Identifying shared genetic loci and common risk genes of rheumatoid arthritis associated with three autoimmune diseases based on large-scale cross-trait genome-wide association studies

Ya-Ping Wen; Zu-Guo Yu

doi:10.3389/fimmu.2023.1160397

Identifying shared genetic loci and common risk genes of rheumatoid arthritis associated with three autoimmune diseases based on large-scale cross-trait genome-wide association studies

Front Immunol. 2023 Jun 12:14:1160397. doi: 10.3389/fimmu.2023.1160397. eCollection 2023.

Authors

Ya-Ping Wen^{1

2}, Zu-Guo Yu^{1

2}

Affiliations

¹ National Center for Applied Mathematics in Hunan, Xiangtan University, Hunan, China.
² Key Laboratory of Intelligent Computing and Information Processing of Ministry of Education, Xiangtan University, Hunan, China.

Abstract

Introduction: Substantial links between autoimmune diseases have been shown by an increasing number of studies, and one hypothesis for this comorbidity is that there is a common genetic cause.

Methods: In this paper, a large-scale cross-trait Genome-wide Association Studies (GWAS) was conducted to investigate the genetic overlap among rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes.

Results and discussion: Through the local genetic correlation analysis, 2 regions with locally significant genetic associations between rheumatoid arthritis and multiple sclerosis, and 4 regions with locally significant genetic associations between rheumatoid arthritis and type 1 diabetes were discovered. By cross-trait meta-analysis, 58 independent loci associated with rheumatoid arthritis and multiple sclerosis, 86 independent loci associated with rheumatoid arthritis and inflammatory bowel disease, and 107 independent loci associated with rheumatoid arthritis and type 1 diabetes were identified with genome-wide significance. In addition, 82 common risk genes were found through genetic identification. Based on gene set enrichment analysis, it was found that shared genes are enriched in exposed dermal system, calf, musculoskeletal, subcutaneous fat, thyroid and other tissues, and are also significantly enriched in 35 biological pathways. To verify the association between diseases, Mendelian randomized analysis was performed, which shows possible causal associations between rheumatoid arthritis and multiple sclerosis, and between rheumatoid arthritis and type 1 diabetes. The common genetic structure of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes was explored by these studies, and it is believed that this important discovery will lead to new ideas for clinical treatment.

Keywords: association studies; autoimmune diseases; cross-trait; rheumatoid arthritis; shared genes.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Arthritis, Rheumatoid* / genetics
Autoimmune Diseases* / genetics
Diabetes Mellitus, Type 1* / genetics
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / genetics
Multiple Sclerosis* / genetics

Grants and funding

This work was supported by funds from the National Key Research and Development Program of China (grant number: 2020YFC0832405); the National Natural Science Foundation of China (grant number: 11871061); The High-Level Talent Aggregation Project in Hunan Province, China Innovation Team (grant number: 2019RS1060), the Science and Technology Innovation Program of Hunan Province of China (grant number: 2022WK2009) and Hunan Provincial Innovation Foundation for Postgraduate (Grant No. CX20200614).