Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study

Authors

Ruth Chia, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892; ruth.chia@nih.gov.
Sara Saez-Atienzar, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892.
Natalie Murphy, Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892.
Adriano Chiò, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin 10126, Italy.
Cornelis Blauwendraat, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892.

Document Type

Journal Article

Publication Date

2-1-2022

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

119

Issue

5

DOI

10.1073/pnas.2108672119

Keywords

genetic correlation; genome-wide association study; myasthenia gravis; pathway analysis

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 () gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit () gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at , , and 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.

APA Citation

Chia, Ruth; Saez-Atienzar, Sara; Murphy, Natalie; Chiò, Adriano; and Blauwendraat, Cornelis, "Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study" (2022). GW Authored Works. Paper 389.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/389

Department

Neurology