| Title: | Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study |
| Journal: | Proceedings of the National Academy of Sciences of the United States of America |
| Published: | 24 Jan 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35074870/ |
| DOI: | https://doi.org/10.1073/pnas.2108672119 |
| Citations: | 62 (49 in last 2 years) as of 8 Aug 2024 |
Publication 12592
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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.</p>
15 Keywords
- Adult
- Female
- Gene Expression
- Gene Frequency
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Muscle, Skeletal
- Myasthenia Gravis
- Polymorphism, Genetic
- Receptors, Cholinergic
- Receptors, Nicotinic
- Signal Transduction
63 Authors
- Ruth Chia
- Sara Saez-Atienzar
- Natalie Murphy
- Adriano Chiò
- Cornelis Blauwendraat
- 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
- Yevgeniya Abramzon
- Richard J. Barohn
- Michael Benatar
- Derrick Blackmore
- Vinay Chaudhry
- Adriano Chiò
- Manisha Chopra
- Andrea Corse
- Anna De Rosa
- Mazen M. Dimachkie
- Amelia Evoli
- Julaine Florence
- Miriam Freimer
- Melania Guida
- James F. Howard
- Theresa Jiwa
- Henry J. Kaminski
- John T. Kissel
- Wilma J. Koopman
- Bernadette Lipscomb
- Michelangelo Maestri
- Mariapaola Marino
- Janice M. Massey
- April McVey
- Michelle M. Mezei
- Srikanth Muppidi
- Michael W. Nicolle
- Joel Oger
- Robert M. Pascuzzi
- Mamatha Pasnoor
- Alan Pestronk
- Loredana Petrucci
- Hannah A. Pliner
- Carlo Provenzano
- Alan E. Renton
- Roberta Ricciardi
- David P. Richman
- Julie Rowin
- Donald B. Sanders
- Mario Sabatelli
- Zaeem Siddiqi
- Aimee Soloway
- Laura Todi
- Gil Wolfe
- Charlie Wulf
- Daniel B. Drachman
- Bryan J. Traynor
1 Application
| Application ID | Title |
|---|---|
| 33601 | Dissecting the genetic architecture of neurodegenerative diseases |
Enabling scientific discoveries that improve human health