Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
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DOI：
10.1136/jmedgenet-2021-107953
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发表时间：
2021-08
影响因子：
4
通讯作者：
Apostolia Topaloudi;Zoi Zagoriti;Alyssa C Flint;Melanie B. Martinez;Zhiyu Yang;Fotis Tsetsos;Y. Christou;George Lagoumintzis;E. Yannaki;E. Zamba-Papanicolaou;J. Tzartos;Xanthippi Tsekmekidou;K. Kotsa;E. Maltezos;N. Papanas;D. Papazoglou;P. Passadakis;Athanasios Roumeliotis;S. Roumeliotis;M. Theodoridis;E. Thodis;S. Panagoutsos;J. Yovos;J. Stamatoyannopoulos;K. Poulas;K. Kleopa;S. Tzartos;Marianthi Georgitsi;P. Paschou
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作者：
Apostolia Topaloudi;Zoi Zagoriti;Alyssa C Flint;Melanie B. Martinez;Zhiyu Yang;Fotis Tsetsos;Y. Christou;George Lagoumintzis;E. Yannaki;E. Zamba-Papanicolaou;J. Tzartos;Xanthippi Tsekmekidou;K. Kotsa;E. Maltezos;N. Papanas;D. Papazoglou;P. Passadakis;Athanasios Roumeliotis;S. Roumeliotis;M. Theodoridis;E. Thodis;S. Panagoutsos;J. Yovos;J. Stamatoyannopoulos;K. Poulas;K. Kleopa;S. Tzartos;Marianthi Georgitsi;P. Paschou
背景重症肌无力（MG）是一种罕见的影响神经肌肉接头（NMJ）的自身免疫性疾病。在这里，我们通过迄今为止分析的最大 MG 数据集的全基因组关联研究 (GWAS) 来研究 MG 的遗传结构。方法 我们整合了三个不同的数据集（总共 1401 个病例和 3508 个对照）进行了 GWAS 荟萃分析。我们进行了人类白细胞抗原 (HLA) 精细定位、基于基因和组织富集分析，并研究了与 13 种其他自身免疫性疾病的遗传相关性以及 MG 和相关疾病的多效性。结果我们证实了先前报道的 MG 与 TNFRSF11A 的关联（rs4369774；p=1.09×10−13，OR=1.4）。此外，基于基因的分析表明 AGRN 是一种新的 MG 易感基因。 HLA 精细定位指向两个独立的 MG 基因座：HLA-DRB1 和 HLA-B。 MG 发病特异性分析揭示了早发 MG (EOMG) 与晚发 MG (LOMG) 遗传结构的差异。此外，我们发现 MG 与 1 型糖尿病 (T1D)、类风湿性关节炎 (RA)、迟发性白癜风和自身免疫性甲状腺疾病 (ATD) 存在遗传相关性。跨疾病荟萃分析揭示了多个风险位点，这些位点在 MG 和相关疾病中表现出多效性。讨论 我们基于基因的分析将 AGRN 确定为一种新型 MG 易感基因，首次暗示编码与 NMJ 激活直接相关的蛋白质（集聚蛋白）的基因座。 AGRN 突变已被发现是先天性肌无力综合征的根源。我们的结果也与之前的研究一致，强调了 HLA 和 TNFRSF11A 在 MG 病因学中的作用以及 EOMG 与 LOMG 中的不同风险基因。最后，我们揭示了 MG 与 T1D、RA、ATD 和迟发性白癜风的遗传相关性，指出了共同的潜在遗传机制。
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.