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

• Published in: Journal of medical genetics Vol. 59; no. 8; pp. 801 - 809
• Main Authors: Topaloudi, Apostolia, Zagoriti, Zoi, Flint, Alyssa Camille, Martinez, Melanie Belle, Yang, Zhiyu, Tsetsos, Fotis, Christou, Yiolanda-Panayiota, Lagoumintzis, George, Yannaki, Evangelia, Zamba-Papanicolaou, Eleni, Tzartos, John, Tsekmekidou, Xanthippi, Kotsa, Kalliopi, Maltezos, Efstratios, Papanas, Nikolaos, Papazoglou, Dimitrios, Passadakis, Ploumis, Roumeliotis, Athanasios, Roumeliotis, Stefanos, Theodoridis, Marios, Thodis, Elias, Panagoutsos, Stylianos, Yovos, John, Stamatoyannopoulos, John, Poulas, Konstantinos, Kleopa, Kleopas, Tzartos, Socrates, Georgitsi, Marianthi, Paschou, Peristera
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.08.2022; BMJ Publishing Group LTD
• Subjects: Age; Agrin; Autoimmune diseases; Biobanks; Datasets; Diabetes mellitus (insulin dependent); Disease; Drb1 protein; Gene loci; Gene mapping; Genetic analysis; Genome-wide association studies; Genome-wide studies; Genomes; Genotype & phenotype; Health risk assessment; Histocompatibility antigen HLA; human genetics; Meta-analysis; Myasthenia; Myasthenia gravis; neuromuscular diseases; Neuromuscular junctions; Osteoprotegerin; Pleiotropy; Proteins; Quality control; Rheumatoid arthritis; Thyroid diseases; Vitiligo; Greece; United Kingdom > UK; Cyprus
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2021-107953

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.