Skip to main content
Premium Trial:

Request an Annual Quote

Myasthenia Gravis Study Identifies Genetic Risk Loci Affecting Acetylcholine Receptor

This story has been updated to include a comment from a researcher.

NEW YORK — Genetic alterations affecting the acetylcholine receptor contribute to the development of the autoimmune disease myasthenia gravis, a new study from researchers at the National Institute on Aging has found.

In myasthenia gravis, which affects about 77 out of every million people, autoantibodies attack proteins at the neuromuscular junction, leading to muscle weakness in the limbs as well as around the eyes, mouth, and throat. The condition tends to arise in two different age cohorts: before the age of 40, when mostly women are affected, and around the age of 60, when more men than women are affected.

By combining a genome-wide and a transcriptome-wide association study, the researchers uncovered signals in two genes that encode acetylcholine receptor subunits that may increase the risk of developing acetylcholine receptor antibody-positive myasthenia gravis. As they additionally reported in the Proceedings of the National Academy of Sciences on Monday, they also uncovered differences in the genetic underpinnings of the early- and late-onset forms of the conditions.

"The variants that we discovered could be operating by influencing immune tolerance or altering the number of receptors … but we cannot comment on which is the actual mechanism. That is why our paper is intriguing — it opens new avenues to explore in myasthenia gravis," senior author Bryan Traynor from NIA said in an email.

Through a GWAS of 1,873 individuals with acetylcholine receptor antibody-positive myasthenia gravis — the type that affects about 90 percent of people with the condition — and 36,370 healthy individuals, the researchers uncovered previously reported signals linked to the disease in genes such as PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A. They also found new signals, for example in a promoter region of the CHRNA1 gene, which encodes an acetylcholine receptor, and in an intron of the SFMBT2 gene and near the FAM76B gene. Only the signal near CHRNA1, though, was replicated in a cohort from the UK Biobank.

The researchers additionally split their GWAS cohort into early- and late-onset myasthenia gravis and found that while both were associated with loci in the MHC regions, the specific variants differed. Further, the PTPN22, TNFRSF11A, and CHRNA1 loci were more strongly associated with late-onset than early-onset disease.

Meanwhile, a TWAS that overlaid the GWAS results on gene expression profiles of skeletal muscle, peripheral nerves, and whole blood from the Genotype-Tissue Expression dataset uncovered six genes whose expression differed with myasthenia gravis risk. These included CHRNB1, which encodes a cholinergic receptor subunit and was a sub-significant hit in the GWAS.

These findings implicating CHRNA1 and CHRNB1 — coding mutations in which are known causes of congenital myasthenia gravis — point to possible disease mechanisms, the researchers noted. For instance, changes to CHRNA1 expression in thymus or other immune cells could interfere with the development of immunological tolerance to the acetylcholine receptor. Alternatively, the variants could affect the overall expression of their receptor subunits and, in turn, decrease the number of acetylcholine receptors present in the neuromuscular synapse.

Using a target prioritization analysis, the researchers further explored what other pathways might be involved in myasthenia gravis and whether any might be amenable drug targets. Enriched pathways included those involved in the adaptive immune response, cytokine signaling in the immune system, and receptor tyrosine kinase signaling.

Further studies into the molecular mechanisms of how CHRNA1 and CHRNB1 expression leads to disease are needed, the researchers said, as are studies of non-European ancestry individuals with myasthenia gravis.