Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis
Anja Tietz, Klemens Angstwurm, Tobias Baumgartner, Kathrin Doppler, Katharina Eisenhut, Martin Elišák, André Franke, Kristin S. Golombeck, Robert Handreka, Max Kaufmann, Markus Kraemer, Andrea Kraft, Jan Lewerenz, Wolfgang Lieb, Marie Madlener, Nico Melzer, Hana Mojžišová, Peter Möller, Thomas Pfefferkorn, Harald Prüß, Kevin Rostásy, Margret Schnegelsberg, Ina Schröder, Kai Siebenbrodt, Kurt‐Wolfram Sühs, Jonathan Wickel, Klaus‐Peter Wandinger, Frank Leypoldt, Gregor Kuhlenbäumer, Markus Kraemer, Wolfgang Heide, Stephan Schreiber, Marina Entscheva, Jürgen Faiss, R. Berger, Oliver Stammel, Anna Hoffmann, G Seidel, Robert Handreka, Harald Prüß, Josef Priller, Carsten Finke, Paul Friedemann, Peter Körtvélyessy, Henning Stolze, Astrid Blaschek, Sebastian Bauer, Felix Rosenow, Kai Siebenbrodt, Susanne Knake, Benjamin Wunderlich, Sven Ehrlich, Lena Edelhoff, Judith Wagner, George Trendelenburg, Anna Gorsler, Sebastian Baatz, Sonka Benesch, Matthias von Mering, Armin Grau, Christian Urbanek, Gernot Reimann, Tobias Neumann‐Haefelin, Thomas Pfefferkorn, Sascha Berning, Christoph Kellinghaus, Michael Nagel, Andreas Binder, Mona Dreeesmann, Fatme Seval Ismail, Ulrich Hofstadt‐van Oy, Christian G. Bien, M. M. Gebhard, Frank Hoffmann, Andrea Kraft, Franz Blaes, Corinna Bien, Andeas Linsa, Katharina Eisenhut, Joachim Havla, Franziska Thaler, Tanja Kümpfel, Til Menge, Manuel A. Friese, Max Kaufmann, Martin Stangel, Kurt‐Wolfram Sühs, Corinna Trebst, Jost Obrocki, Jens Schaumberg, Ilya Ayzenberg, Kerstin Hellwig, Christos Krogias, Friedrich Ebinger, Alexander Finke, Marie‐Luise Mono, Daniel Bittner, Stefan Bittner, Simone C. Tauber, Martin Häusler
Abstract
<h3>Background and Objectives</h3> To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. <h3>Methods</h3> 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. <h3>Results</h3> We identified 2 independent risk loci harboring genome-wide significant variants (<i>p</i> < 5 × 10<sup>−8</sup>, OR ≥ 2.2), 1 on chromosome 15, harboring only the <i>LRRK1</i> gene, and 1 on chromosome 11 centered on the <i>ACP2</i> and <i>NR1H3</i> 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 <i>ACP2</i>, <i>NR1H3</i>, <i>MADD</i>, <i>DDB2</i>, and <i>C11orf49</i> as putatively causal genes. The best candidate genes in each region are <i>LRRK1</i>, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and <i>NR1H3</i> liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. <h3>Discussion</h3> 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.