Myasthenia gravis genome-wide association study implicates AGRN as a risk locus

Abstract

BackgroundMyasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.MethodsWe performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders.ResultsWe confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10−13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders.DiscussionOur gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

Overview of biomarkers in myasthenia gravis

“…In addition, the genes of protein tyrosine phosphatase non-receptor type 22 protein (PTPN22), TNF receptor superfamily member 11a protein (TNFRSF11A), and HLA-DQA1/HLA-B showed MG-associated signals. A genome-wide association study including 1,401 MG patients and 3,508 healthy controls, also showed an association between HLA-DRB1/HLA-B and TNFRSF11A gene [70]. Like the previously discussed study, autoimmune diseases like type 1 diabetes, rheumatoid arthritis, late-onset vitiligo, and autoimmune thyroid disease were related to MG in this study.…”

PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

“…However in the GWAS catalog ( 41 ) FLI1 has a significant association with Vitiligo, when the onset age is not taken into account ( 42 ), and CTLA4 is found associated with different GWASs (not studied here) for both Myasthenia gravis ( 43 ) and Vitiligo ( 42 ). CTLA4 was also significant in the gene-based analysis ( 44 ) of the data we used in this meta-analysis. The gene set enrichment analysis including the genes in the significant and pleiotropic regions identified four significantly enriched GO : BP terms; bone cell development, immune system development, myeloid cell development, and immune system process ( Figure 6A ; Table S5 ).…”

PheWAS and cross-disorder analyses reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

“…However in the GWAS catalog (41) FLI1 has a significant association with Vitiligo, when the onset age is not taken into account (42), and CTLA4 is found associated with different GWASs (not studied here) for both Myasthenia gravis (43) and Vitiligo (42). CTLA4 was also significant in the gene-based analysis (44) of the data we used in this meta-analysis. The gene set enrichment analysis including the genes in the significant and pleiotropic regions identified four significantly enriched GO:BP terms; bone cell development, immune system development, myeloid cell development, and immune system process (Figure 6A, Table S4).…”