RT Journal Article
SR Electronic
T1 Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 801
OP 809
DO 10.1136/jmedgenet-2021-107953
VO 59
IS 8
A1 Apostolia Topaloudi
A1 Zoi Zagoriti
A1 Alyssa Camille Flint
A1 Melanie Belle Martinez
A1 Zhiyu Yang
A1 Fotis Tsetsos
A1 Yiolanda-Panayiota Christou
A1 George Lagoumintzis
A1 Evangelia Yannaki
A1 Eleni Zamba-Papanicolaou
A1 John Tzartos
A1 Xanthippi Tsekmekidou
A1 Kalliopi Kotsa
A1 Efstratios Maltezos
A1 Nikolaos Papanas
A1 Dimitrios Papazoglou
A1 Ploumis Passadakis
A1 Athanasios Roumeliotis
A1 Stefanos Roumeliotis
A1 Marios Theodoridis
A1 Elias Thodis
A1 Stylianos Panagoutsos
A1 John Yovos
A1 John Stamatoyannopoulos
A1 Konstantinos Poulas
A1 Kleopas Kleopa
A1 Socrates Tzartos
A1 Marianthi Georgitsi
A1 Peristera Paschou
YR 2022
UL http://jmg.bmj.com/content/59/8/801.abstract
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).