Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

中文翻译：

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LGI1 抗体脑炎的新风险位点：全基因组关联研究发现和验证队列


伴有富含亮氨酸的胶质瘤失活 1 （LGI1-Ab-E） 抗体的脑炎是自身免疫性脑炎的一种常见形式，表现为癫痫发作和神经精神变化，主要见于老年男性。超过 90% 的患者携带人类白细胞抗原 （HLA） II 类等位基因 HLA-DRB1*07：01。然而，这也存在于 25% 的健康对照中。因此，我们假设存在额外的遗传易感性。在这项全基因组关联研究和荟萃分析中，我们研究了 131 名法国 LGI1-Ab-E 的发现队列和 126 名美国、英国和爱尔兰 LGI1-Ab-E 患者的验证队列，血统分别与 2613 名和 2538 名欧洲对照。在已知的主要 HLA 信号之外，我们发现了两个具有全基因组显着性的单核苷酸多态性 （SNP） （p < 5 x 10−8），涉及 PTPRD（一种蛋白酪氨酸磷酸酶）和 LINC00670（一种非蛋白编码 RNA 基因）。Meta 分析定义了 4 个额外的非 HLA 基因位点，包括编码 COBL 基因的蛋白质。有和没有 HLA 变异的多基因风险评分表明非 HLA 基因座的贡献。计算机网络分析表明，LGI1 和 PTPRD 通过已建立的 LGI1、ADAM22 和 ADAM23 受体介导相互作用。我们的结果在 LGI1-Ab-E 中发现了新的遗传位点。这些发现为机制研究提供了机会，并提供了易感性、预后和治疗反应的潜在标志物。