PT - JOURNAL ARTICLE AU - Tietz, Anja K. AU - Angstwurm, Klemens AU - Baumgartner, Tobias AU - Doppler, Kathrin AU - Eisenhut, Katharina AU - Elisak, Martin AU - Franke, Andre AU - Golombeck, Kristin S. AU - Handreka, Robert AU - Kaufmann, Max AU - Kraemer, Markus AU - Kraft, Andrea AU - Lewerenz, Jan AU - Lieb, Wolfgang AU - Madlener, Marie AU - Melzer, Nico AU - Mojzisova, Hana AU - Möller, Peter AU - Pfefferkorn, Thomas AU - Prüss, Harald AU - Rostásy, Kevin AU - Schnegelsberg, Margret AU - Schröder, Ina AU - Siebenbrodt, Kai AU - Sühs, Kurt-Wolfram AU - Wickel, Jonathan AU - Wandinger, Klaus-Peter AU - Leypoldt, Frank AU - Kuhlenbäumer, Gregor AU - on behalf of the German Network for Research on Autoimmune Encephalitis (GENERATE) TI - Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis AID - 10.1212/NXI.0000000000001085 DP - 2021 Nov 01 TA - Neurology - Neuroimmunology Neuroinflammation PG - e1085 VI - 8 IP - 6 4099 - http://nn.neurology.org/content/8/6/e1085.short 4100 - http://nn.neurology.org/content/8/6/e1085.full SO - Neurol Neuroimmunol Neuroinflamm2021 Nov 01; 8 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