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Published on: June 21, 2018
Phenome-wide Mendelian randomization analysis reveals multiple health comorbidities of coeliac disease
Shuai Yuan1, Fangyuan Jiang2, Jie Chen2
1School 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.
Insights
Genetic predisposition to celiac disease (CeD) is linked to numerous health conditions, including autoimmune diseases and osteoporosis. Monitoring for these comorbidities in CeD patients is crucial for better health outcomes.
Area of Science:
- Genetics
- Immunology
- Epidemiology
Background:
- Observational studies suggest associations between celiac disease (CeD) and various diseases, but causal links remain unclear.
- Investigating these potential comorbidities is essential for understanding the full impact of CeD.
Purpose of the Study:
- To employ Mendelian randomization phenome-wide association studies (MR-PheWAS) to identify causal comorbidities of CeD.
- To explore the genetic liability associated with CeD and its impact on a wide range of clinical outcomes.
Main Methods:
- Utilized genome-wide association study data for CeD (12,041 cases) to select instrumental variables (SNPs).
- Constructed a polygenic risk score for CeD and assessed its association with 1060 clinical outcomes in the UK Biobank (N=385,917).
- Replicated findings using two-sample MR analysis in the FinnGen study (N=377,277) and performed secondary analysis excluding MHC region SNPs.
Main Results:
- Genetic liability to CeD was associated with 68 clinical outcomes in the UK Biobank, with 38 replicated in FinnGen.
- Significant associations included increased risk for autoimmune diseases (type 1 diabetes, Graves' disease, Sjögren syndrome, etc.), non-Hodgkin's lymphoma, and osteoporosis.
- A decreased risk for prostate diseases was also observed. Shared genetic etiology was indicated for type 1 diabetes and non-Hodgkin's lymphoma by MHC region analysis.
Conclusions:
- This MR-PheWAS identified multiple clinical outcomes causally linked to genetic liability for CeD.
- Findings underscore the importance of monitoring for comorbidities in individuals with celiac disease.
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.
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