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

Abstract

Background and objectives: To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis.

Methods: We 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.

Results: We 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.

Discussion: This 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.

Figure 1. Association Plots for Anti-NMDAR Encephalitis

(A) Quantile-quantile plot of association analysis for 8,073,349 variants. The plot shows deviation from the null distribution in the upper tail, which corresponds to variants with the strongest evidence for association. (B) Manhattan plot of the association results. The plot shows −log10 marker-wise p values against their genomic base pair position. The red line indicates the genome-wide significance threshold of 5 × 10⁻⁸. (C) LocusZoom plot for the association between anti-NMDA receptor encephalitis and variants on chromosome 11 in the genomic region from 46.6 to 48.2 Mb. A circle represents a genotyped and a plus symbol an imputed variant. The r² metric displays the pairwise LD between the leading and the respective variant. Gene positions are present in the bottom part. (D) LocusZoom plot for associations on chromosome 15 in the genomic region from 100.9 to 101.1 Mb.

Figure 2. Colocalization Results for Brain Tissues

Gene- and SNP-wise results of the colocalization analysis for brain tissues represented in Genotype-Tissue Expression types. Only genes with a PP4 > 0.7 and variants with a p value < 10⁻⁵ are shown. ACP2 = acid phosphatase 2, lysosomal; GWAS = genome-wide association study; MADD = mitogen-activated protein kinase activating death domain; NR1H3 = nuclear receptor subfamily 1 group H member 3.

Figure 3. Colocalization Results for Immune Cells

Gene- and SNP-wise results of the colocalization for immune cells represented in the BLUEPRINT data set. Only genes with a PP4 > 0.7 and variants with a p value < 10⁻⁵ are shown. ACP2 = acid phosphatase 2, lysosomal; C11orf49 = chromosome 11 open reading frame 49; DDB2 = damage-specific DNA binding protein 2; GWAS = genome-wide association study; NR1H3 = nuclear receptor subfamily 1 group H member 3.