Abstract |
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.
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Authors | Ruth Chia, Sara Saez-Atienzar, Natalie Murphy, Adriano Chiò, Cornelis Blauwendraat, International Myasthenia Gravis Genomics Consortium, Ricardo H Roda, Pentti J Tienari, Henry J Kaminski, Roberta Ricciardi, Melania Guida, Anna De Rosa, Loredana Petrucci, Amelia Evoli, Carlo Provenzano, Daniel B Drachman, Bryan J Traynor |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 119
Issue 5
(02 01 2022)
ISSN: 1091-6490 [Electronic] United States |
PMID | 35074870
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2022 the Author(s). Published by PNAS. |
Chemical References |
- Receptors, Cholinergic
- Receptors, Nicotinic
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Topics |
- Adult
- Female
- Gene Expression
(genetics)
- Gene Frequency
(genetics)
- Genetic Loci
(genetics)
- Genetic Predisposition to Disease
(genetics)
- Genome-Wide Association Study
(methods)
- Humans
- Male
- Muscle, Skeletal
(pathology)
- Myasthenia Gravis
(genetics)
- Polymorphism, Genetic
(genetics)
- Receptors, Cholinergic
(genetics)
- Receptors, Nicotinic
(genetics)
- Signal Transduction
(genetics)
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