Integrative GWAS and Mendelian randomization study of rheumatoid arthritis based on the 2019 UK Biobank questionnaire

Tengda Cai; Yiwen Tao; Qi Pan; Luning Yang; Sen Lin; Anal Chatterjee; Weihua Meng; Jingjing Song

doi:10.1007/s10067-025-07590-x

Integrative GWAS and Mendelian randomization study of rheumatoid arthritis based on the 2019 UK Biobank questionnaire

Tengda Cai, Yiwen Tao, Qi Pan, Luning Yang, Sen Lin, Anal Chatterjee, Weihua Meng (Lead / Corresponding author), Jingjing Song (Lead / Corresponding author)

Population Health and Genomics

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: Rheumatoid arthritis (RA) is the most prevalent autoimmune inflammatory joint disorder worldwide. We aimed to identify the genetic variants contributing to RA and investigate the potential influence of related diseases on RA risk. Methods: We performed genome-wide association studies (GWAS) on RA using the 2019 UK Biobank pain questionnaire. We conducted a primary GWAS (9,389 RA cases; 132,108 controls) and separate sex-stratified GWAS for females (4,832 cases; 75,184 controls) and males (4,557 cases; 56,924 controls). We incorporated 12 phenotypes from downstream analyses, such as genetic correlation analyses, transcriptome-wide association studies (TWAS), phenome-wide association studies (PheWAS), and Mendelian randomization (MR) studies to determine causal relationships with RA. Results: Two loci reached genome-wide significance in the primary GWAS. The top SNP, rs35139284 (p = 3.67 × 10⁻²⁵) in the HLA-DRB1 gene on chromosome 6, exhibited a robust replication. Another locus, harboring the top SNP rs539837 (p = 6.26 × 10⁻⁹) near the LINC01680 gene on chromosome 1, also showed a significant association. In the female-specific GWAS, rs35139284 (p = 1.91 × 10⁻²²) remained the top signal, whereas the male-specific GWAS revealed a suggestive significance at rs9267989 (p = 5.28 × 10⁻⁸) in TSBP1-AS1. TWAS and tissue specificity studies pointed to the spleen, lung, and small intestine as key tissues implicated in RA. PheWAS and MR analyses highlighted asthma and eosinophils associated with RA. Conclusion: Our findings confirmed an RA locus at chromosome 6 and highlighted associations between RA and a spectrum of immune-related and inflammatory phenotypes. Further analyses may provide greater insights into the genetic architecture of RA. (Table presented.)

Original language	English
Number of pages	11
Journal	Clinical Rheumatology
Early online date	5 Aug 2025
DOIs	https://doi.org/10.1007/s10067-025-07590-x
Publication status	E-pub ahead of print - 5 Aug 2025

Keywords

Genetics
Genome-wide association study
Mendelian randomization
Rheumatoid arthritis

ASJC Scopus subject areas

Rheumatology

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10.1007/s10067-025-07590-x

Author Accepted ManuscriptAccepted author manuscript, 760 KBLicence: CC BY

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title = "Integrative GWAS and Mendelian randomization study of rheumatoid arthritis based on the 2019 UK Biobank questionnaire",

abstract = "Introduction: Rheumatoid arthritis (RA) is the most prevalent autoimmune inflammatory joint disorder worldwide. We aimed to identify the genetic variants contributing to RA and investigate the potential influence of related diseases on RA risk. Methods: We performed genome-wide association studies (GWAS) on RA using the 2019 UK Biobank pain questionnaire. We conducted a primary GWAS (9,389 RA cases; 132,108 controls) and separate sex-stratified GWAS for females (4,832 cases; 75,184 controls) and males (4,557 cases; 56,924 controls). We incorporated 12 phenotypes from downstream analyses, such as genetic correlation analyses, transcriptome-wide association studies (TWAS), phenome-wide association studies (PheWAS), and Mendelian randomization (MR) studies to determine causal relationships with RA. Results: Two loci reached genome-wide significance in the primary GWAS. The top SNP, rs35139284 (p = 3.67 × 10−25) in the HLA-DRB1 gene on chromosome 6, exhibited a robust replication. Another locus, harboring the top SNP rs539837 (p = 6.26 × 10−9) near the LINC01680 gene on chromosome 1, also showed a significant association. In the female-specific GWAS, rs35139284 (p = 1.91 × 10−22) remained the top signal, whereas the male-specific GWAS revealed a suggestive significance at rs9267989 (p = 5.28 × 10−8) in TSBP1-AS1. TWAS and tissue specificity studies pointed to the spleen, lung, and small intestine as key tissues implicated in RA. PheWAS and MR analyses highlighted asthma and eosinophils associated with RA. Conclusion: Our findings confirmed an RA locus at chromosome 6 and highlighted associations between RA and a spectrum of immune-related and inflammatory phenotypes. Further analyses may provide greater insights into the genetic architecture of RA. (Table presented.)",

keywords = "Genetics, Genome-wide association study, Mendelian randomization, Rheumatoid arthritis",

author = "Tengda Cai and Yiwen Tao and Qi Pan and Luning Yang and Sen Lin and Anal Chatterjee and Weihua Meng and Jingjing Song",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR) 2025.",

year = "2025",

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day = "5",

doi = "10.1007/s10067-025-07590-x",

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TY - JOUR

T1 - Integrative GWAS and Mendelian randomization study of rheumatoid arthritis based on the 2019 UK Biobank questionnaire

AU - Cai, Tengda

AU - Tao, Yiwen

AU - Pan, Qi

AU - Yang, Luning

AU - Lin, Sen

AU - Chatterjee, Anal

AU - Meng, Weihua

AU - Song, Jingjing

N1 - Publisher Copyright: © The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR) 2025.

PY - 2025/8/5

Y1 - 2025/8/5

N2 - Introduction: Rheumatoid arthritis (RA) is the most prevalent autoimmune inflammatory joint disorder worldwide. We aimed to identify the genetic variants contributing to RA and investigate the potential influence of related diseases on RA risk. Methods: We performed genome-wide association studies (GWAS) on RA using the 2019 UK Biobank pain questionnaire. We conducted a primary GWAS (9,389 RA cases; 132,108 controls) and separate sex-stratified GWAS for females (4,832 cases; 75,184 controls) and males (4,557 cases; 56,924 controls). We incorporated 12 phenotypes from downstream analyses, such as genetic correlation analyses, transcriptome-wide association studies (TWAS), phenome-wide association studies (PheWAS), and Mendelian randomization (MR) studies to determine causal relationships with RA. Results: Two loci reached genome-wide significance in the primary GWAS. The top SNP, rs35139284 (p = 3.67 × 10−25) in the HLA-DRB1 gene on chromosome 6, exhibited a robust replication. Another locus, harboring the top SNP rs539837 (p = 6.26 × 10−9) near the LINC01680 gene on chromosome 1, also showed a significant association. In the female-specific GWAS, rs35139284 (p = 1.91 × 10−22) remained the top signal, whereas the male-specific GWAS revealed a suggestive significance at rs9267989 (p = 5.28 × 10−8) in TSBP1-AS1. TWAS and tissue specificity studies pointed to the spleen, lung, and small intestine as key tissues implicated in RA. PheWAS and MR analyses highlighted asthma and eosinophils associated with RA. Conclusion: Our findings confirmed an RA locus at chromosome 6 and highlighted associations between RA and a spectrum of immune-related and inflammatory phenotypes. Further analyses may provide greater insights into the genetic architecture of RA. (Table presented.)

AB - Introduction: Rheumatoid arthritis (RA) is the most prevalent autoimmune inflammatory joint disorder worldwide. We aimed to identify the genetic variants contributing to RA and investigate the potential influence of related diseases on RA risk. Methods: We performed genome-wide association studies (GWAS) on RA using the 2019 UK Biobank pain questionnaire. We conducted a primary GWAS (9,389 RA cases; 132,108 controls) and separate sex-stratified GWAS for females (4,832 cases; 75,184 controls) and males (4,557 cases; 56,924 controls). We incorporated 12 phenotypes from downstream analyses, such as genetic correlation analyses, transcriptome-wide association studies (TWAS), phenome-wide association studies (PheWAS), and Mendelian randomization (MR) studies to determine causal relationships with RA. Results: Two loci reached genome-wide significance in the primary GWAS. The top SNP, rs35139284 (p = 3.67 × 10−25) in the HLA-DRB1 gene on chromosome 6, exhibited a robust replication. Another locus, harboring the top SNP rs539837 (p = 6.26 × 10−9) near the LINC01680 gene on chromosome 1, also showed a significant association. In the female-specific GWAS, rs35139284 (p = 1.91 × 10−22) remained the top signal, whereas the male-specific GWAS revealed a suggestive significance at rs9267989 (p = 5.28 × 10−8) in TSBP1-AS1. TWAS and tissue specificity studies pointed to the spleen, lung, and small intestine as key tissues implicated in RA. PheWAS and MR analyses highlighted asthma and eosinophils associated with RA. Conclusion: Our findings confirmed an RA locus at chromosome 6 and highlighted associations between RA and a spectrum of immune-related and inflammatory phenotypes. Further analyses may provide greater insights into the genetic architecture of RA. (Table presented.)

KW - Genetics

KW - Genome-wide association study

KW - Mendelian randomization

KW - Rheumatoid arthritis

UR - https://www.scopus.com/pages/publications/105012633008

U2 - 10.1007/s10067-025-07590-x

DO - 10.1007/s10067-025-07590-x

M3 - Article

C2 - 40762897

AN - SCOPUS:105012633008

SN - 0770-3198

JO - Clinical Rheumatology

JF - Clinical Rheumatology

ER -

Integrative GWAS and Mendelian randomization study of rheumatoid arthritis based on the 2019 UK Biobank questionnaire

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