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Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis
Anja K Tietz1, Klemens Angstwurm1, Tobias Baumgartner1
1From the Department of Neurology (A.K.T., F.L., G.K.), Kiel University; Department of Neurology (K.A.), University Hospital Regensburg; Department of Epileptiology (T.B.), University Hospital Bonn; Department of Neurology (K.D.), University Hospital Würzburg; Institute of Clinical Neuroimmunology (K.E.), Biomedical Center and University Hospital, Ludwig Maximilians University, Munich, Germany; Department of Neurology (M.E., H.M.), Charles University, Second Faculty of Medicine and Motol University Hospital, Prague, Czech Republic; Institute of Clinical Molecular Biology (A.F.), Kiel University; Department of Neurology (K.S.G.), University Hospital Münster; Department of Neurology (R.H.), Carl-Thiem-Klinikum Cottbus; Institute of Neuroimmunology and Multiple Sclerosis (INIMS) (Max Kaufmann), University Medical Center Hamburg-Eppendorf; Department of Neurology (Markus Kraemer), Alfried Krupp Hospital, Essen; Department of Neurology (Markus Kraemer, N.M.), Medical Faculty, Heinrich-Heine University Düsseldorf; Department of Neurology (A.K.), Martha-Maria Hospital Halle; Department of Neurology (J.L.), University of Ulm; Institute of Epidemiology (W.L.), Kiel University; Department of Neurology (M.M.), University Hospital Cologne; Department of Neurology and Clinical Neurophysiology (P.M.), Klinikum Weimar; Department of Neurology (T.P.), Klinikum Ingolstadt; Department of Neurology and Experimental Neurology (H.P.), Charité - Universitätsmedizin Berlin and German Center for Neurodegenerative Diseases (DZNE) Berlin; Department of Pediatric Neurology (K.R.), Children's Hospital Datteln, Witten/Herdecke University; Department of Neurology (M.S.), Asklepios Hospitals Schildautal, Seesen; Neuroimmunology (I.S., K.-P.W., F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck; Epilepsy Center Frankfurt Rhine-Main and Department of Neurology (K.S.), Unversity Hospital and Goethe Universiy Frankfurt; Department of Neurology (K.-W.S.), Hannover Medical School; and Section Translational Neuroimmunology (J.W.), Department of Neurology, University Hospital Jena, Germany.
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.
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