Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis.
Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.
Department of Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.|Institute for Computing and Information Sciences, Radboud University, Nijmegen, The Netherlands.
Christiaan
C
de Leeuw
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
Andrea
A
Goudriaan
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
August B
AB
Smit
Psychiatric and Neurodevelopmental Genetics Unit, Departments of Psychiatry and Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Dongmei
D
Yu
Department of Psychiatry, Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Carol A
CA
Mathews
Psychiatric and Neurodevelopmental Genetics Unit, Departments of Psychiatry and Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Division of Cognitive and Behavioral Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jeremiah M
JM
Scharf
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
Mark H G
MH
Verheijen
Department of Complex Trait Genetics, VU University Medical Center, Amsterdam, The Netherlands.|Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.|Department of Child and Adolescent Psychiatry, Erasmus University Rotterdam, Sophia Child Hospital, Rotterdam, The Netherlands.
Danielle
D
Posthuma
D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D018698:Glutamic Acid; D006801:Humans; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D005879:Tourette Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D018698:Glutamic Acid