Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
Sophie Binks, Katherine S. Elliott, Sergio Muñiz‐Castrillo, Edmund Gilbert, Tânia Kawasaki de Araujo, Andrew R. Harper, Andrew Brown, Amanda Y. Chong, Gavin Band, Vicente Peris Sempere, Anne‐Laurie Pinto, Félicie Costantino, N. William Rayner, Alexander J. Mentzer, Norman Delanty, Véronique Rogemond, Géraldine Picard, Adam E. Handel, Nico Melzer, Maarten J. Titulaer, Soon‐Tae Lee, Frank Leypoldt, Gregor Kuhlenbäeumer, Jérôme Honnorat, Emmanuel Mignot, Gianpiero L Cavelleri, Julian C. Knight, Sarosh R. Irani
Abstract
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 leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized 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 at genome-wide significance (P < 5 × 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.