Journal Article

Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis

Tienari, Pentti J., Guida, Melania, Kaminski, Henry J., Roda, Ricardo H., Traynor, Bryan J., Evoli, Amelia, Blauwendraat, Cornelis, Murphy, Natalie, Chiò, Adriano, Saez-Atienzar, Sara, Petrucci, Loredana, Chia, Ruth, Drachman, Daniel B., De Rosa, Anna, Provenzano, Carlo, Ricciardi, Roberta

2022

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Acetylcholine receptors / Adult / Antibodies / Antigens / Arthritis / Autoantibodies / Autoimmune diseases / Biological Sciences / Cholinergics / Chromosome 10 / Correlation analysis / Diabetes mellitus (insulin dependent) / Disease / DQA1 protein / Female / Gene expression / Gene Expression - genetics / Gene Frequency - genetics / Genes / Genetic analysis / Genetic factors / Genetic Loci - genetics / Genetic Predisposition to Disease - genetics / Genetics / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Health risk assessment / Histocompatibility antigen HLA / Humans / Hypothyroidism / Loci / Male / Multiple sclerosis / Muscle, Skeletal - pathology / Muscles / Musculoskeletal system / Myasthenia gravis / Myasthenia Gravis - genetics / Neuromuscular junctions / Osteoprotegerin / Pathogenesis / Polymorphism, Genetic - genetics / Protein-tyrosine-phosphatase / Receptors / Receptors, Cholinergic - genetics / Receptors, Nicotinic - genetics / Rheumatoid arthritis / Risk analysis / Risk factors / Signal Transduction - genetics / Signal transmission / Skeletal muscle / Subgroups / Tibial nerve / Transcriptomes