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

Authors :
Binks SNM
Elliott KS
Muñiz-Castrillo S
Gilbert E
Kawasaki de Araujo T
Harper AR
Brown AC
Chong AY
Band G
Peris Sempere V
Pinto AL
Costantino F
Rayner NW
Mentzer AJ
Delanty N
Rogemond V
Picard G
Handel AE
Melzer N
Titulaer MJ
Lee ST
Leypoldt F
Kuhlenbaeumer G
Honnorat J
Mignot E
Cavelleri GL
Knight JC
Irani SR
Source :
Brain : a journal of neurology [Brain] 2024 Oct 26. Date of Electronic Publication: 2024 Oct 26.
Publication Year :
2024
Publisher :
Ahead of Print

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.<br /> (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Details

Language :
English
ISSN :
1460-2156
Database :
MEDLINE
Journal :
Brain : a journal of neurology
Publication Type :
Academic Journal
Accession number :
39454566
Full Text :
https://doi.org/10.1093/brain/awae349