Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts.

in Brain : a journal of neurology by Sophie N M Binks, Katherine S Elliott, Sergio Muñiz-Castrillo, Edmund Gilbert, Tânia Kawasaki de Araujo, Andrew R Harper, Andrew C Brown, Amanda Y Chong, Gavin Band, Vicente Peris Sempere, Anne-Laurie Pinto, Felicie Costantino, N William Rayner, Alexander J Mentzer, Norman Delanty, Veronique Rogemond, Géraldine Picard, Adam E Handel, Nico Melzer, Maarten J Titulaer, Soon-Tae Lee, Frank Leypoldt, Gregor Kuhlenbaeumer, Jérôme Honnorat, Emmanuel Mignot, Gianpiero L Cavelleri, Julian C Knight, Sarosh R Irani

TLDR

  • ELI5: This study found that people with a certain type of autoimmune encephalitis (LGI1-Ab-E) have a higher chance of having a specific genetic makeup. The study looked at a group of people with LGI1-Ab-E and compared them to a group of healthy people. They found that two specific genes were more likely to be present in people with LGI1-Ab-E. The study also found that other genes were more likely to be present in people with LGI1-Ab-E, but these genes were not as strongly linked to the condition as the two specific genes. The study suggests that these genes may be involved in the development of LGI1-Ab-E and could be used as markers to help diagnose and treat the condition.

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 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.

Overview

  • The study focuses on encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E), a common form of autoimmune encephalitis in older males. The study aims to identify additional genetic predispositions beyond the known major HLA signal. The methodology used includes a genome-wide association study and meta-analysis of a discovery cohort of 131 French LGI1-Ab-E patients and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. The study identifies 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 defines four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants propose a contribution of non-HLA loci. The study aims to identify new genetic loci in LGI1-Ab-E and offers potential markers of susceptibility, prognostics and therapeutic responses.

Comparative Analysis & Findings

  • The study compares the outcomes observed in the discovery and validation cohorts. The results identify two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD and LINC00670. Meta-analysis defines four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants propose a contribution of non-HLA loci. The study finds that the presence of additional genetic predispositions beyond the known major HLA signal is associated with LGI1-Ab-E. The findings suggest that LGI1 and PTPRD may mediate interactions via established receptors of LGI1, ADAM22 and ADAM23.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The identification of new genetic loci in LGI1-Ab-E offers potential markers of susceptibility, prognostics and therapeutic responses. The study suggests that LGI1 and PTPRD may mediate interactions via established receptors of LGI1, ADAM22 and ADAM23. Future research should focus on understanding the mechanisms underlying these interactions and identifying potential therapeutic targets. The study also highlights the importance of considering non-HLA loci in the study of autoimmune encephalitis. Limitations of the study include the relatively small sample size and the need for further validation in larger cohorts. Future research should also explore the role of environmental factors in the development of LGI1-Ab-E.
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