Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms
| Autor: | Abigail Wood, Andrew P. Morris, John Bowes, Wendy Thomson, Vasanthi Priyadarshini Gaddi, Paul Martin, Marc Sudman, Miranda C. Marion, Gisela Orozco, Stephen Eyre, Chenfu Shi, Annie Yarwood, Sampath Prahalad, Samantha L. Smith, Susan D. Thompson, Elena López-Isac, Carl D. Langefeld |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases Genotype Immunology Arthritis Single-nucleotide polymorphism Genome-wide association study Disease Computational biology Polymorphism Single Nucleotide Genetic analysis General Biochemistry Genetics and Molecular Biology polymorphism 03 medical and health sciences 0302 clinical medicine Rheumatology Polymorphism (computer science) Humans Medicine Juvenile Immunology and Allergy Genetic Predisposition to Disease Gene 030203 arthritis & rheumatology business.industry Biochemistry Genetics and Molecular Biology(all) Paediatric Rheumatology Bayes Theorem medicine.disease Arthritis Juvenile 030104 developmental biology juvenile arthritis Genetic Loci biological therapy genetic business Genome-Wide Association Study |
| Zdroj: | Lopez Isac, E, Smith, S, Marion, M C, Wood, A, Sudman, M, Yarwood, A, Shi, C, Gaddi, V, Martin, P, Prahalad, S, Eyre, S, Orozco, G, Morris, A, Langefeld, C D, Thompson, S D, Thomson, W & Bowes, J 2021, ' Combined genetic analysis of juvenile idiopathic arthritis clinical subtypes identifies novel risk loci, target genes and key regulatory mechanisms ', Annals of the rheumatic diseases, vol. 80, pp. 321-328 . https://doi.org/10.1136/annrheumdis-2020-218481 Annals of the Rheumatic Diseases |
| DOI: | 10.1136/annrheumdis-2020-218481 |
| Popis: | ObjectivesJuvenile idiopathic arthritis (JIA) is the most prevalent form of juvenile rheumatic disease. Our understanding of the genetic risk factors for this disease is limited due to low disease prevalence and extensive clinical heterogeneity. The objective of this research is to identify novel JIA susceptibility variants and link these variants to target genes, which is essential to facilitate the translation of genetic discoveries to clinical benefit.MethodsWe performed a genome-wide association study (GWAS) in 3305 patients and 9196 healthy controls, and used a Bayesian model selection approach to systematically investigate specificity and sharing of associated loci across JIA clinical subtypes. Suggestive signals were followed-up for meta-analysis with a previous GWAS (2751 cases/15 886 controls). We tested for enrichment of association signals in a broad range of functional annotations, and integrated statistical fine-mapping and experimental data to identify target genes.ResultsOur analysis provides evidence to support joint analysis of all JIA subtypes with the identification of five novel significant loci. Fine-mapping nominated causal single nucleotide polymorphisms with posterior inclusion probabilities ≥50% in five JIA loci. Enrichment analysis identified RELA and EBF1 as key transcription factors contributing to disease risk. Our integrative approach provided compelling evidence to prioritise target genes at six loci, highlighting mechanistic insights for the disease biology andIL6STas a potential drug target.ConclusionsIn a large JIA GWAS, we identify five novel risk loci and describe potential function of JIA association signals that will be informative for future experimental works and therapeutic strategies. |
| Databáze: | OpenAIRE |
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