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

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, pperm = 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, pperm = 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.