Jessica B Lennington1, Gianfilippo Coppola1, Yuko Kataoka-Sasaki1, Thomas V Fernandez2, Dean Palejev1, Yifan Li3, Anita Huttner4, Mihovil Pletikos5, Nenad Sestan6, James F Leckman3, Flora M Vaccarino7. 1. Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut. 2. Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut. 3. Child Study Center, Yale University School of Medicine, New Haven, Connecticut. 4. Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. 5. Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut. 6. Yale Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut. 7. Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut; Yale Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: flora.vaccarino@yale.edu.
Abstract
BACKGROUND: Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to investigate the pathophysiology of this disorder. METHODS: We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects. RESULTS: We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients' striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module. CONCLUSIONS: Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction.
BACKGROUND: Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to investigate the pathophysiology of this disorder. METHODS: We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects. RESULTS: We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients' striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module. CONCLUSIONS: Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction.
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