Phenome-wide Mendelian randomization analysis reveals multiple health comorbidities of coeliac diseaseResearch in context
Shuai Yuan,
Fangyuan Jiang,
Jie Chen,
Benjamin Lebwohl,
Peter H.R. Green,
Daniel Leffler,
Susanna C. Larsson,
Xue Li,
Jonas F. Ludvigsson
Affiliations
Shuai Yuan
School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Corresponding author. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Fangyuan Jiang
School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Jie Chen
School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Benjamin Lebwohl
Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, NY, USA
Peter H.R. Green
Departments of Medicine and Surgical Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
Daniel Leffler
The Celiac Center at Beth Israel Deaconess Medical Center, Harvard Medical School, USA
Susanna C. Larsson
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Xue Li
School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Corresponding author.
Jonas F. Ludvigsson
Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, NY, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Corresponding author. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Summary: Background: Coeliac disease (CeD) has been associated with a broad range of diseases in observational data; however, whether these associations are causal remains undetermined. We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to investigate the comorbidities of CeD. Methods: Single nucleotide polymorphisms (SNPs) associated with CeD at the genome-wide significance threshold and without linkage disequilibrium (R2 <0.001) were selected from a genome-wide association study including 12,041 CeD cases as the instrumental variables. We first constructed a polygenic risk score for CeD and estimated its associations with 1060 unique clinical outcomes in the UK Biobank study (N = 385,917). We then used two-sample MR analysis to replicate the identified associations using data from the FinnGen study (N = 377,277). We performed a secondary analysis using a genetic instrument without extended MHC gene SNPs. Findings: Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, and 38 of the associations were replicated in the FinnGen study. Genetic liability to CeD was associated with a higher risk of several autoimmune diseases (type 1 diabetes and its complications, Graves' disease, Sjögren syndrome, chronic hepatitis, systemic and cutaneous lupus erythematosus, and sarcoidosis), non-Hodgkin's lymphoma, and osteoporosis and a lower risk of prostate diseases. The associations for type 1 diabetes and non-Hodgkin's lymphoma attenuated when excluding SNPs in the MHC region, indicating shared genetic aetiology. Interpretation: This study uncovers multiple clinical outcomes associated with genetic liability to CeD, which suggests the necessity of comorbidity monitoring among this population. Funding: This project was funded by Karolinska Institutet and the Swedish Research Council.
