A Phenome-Wide Mendelian Randomization and Colocalization Study Reveals Genetic Association Between PBC and Other Autoimmune Disorders
Shuyi Shi
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorMinghui Liu
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorHaonan Gao
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorCorresponding Author
Fang Liu
Institute of Hematology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorCorresponding Author
Yuhu Song
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorShuyi Shi
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorMinghui Liu
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorHaonan Gao
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorCorresponding Author
Fang Liu
Institute of Hematology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorCorresponding Author
Yuhu Song
Department of Gastroenterology , Union Hospital , Tongji Medical College , Huazhong University of Science and Technology , Wuhan , 430022 , China , hust.edu.cn
Search for more papers by this authorAbstract
Background: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that is commonly associated with various other autoimmune disorders. We conducted a phenome-wide association study Mendelian randomization (MR-PheWAS) to determine genetic association between PBC and other diseases, particularly autoimmune disorders.
Methods: We performed a PheWAS to investigate the causal associations between PBC and related traits by conducting enrichment analysis of 35 PBC risk loci identified by prior GWAS and their matched control SNP sets in UK Biobank database. MR-PheWAS and bidirectional two-sample Mendelian randomization analysis were conducted to determine causal association between PBC and hypothyroidism. Colocalization analysis was conducted to investigate common genetic variants with hypothyroidism.
Results: Genetic liability to PBC was associated with a higher risk of 25 traits (hypothyroidism, asthma, allergic rhinitis, psoriasis, ulcerative colitis, and multiple sclerosis). After false discovery rate (FDR) correction, there exist 9 traits significantly difference. MR-PheWAS analysis demonstrated causal association between PBC and hypothyroidism, and bidirectional two-sample Mendelian randomization analysis was performed to validate it. The OR of hypothyroidism on PBC was 113.61(p = 9.30E − 05), and PBC was also causally associated with hypothyroidism (OR: 1.005; p = 4.33E − 09). Among the genes identified, CCDC88B and MMEL1 were found to have positive associations with the risk of hypothyroidism (CCDC88B: OR = 1.004, p = 4.69E − 07; MMEL1: OR = 1.004, p = 6.65E − 06) and FinnGen cohorts (CCDC88B: OR = 1.044; MMEL1: OR = 1.038). The two genes may be the drug targets for hypothyroidism (CCDC88B: coloc.abf-PPH4 = 94.7%; MMEL1: coloc.abf-PPH4 = 91.8%).
Conclusions: Our study revealed genetic association between PBC and hypothyroidism through a phenome-wide Mendelian randomization, and then, colocalization identified two potential drug targets for hypothyroidism.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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| cjgh1716853-sup-0001-f1.docxWord 2007 document , 10.6 MB | Supporting Information Additional supporting information can be found online in the Supporting Information section. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Tanaka A., Current Understanding of Primary Biliary Cholangitis, Clinical and Molecular Hepatology. (2021) 27, no. 1, 1–21, https://doi.org/10.3350/cmh.2020.0028.
- 2 Liu F., Pan Z. G., Ye J. et al., Primary Biliary Cirrhosis-Autoimmune Hepatitis Overlap Syndrome: Simplified Criteria May Be Effective in the Diagnosis in Chinese Patients, Journal of Digestive Diseases. (2014) 15, no. 12, 660–668, https://doi.org/10.1111/1751-2980.12196, 2-s2.0-84920092605.
- 3 Kintu C., Soremekun O., Kamiza A. B. et al., The Causal Effects of Lipid Traits on Kidney Function in Africans: Bidirectional and Multivariable Mendelian-Randomization Study, EBioMedicine. (2023) 90, https://doi.org/10.1016/j.ebiom.2023.104537.
- 4 Bowden J. and Holmes M. V., Meta-Analysis and Mendelian Randomization: A Review, Research Synthesis Methods. (2019) 10, no. 4, 486–496, https://doi.org/10.1002/jrsm.1346.
- 5 Wei N., Liu M. H., and Song Y. H., Causal Associations Between Gastroesophageal Reflux Disease and Essential Hypertension: A Bidirectional Mendelian Randomization Study, World Journal of Clinical Cases. (2024) 12, no. 5, 880–890, https://doi.org/10.12998/wjcc.v12.i5.880.
- 6 Burgess S., Scott R. A., Timpson N. J., Davey Smith G., and Thompson S. G., Using Published Data in Mendelian Randomization: A Blueprint for Efficient Identification of Causal Risk Factors, European Journal of Epidemiology. (2015) 30, no. 7, 543–552, https://doi.org/10.1007/s10654-015-0011-z, 2-s2.0-84943354221.
- 7 Zhang H., Chen L., Fan Z., and Lv G., The Causal Effects of Inflammatory Bowel Disease on Primary Biliary Cholangitis: A Bidirectional Two-Sample Mendelian Randomization Study, Liver International. (2023) 43, no. 8, 1741–1748, https://doi.org/10.1111/liv.15616.
- 8 Huang P., Hou Y., Zou Y., Ye X., Yu R., and Yang S., The Causal Effects of Primary Biliary Cholangitis on Thyroid Dysfunction: A Two-Sample Mendelian Randomization Study, Frontiers in Genetics. (2021) 12, https://doi.org/10.3389/fgene.2021.791778.
- 9 Fan J., Jiang T., and He D., Genetic Link Between Rheumatoid Arthritis and Autoimmune Liver Diseases: A Two-Sample Mendelian Randomization Study, Seminars in Arthritis and Rheumatism. (2023) 58, https://doi.org/10.1016/j.semarthrit.2022.152142.
- 10 Huang W., Jin T., Zheng W. et al., Identifying the Genetic Association Between Systemic Lupus Erythematosus and the Risk of Autoimmune Liver Diseases, Journal of Autoimmunity. (2024) 145, https://doi.org/10.1016/j.jaut.2024.103188.
- 11 Liu Z., Shao Y., and Duan X., Genetic Link Between Primary Biliary Cholangitis and Connective Tissue Diseases in European Populations: A Two-Sample Mendelian Randomization Study, PLoS One. (2024) 19, no. 2, https://doi.org/10.1371/journal.pone.0298225.
- 12
Zhao D.,
Zhao Q.,
Xu F.,
Zhang F., and
Bai W., Primary Biliary Cirrhosis and Psoriasis: A Two-Sample Mendelian Randomization Study, Frontiers in Immunology. (2023) 14, https://doi.org/10.3389/fimmu.2023.1264554.
10.3389/fimmu.2023.1269069 Google Scholar
- 13 Wang L., Zhang X., Meng X. et al., Methodology in Phenome-Wide Association Studies: A Systematic Review, Journal of Medical Genetics. (2021) 58, no. 11, 720–728, https://doi.org/10.1136/jmedgenet-2021-107696.
- 14 Cordell H. J., Fryett J. J., Ueno K. et al., An International Genome-Wide Meta-Analysis of Primary Biliary Cholangitis: Novel Risk Loci and Candidate Drugs, Journal of Hepatology. (2021) 75, no. 3, 572–581, https://doi.org/10.1016/j.jhep.2021.04.055.
- 15 Clarke L., Zheng-Bradley X., Smith R. et al., The 1000 Genomes Project: Data Management and Community Access, Nature Methods. (2012) 9, no. 5, 459–462, https://doi.org/10.1038/nmeth.1974, 2-s2.0-84860373866.
- 16 Machiela M. J. and Chanock S. J., Ldlink: A Web-Based Application for Exploring Population-Specific Haplotype Structure and Linking Correlated Alleles of Possible Functional Variants, Bioinformatics. (2015) 31, no. 21, 3555–3557, https://doi.org/10.1093/bioinformatics/btv402, 2-s2.0-84947599300.
- 17 Johnson A. D., Handsaker R. E., Pulit S. L., Nizzari M. M., O’Donnell C. J., and de Bakker P. I., SNAP: A Web-Based Tool for Identification and Annotation of Proxy Snps Using Hapmap, Bioinformatics. (2008) 24, no. 24, 2938–2939, https://doi.org/10.1093/bioinformatics/btn564, 2-s2.0-57249114505.
- 18 Hennessy S., Bilker W. B., Berlin J. A., and Strom B. L., Factors Influencing the Optimal Control-to-Case Ratio in Matched Case-Control Studies, American Journal of Epidemiology. (1999) 149, no. 2, 195–197, https://doi.org/10.1093/oxfordjournals.aje.a009786, 2-s2.0-0033555939.
- 19 Allen N. E., Sudlow C., Peakman T., Collins R., and UK Biobank, UK Biobank Data: Come and Get It, Science Translational Medicine. (2014) 6, no. 224, https://doi.org/10.1126/scitranslmed.3008601, 2-s2.0-84896386442.
- 20 Ward L. D. and Kellis M., Haploreg: A Resource for Exploring Chromatin States, Conservation, and Regulatory Motif Alterations Within Sets of Genetically Linked Variants, Nucleic Acids Research. (2012) 40, no. D1, D930–D934, https://doi.org/10.1093/nar/gkr917, 2-s2.0-84858779229.
- 21 Võsa U., Claringbould A., Westra H. J. et al., Large-Scale Cis- and Trans-Eqtl Analyses Identify Thousands of Genetic Loci and Polygenic Scores That Regulate Blood Gene Expression, Nature Genetics. (2021) 53, no. 9, 1300–1310, https://doi.org/10.1038/s41588-021-00913-z.
- 22 Giambartolomei C., Vukcevic D., Schadt E. E. et al., Bayesian Test for Colocalisation Between Pairs of Genetic Association Studies Using Summary Statistics, PLoS Genetics. (2014) 10, no. 5, https://doi.org/10.1371/journal.pgen.1004383, 2-s2.0-84901631426.
- 23 Wang G., Sarkar A., Carbonetto P., and Stephens M., A Simple New Approach to Variable Selection in Regression, With Application to Genetic Fine Mapping, Journal of the Royal Statistical Society—Series B: Statistical Methodology. (2020) 82, no. 5, 1273–1300, https://doi.org/10.1111/rssb.12388.
- 24 Crowe J. P., Christensen E., Butler J. et al., Primary Biliary Cirrhosis: The Prevalence of Hypothyroidism and Its Relationship to Thyroid Autoantibodies and Sicca Syndrome, Gastroenterology. (1980) 78, no. 6, 1437–1441, https://doi.org/10.1016/s0016-5085(19)30497-4.
- 25 Elta G. H., Sepersky R. A., Goldberg M. J., Connors C. M., Miller K. B., and Kaplan M. M., Increased Incidence of Hypothyroidism in Primary Biliary Cirrhosis, Digestive Diseases and Sciences. (1983) 28, no. 11, 971–975, https://doi.org/10.1007/bf01311724, 2-s2.0-0021026680.
- 26 Hollowell J. G., Staehling N. W., Flanders W. D. et al., Serum TSH, T4, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III), Journal of Clinical Endocrinology and Metabolism. (2002) 87, no. 2, 489–499, https://doi.org/10.1210/jcem.87.2.8182, 2-s2.0-0036173697.
- 27 Kennedy J. M., Fodil N., Torre S. et al., CCDC88B is a Novel Regulator of Maturation and Effector Functions of T Cells During Pathological Inflammation, Journal of Experimental Medicine. (2014) 211, no. 13, 2519–2535, https://doi.org/10.1084/jem.20140455, 2-s2.0-84927646479.
- 28 Fischer A., Schmid B., Ellinghaus D. et al., A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1, American Journal of Respiratory and Critical Care Medicine. (2012) 186, no. 9, 877–885, https://doi.org/10.1164/rccm.201204-0708oc, 2-s2.0-84868031310.
- 29 Fodil N., Moradin N., Leung V. et al., CCDC88B is Required for Pathogenesis of Inflammatory Bowel Disease, Nature Communications. (2017) 8, no. 1, https://doi.org/10.1038/s41467-017-01381-y, 2-s2.0-85031699072.
- 30 Tsoi L. C., Spain S. L., Knight J. et al., Identification of 15 New Psoriasis Susceptibility Loci Highlights the Role of Innate Immunity, Nature Genetics. (2012) 44, no. 12, 1341–1348, https://doi.org/10.1038/ng.2467, 2-s2.0-84870512735.
- 31 International Multiple Sclerosis Genetics Consortium IMSGC, Patsopoulos N. A., Xifara D. K. et al., Analysis of Immune-Related Loci Identifies 48 New Susceptibility Variants for Multiple Sclerosis, Nature Genetics. (2013) 45, no. 11, 1353–1360, https://doi.org/10.1038/ng.2770, 2-s2.0-84887058596.
- 32 Juran B. D., Hirschfield G. M., Invernizzi P. et al., Immunochip Analyses Identify a Novel Risk Locus for Primary Biliary Cirrhosis at 13q14, Multiple Independent Associations at Four Established Risk Loci and Epistasis Between 1p31 and 7q32 Risk Variants, Human Molecular Genetics. (2012) 21, no. 23, 5209–5221, https://doi.org/10.1093/hmg/dds359, 2-s2.0-84869060864.
- 33 Hirschfield G. M., Liu X., Han Y. et al., Variants at IRF5-TNPO3, 17q12-21 and MMEL1 Are Associated With Primary Biliary Cirrhosis, Nature Genetics. (2010) 42, no. 8, 655–657, https://doi.org/10.1038/ng.631, 2-s2.0-77955087537.
- 34 Danoy P., Wei M., Johanna H. et al., Association of Variants in MMEL1 and CTLA4 With Rheumatoid Arthritis in the Han Chinese Population, Annals of the Rheumatic Diseases. (2011) 70, no. 10, 1793–1797, https://doi.org/10.1136/ard.2010.144576, 2-s2.0-80052511445.
- 35 Ban M., McCauley J. L., Zuvich R. et al., A Non-Synonymous SNP Within Membrane Metalloendopeptidase-Like 1 (MMEL1) is Associated With Multiple Sclerosis, Genes and Immunity. (2010) 11, no. 8, 660–664, https://doi.org/10.1038/gene.2010.36, 2-s2.0-78649699944.
- 36 Lin J., Zhou J., and Xu Y., Potential Drug Targets for Multiple Sclerosis Identified Through Mendelian Randomization Analysis, Brain. (2023) 146, no. 8, 3364–3372, https://doi.org/10.1093/brain/awad070.
- 37 Kuś A., Grabowska M. A., Szymański K. et al., Genetic Risk Factors for Autoimmune Thyroid Disease Might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis, Journal of Gastrointestinal and Liver Diseases. (2017) 26, no. 3, 245–252, https://doi.org/10.15403/jgld.2014.1121.263.kus, 2-s2.0-85030314955.
- 38 Blanco-Gómez A., Castillo-Lluva S., del Mar Sáez-Freire M. et al., Missing Heritability of Complex Diseases: Enlightenment by Genetic Variants from Intermediate Phenotypes, BioEssays. (2016) 38, no. 7, 664–673, https://doi.org/10.1002/bies.201600084, 2-s2.0-84976543884.
