Genomic Insights into Myasthenia Gravis Identify Distinct Immunological Mechanisms in Early and Late Onset Disease.
Handunnetthi L., Knezevic B., Kasela S., Burnham KL., Milani L., Irani SR., Fang H., Knight JC.
OBJECTIVE: The purpose of this study was to identify disease relevant genes and explore underlying immunological mechanisms that contribute to early and late onset forms of myasthenia gravis. METHODS: We used a novel genomic methodology to integrate genomewide association study (GWAS) findings in myasthenia gravis with cell-type specific information, such as gene expression patterns and promotor-enhancer interactions, in order to identify disease-relevant genes. Subsequently, we conducted additional genomic investigations, including an expression quantitative analysis of 313 healthy people to provide mechanistic insights. RESULTS: We identified several genes that were specifically linked to early onset myasthenia gravis including TNIP1, ORMDL3, GSDMB, and TRAF3. We showed that regulators of toll-like receptor 4 signaling were enriched among these early onset disease genes (fold enrichment = 3.85, p = 6.4 × 10-3 ). In contrast, T-cell regulators CD28 and CTLA4 were exclusively linked to late onset disease. We identified 2 causal genetic variants (rs231770 and rs231735; posterior probability = 0.98 and 0.91) near the CTLA4 gene. Subsequently, we demonstrated that these causal variants result in low expression of CTLA4 (rho = -0.66, p = 1.28 × 10-38 and rho = -0.52, p = 7.01 × 10-22 , for rs231735 and rs231770, respectively). INTERPRETATION: The disease-relevant genes identified in this study are a unique resource for many disciplines, including clinicians, scientists, and the pharmaceutical industry. The distinct immunological pathways linked to early and late onset myasthenia gravis carry important implications for drug repurposing opportunities and for future studies of drug development. ANN NEUROL 2021.