Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study
| Autor: | Chia, Ruth, Saez-Atienzar, Sara, Murphy, Natalie, Chiò, Adriano, Blauwendraat, Cornelis, Roda, Ricardo H, Tienari, Pentti J, Kaminski, Henry J, Ricciardi, Roberta, Guida, Melania, De Rosa, Anna, Petrucci, Loredana, Evoli, Amelia, Provenzano, Carlo, Drachman, Daniel B, Traynor, Bryan J |
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| Přispěvatelé: | Clinicum, Department of Neurosciences, HUS Neurocenter |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
EXPRESSION
Adult Male Gene Expression Nicotinic 3124 Neurology and psychiatry Gene Frequency Genetic Receptors Humans Genetic Predisposition to Disease RATES Polymorphism Cholinergic myasthenia gravis Multidisciplinary genome-wide association study 3112 Neurosciences 1184 Genetics developmental biology physiology Skeletal genetic correlation pathway analysis Settore MED/26 - NEUROLOGIA ANTIBODY Genetic Loci Muscle Female Genome-Wide Association Study Muscle Skeletal Myasthenia Gravis Polymorphism Genetic Receptors Cholinergic Receptors Nicotinic Signal Transduction |
| Popis: | Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early-and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis. |
| Databáze: | OpenAIRE |
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