Peer-Reviewed Publication
Mol Psychiatry2026;31(1):374-382.January 1, 2026Journal Article
GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy.
Johannes R Lemke1,2, Andrea Eoli3,4, Ilona Krey5,6, Bernt Popp5, Vincent Strehlow5, Dirk A Wittekind7,8, Anna-Leena Vuorinen9,10, Hesham M Aldhalaan11, Sarah Baer12, Anne de Saint Martin12, Trine B Hammer13,14, Isabella Herman15, Frauke Hornemann16, Trine Ingebrigtsen17, Damien Lederer18, Gaetan Lesca19, Dana Marafie15,20, Mikael Mathot21, Jill A Rosenfeld15,22, Rikke S Møller14,23, Helenius J Schelhaas24, Chelsey Stillman25, Alessandro Orsini26, Anup D Patel27, Juliette Piard28,29, Pierangelo Veggiotti30,31, Danique R M Vlaskamp32, Sarah Weckhuysen33,34,35, Stephen F Traynelis36,37, Tim A Benke25, Henrike O Heyne38,39,40, Steffen Syrbe41
1Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.
2Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany. johannes.lemke@medizin.uni-leipzig.de.
3Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
4Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
6Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.
7Department of Psychiatry and Psychotherapy, University of Leipzig Medical Center, Leipzig, Germany.
8Institue for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
9Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
10Faculty of Social Sciences, Unit of Health Sciences, Tampere University, Tampere, Finland.
11Department of Neuroscience Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
12Department of Pediatric Neurology, University Hospitals of Strasbourg, Strasbourg, France.
13Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
14Department of Epilepsy Genetics and Personalized Medicine, The Danish Epilepsy Centre, Dianalund, Denmark.
15Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
16Department of Pediatrics, Klinikum Chemnitz, Chemnitz, Germany.
17National Centre for Epilepsy, Oslo University Hospital, Oslo, Norway.
18Centre de Génétique Humaine, Institut de Pathologie et Génétique (IPG), Charleroi (Gosselies), Belgium.
19Department of Medical Genetics, University Hospital of Lyon, Claude Bernard University Lyon 1, Lyon, France.
20Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait.
21Neuropediatric Unit, CHU UCL-Namur, Namur, Belgium.
22Baylor Genetics Laboratory, Houston, TX, USA.
23Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
24Department of Neurology, Stichting Epilepsie Instellingen Nederland, SEIN, Zwolle, The Netherlands.
25Section of Child Neurology, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
26Section of Pediatric Neurology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
27Division of Pediatric Neurology, Nationwide Children's Hospital, Department of Pediatrics, The Ohio State College of Medicine, Columbus, OH, USA.
28Centre de Génétique Humaine, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France.
29UMR 1231 GAD, Inserm, Université de Bourgogne, Dijon, France.
30Neuroscience Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
31Pediatric Neurology Unit, Buzzi Children's Hospital, Milan, Italy.
32Department of Genetics and Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.
33VIB-Center for Molecular Neurology, VIB, Antwerp, Belgium.
34Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
35Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
36Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
37Center for the Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
38Hasso Plattner Institute, Digital Engineering Faculty, University of Potsdam, Potsdam, Germany. Henrike.Heyne@hpi.de.
39Windreich Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Henrike.Heyne@hpi.de.
40Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland. Henrike.Heyne@hpi.de.
41Heidelberg University, Medical Faculty of Heidelberg, Center for Child and Adolescent Medicine, Clinic 1, Division of Pediatric Epileptology, Heidelberg, Germany.
Abstract
Rare genetic factors have been shown to substantially contribute to mental illness, but so far, no precision treatments for mental disorders have been described. It was recently identified that rare variants in GRIN2A encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) confer a substantial risk for schizophrenia. To determine the prevalence of mental disorders among individual…
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