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