A Genome-Wide Association Study of Myasthenia Gravis

IMPORTANCE-Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups.Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.OBJECTIVE-To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.DESIGN, SETTING, AND PARTICIPANTS-DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011.These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays.An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES-We calculated P values for association between8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling.A threshold P value of 5.0 × 10 -8 was set for genomewide significance after Bonferroni correction for multiple testing. RESULTS-In the over all case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10 -8 ; odds ratio, 1.37; 95% CI, 1.25-1.49),HLA-DQA1 (rs9271871; P = 1.08 × 10 -8 ; odds ratio, 2.31; 95% CI, 2.02 -2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10 -9 ; odds ratio, 1.41; 95% CI, 1.29-1.53).These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals.Further analysis revealed distinct,