RT Journal Article SR Electronic T1 Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis JF Neurology - Neuroimmunology Neuroinflammation JO Neurol Neuroimmunol Neuroinflamm FD Lippincott Williams & Wilkins SP e1085 DO 10.1212/NXI.0000000000001085 VO 8 IS 6 A1 Tietz, Anja K. A1 Angstwurm, Klemens A1 Baumgartner, Tobias A1 Doppler, Kathrin A1 Eisenhut, Katharina A1 Elisak, Martin A1 Franke, Andre A1 Golombeck, Kristin S. A1 Handreka, Robert A1 Kaufmann, Max A1 Kraemer, Markus A1 Kraft, Andrea A1 Lewerenz, Jan A1 Lieb, Wolfgang A1 Madlener, Marie A1 Melzer, Nico A1 Mojzisova, Hana A1 Möller, Peter A1 Pfefferkorn, Thomas A1 Prüss, Harald A1 Rostásy, Kevin A1 Schnegelsberg, Margret A1 Schröder, Ina A1 Siebenbrodt, Kai A1 Sühs, Kurt-Wolfram A1 Wickel, Jonathan A1 Wandinger, Klaus-Peter A1 Leypoldt, Frank A1 Kuhlenbäumer, Gregor A1 on behalf of the German Network for Research on Autoimmune Encephalitis (GENERATE) YR 2021 UL http://nn.neurology.org/content/8/6/e1085.abstract AB 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.AAO=age at onset; eQTL=expression quantitative trait loci; GENERATE=German Network for Research on Autoimmune Encephalitis; GSA=global screening array; GT=genotyped; GTEx=Genotype-Tissue Expression; GWAS=genome-wide association study; HLA=human leukocyte antigen; HSV-1=herpes simplex virus type 1 (HSV-1); HWE=Hardy-Weinberg equilibrium; IBD=identity by descent; IM=imputed; IgG=immunoglobulin G; LD=linkage disequilibrium; LDSC=LD score regression; LXRα=liver X receptor alpha; MADD=mitogen-activated protein kinase activating death domain; MAF=minor allele frequency; MAP=mitogen-activated protein; NMDAR=NMDA receptor; PC=principal component; PP=posterior probability; SNP=single nucleotide polymorphism; TNF-α=tumor necrosis factor alpha; TOPmed=Trans-Omics for Precision medicine