscle, skin (sun-exposed lower leg), and whole blood GTEx Portal.
• LY6G6C expression (esophageal mucosa): This variant is associated with reduced expression of LY6G6C in esophageal mucosa GTEx Portal.
• MPIG6B expression (esophageal mucosa): This variant is associated with reduced expression of MPIG6B in esophageal mucosa GTEx Portal.
• PSORS1C1 expression (esophageal mucosa): This variant is associated with increased expression of PSORS1C1 in esophageal mucosa, in contrast to the reduced expression pattern seen for the other three nearby genes GTEx Portal.

Evidence quality The cross-trait autoimmune GWAS findings are based on large-scale meta-analyses meeting genome-wide significance thresholds, with Mendelian randomization applied for causal inference between specific disease pairs. The proteogenomics analysis drew on over 54,000 UK Biobank participants with 1,463 proteins measured by Olink, representing one of the largest proteomics datasets available. The GTEx eQTL associations are based on 953 donors with FDR<0.05 significance thresholds. Specific effect sizes for rs1150793 such as odds ratios or protein concentration differences are not reported in the available study excerpts. Independent replication of variant-specific associations at this locus is not described in the provided materials. The available full-text excerpts cover only introductory sections of both primary studies, which limits direct assessment of variant-level evidence; these findings should be considered preliminary pending review of the full results sections.

Tissue-specific expression effects

• LY6G5C: Reduced expression across five tissues (spleen, unexposed skin, skeletal muscle, sun-exposed skin, whole blood); the consistency of this reduction across immune and non-immune tissues is notable GTEx Portal.
• LY6G6C: Reduced expression in esophageal mucosa GTEx Portal.
• MPIG6B: Reduced expression in esophageal mucosa GTEx Portal.
• PSORS1C1: Increased expression in esophageal mucosa; this is the only one of the four affected genes at this locus showing increased rather than decreased expression GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.