| Title: | Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts |
| Journal: | Brain |
| Published: | 26 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39454566/ |
| DOI: | https://doi.org/10.1093/brain/awae349 |
Publication 14586
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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.</p>
15 Keywords
- Adult
- Aged
- Autoantibodies
- Cohort Studies
- Encephalitis
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Intracellular Signaling Peptides and Proteins
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- RNA, Long Noncoding
- Receptor-Like Protein Tyrosine Phosphatases, Class 2
28 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 43920 | The epidemiology of infectious diseases within UK Biobank |
Enabling scientific discoveries that improve human health