Genetic Crosstalk Between Type 1 Diabetes and Sjögren's Syndrome: A Systematic Exploration of Risk Genes and Common Pathways

TL;DR

This study explores shared genetic factors and pathways between Type 1 Diabetes and Sjögren's Syndrome, revealing common mechanisms involving cysteine-related processes and immune responses.

Contribution

The study identifies 36 shared genetic loci and novel gene associations between Type 1 Diabetes and Sjögren's Syndrome using multiomic and functional analyses.

Findings

36 shared loci were identified, showing genetic enrichment between Sjögren's Syndrome and Type 1 Diabetes.

Cysteine-related processes, apoptotic signaling, and immune responses were highlighted as key pathways.

Genes like AC007283.5, PLEKHM1, and CRHR1-T1 showed significant associations with both diseases.

Abstract

Sjögren's Syndrome (SS) and Type 1 Diabetes (T1D) are autoimmune disorders that can co‐occur in patients, leading to complex clinical presentations. Despite observational evidence of their co‐occurrence, the underlying genetic mechanisms remain poorly understood. To investigate the shared genetic factors and pathways between SS and T1D, we conducted a comprehensive analysis using multiomic approaches. Conditional and conjunctional false discovery rate analyses were performed to identify genetic polygenicity and overlap between the two diseases. Functional annotation and pathway analysis identified SNPs with regulatory potential. Furthermore, Mendelian Randomization (MR) analyses were employed to investigate causal associations between gene expression and disease risk. Single‐cell differential gene expression analysis was also employed to validate the associations of risk genes with T1D and SS. Our analysis identified 36 shared loci, revealing common genetic enrichment between SS and T1D. Functional annotation and pathway analysis revealed 52 credible genes involved in cysteine‐related processes, apoptotic signalling and immune responses. MR analyses revealed that AC007283.5 was positively linked with both SS and T1D, while PLEKHM1 and CRHR1‐T1 were negatively associated. Additionally, CERS2 was positively associated with SS, DEF6 was positively associated with T1D, and KANSL1‐AS1 was negatively associated with T1D, indicating the presence of complex regulatory mechanisms. Moreover, Single‐cell differential gene expression analysis confirmed the dysregulation of risk genes in SS and T1D. This study identified shared genetic factors and pathways underlying SS and T1D, highlighting cysteine‐related processes and apoptotic signalling. The findings underscore the complex interplay of autoimmunity and the need for targeted treatments addressing their common mechanisms.

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