Background Myasthenia 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. Methods We 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. Findings We observed the strongest MG association to TNFRSF11A (rs4369774, p=1.09x10-13; 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. Interpretation Overall, 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. Funding This 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.
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.
Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
<p>Hallmark E2F Targets Enrichment Plot and Top DEGs</p>
<p>Etv4, Dusp6, Phlda1, and Dusp4 mRNA expression</p>
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