Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis

Abstract

Background and ObjectivesTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10−8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes.DiscussionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.

Paraneoplastic Neurologic Syndromes

“…A family history of autoimmune disease is more common in patients with paraneoplastic syndromes 11 . An underlying immunogenetic predisposition to paraneoplastic neurologic disorders may be present, as seen with human leukocyte antigen–type and immune gene associations for NMDA-receptor encephalitis 12 . This is most suggestive in syndromes with a low incidence of associated tumors: 90% of patients with IgLON family member 5 (IgLON5)-related syndromes have the DQB1*05 allele and 60% also have the DRB1*10:01 allele; 90% of patients with contactin-associated proteinlike 2 (CASPR2)-related syndromes have the DRB1*11:01 allele; and 40% of patients with glutamic acid decarboxylase 65 (GAD65)-related syndromes have the DQB*02:01 allele.…”

A protein with broad functions: damage-specific DNA-binding protein 2

“…In addition, by studying the colocalization signals in different brain regions and immune cells expressing quantitative characteristic loci, Tietz et al found that DDB2 may be the pathogenic gene that causes anti-NMDAR receptor (antiNMDAR) encephalitis [ 103 ].…”

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis

“…Later, very weak and doubtful associations were reported with B*07:02 in adult patients of Caucasian origin [ 96 ] and with DRB1*16:02 in a Chinese cohort [ 97 ]. However, these associations have not been confirmed in a very recent genome-wide association study (GWAS) including the largest cohort ( n = 178) investigated to date [ 98 ].…”

“…Nevertheless, the first GWAS performed in anti-NMDAR encephalitis obtained no positive results, although the number of patients included was fairly small [ 96 ]. The same authors have very recently doubled the sample size and reported a significant association with LRRK1 (leucine-rich repeat kinase 1), ACP2 (lysosomal acid phosphatase), and NR1H3 (nuclear receptor subfamily 1 group H member 3) genes, which might have some yet poorly defined functions in immune and inflammatory responses [ 98 ]. Despite being appealing, these results have to be carefully considered, since there was no replication cohort due to the still insufficient sample size [ 98 ].…”