PT  - JOURNAL ARTICLE
AU  - Apostolia Topaloudi
AU  - Zoi Zagoriti
AU  - Alyssa Camille Flint
AU  - Melanie Belle Martinez
AU  - Zhiyu Yang
AU  - Fotis Tsetsos
AU  - Yiolanda-Panayiota Christou
AU  - George Lagoumintzis
AU  - Evangelia Yannaki
AU  - Eleni Zamba-Papanicolaou
AU  - John Tzartos
AU  - Xanthippi Tsekmekidou
AU  - Kalliopi Kotsa
AU  - Efstratios Maltezos
AU  - Nikolaos Papanas
AU  - Dimitrios Papazoglou
AU  - Ploumis Passadakis
AU  - Athanasios Roumeliotis
AU  - Stefanos Roumeliotis
AU  - Marios Theodoridis
AU  - Elias Thodis
AU  - Stylianos Panagoutsos
AU  - John Yovos
AU  - John Stamatoyannopoulos
AU  - Konstantinos Poulas
AU  - Kleopas Kleopa
AU  - Socrates Tzartos
AU  - Marianthi Georgitsi
AU  - Peristera Paschou
TI  - Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
AID  - 10.1136/jmedgenet-2021-107953
DP  - 2022 Aug 01
TA  - Journal of Medical Genetics
PG  - 801--809
VI  - 59
IP  - 8
4099  - http://jmg.bmj.com/content/59/8/801.short
4100  - http://jmg.bmj.com/content/59/8/801.full
SO  - J Med Genet2022 Aug 01; 59
AB  - Background Myasthenia 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.Methods We 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.Results We 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.Discussion Our 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.Data are available in a public, open access repository. Data are available upon reasonable request. Summary statistics will become available upon publication of this study at the Paschou Lab website. De-identified raw genotype data can become available upon request by email to the corresponding author (ppaschou@purdue.edu).