A Myasthenia Gravis genomewide association study of three cohorts identifies Agrin as a novel risk locus

Abstract

AbstractBackgroundMyasthenia Gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction. Here, we investigate the genetic architecture of MG performing a genomewide association study (GWAS) of the largest MG dataset analyzed to date.MethodsWe integrated GWAS from three different datasets (1,401 cases, 3,508 controls) and performed MG GWAS and onset-specific analyses. We also carried out HLA fine-mapping, gene-based, gene ontology and tissue enrichment analyses and investigated genetic correlation to other autoimmune disorders.FindingsWe observed the strongest MG association to TNFRSF11A (rs4369774, p=1.09×10−13; OR=1.4). Gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent loci significantly associated with MG: HLA-DRB1 (with a protective role) and HLA-B. MG onset-specific analysis, reveals differences in the genetic architecture of Early-Onset vs Late-Onset MG. Furthermore, we find MG to be genetically correlated with Type 1 Diabetes, Rheumatoid Arthritis and late-onset Vitiligo.InterpretationOverall, our results are consistent with previous studies highlighting the role of the HLA and TNFRSF11A in MG etiology and different risk genes in EOMG vs LOMG. Furthermore, our gene-based analysis implicates, for the first time, AGRN as a MG susceptibility locus. AGRN encodes agrin, which is involved in neuromuscular junction formation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Gene ontology analysis suggests an intriguing role for symbiotic processes in MG etiology. We also uncover genetic correlation of MG to Type 1 Diabetes, Rheumatoid Arthritis and late-onset Vitiligo, pointing to shared underlying genetic mechanisms.FundingThis work was supported by NSF award #1715202, the European Social Fund and Greek funds through the National Strategic Reference Framework (NSRF) THALES Programme 2012–2015 and the NSRF ARISTEIA II Programme 2007–2013 to PP, and grants from the Association Francaise contre les Myopathies (AFM, Grant No. 80077) to ST.Research in contextEvidence before this studyMyasthenia Gravis (MG) is a complex disease caused by the interaction of genetic and environmental factors that lead to autoimmune activation. Previous studies have shown that the human leukocyte antigen (HLA) displays the most robust genetic association signals to MG. Additional susceptibility genes that have emerged through genomewide association studies (GWAS), include CTLA4 and TNFRSF11A. Previous studies also support the hypothesis of distinct risk loci underlying Early-Onset versus Late-Onset MG subgroups (EOMG vs LOMG). For instance, PTPN22 and TNIP1 genes have been implicated in EOMG and ZBTB10 in LOMG. In the GWAS studies published so far, HLA and TNFRSF11A associations appear to be confirmed; however, the association of other implicated genes still requires replication.Added value of this studyWe present the largest GWAS for MG to date, integrating three different datasets. We identify AGRN as a novel MG risk locus and replicate previously reported susceptibility loci, including HLA, TNFRSF11A, and CTLA4. Our analysis also supports the existence of a different genetic architecture in EOMG vs LOMG and identifies a region between SRCAP and FBRS as a novel EOMG risk locus. Additionally, through HLA fine-mapping, we observe different HLA genes implicated in EOMG vs LOMG (HLA-B and HLA-DRB1 respectively). Finally, we detect positive genetic correlation of MG with other autoimmune disorders including Type 1 Diabetes, Rheumatoid Arthritis, and late-onset Vitiligo, suggesting a shared genetic basis across them.Implications of all the available evidenceOur study sheds light into the etiology of MG identifying AGRN as a novel risk locus. AGRN encodes agrin, a protein with a significant role in the formation of the neuromuscular junction and mutations in this gene have been associated with congenital myasthenic syndrome. Our findings hint to an intriguing hypothesis of symbiotic processes underlying MG pathogenesis and points to muscle growth and development in EOMG and steroid hormones synthesis in LOMG. The observed genetic correlations between MG and certain other autoimmune disorders could possibly underlie comorbidity patterns across this group of disorders.