Work

Causal Variants in CHRNA1 and CHRNB1 Genes for Anti-acetylcholine Receptor Antibody Positive Myasthenia Gravis: Evidence from Bayesian Fine-Mapping and Genetic Association Study

Year: 2025

Type: book-chapter

Abstract: Autoantibodies target the acetylcholine receptor (AChR) in 85% of myasthenia gravis (MG) patients. Genomic studies highlighted the association of genes encoding AChR subunits ( CHRNA1 and CHRNB1 ) and MG in European populations. Additionally, Mendelian randomization revealed rs4151121 at the CHRNB1 locus as a potential causal variant. Here, we performed Bayesian fine-mapping of the CHRNA1 locus using GWAS summary statistics, a linkage disequilibrium matrix and functional annotations. The GWAS lead hit rs35274388 was identified as a causal variant overlapping with the promoter region ( p < 0.01). Next, we performed a candidate gene study including 1038 participants from Serbia. Rs4151121 minor allele G was associated with late-onset MG (LOMG) (OR = 1.327, 95% CI = 1.084–1.625, p = 0.006, p perm = 0.007). Carriers of the rs4151121 GG and AG genotypes had an almost 1.5-fold increased risk of developing LOMG. A borderline association of the rs35274388 minor allele A with MG was observed (OR = 1.478, 95% CI = 1.009–2.166, p = 0.044, p perm = 0.060). Individuals with AA and GA genotypes also showed a nearly 1.5-fold higher risk of developing MG. In silico-identified causal variants at the CHRNA1 and CHRNB1 loci represent risk factors for MG in European populations, and to a greater extent for LOMG. Studies on non-European populations and functional research are needed to elucidate the role of AChR genes in the genetic architecture and development of MG.

Source: Molecular Neurobiology

DOI: 10.1007/s12035-025-04958-7