title: Transcriptome Analysis of the Human Striatum in Tourette Syndrome.
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.
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Lennington
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kataoka-Sasaki
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Fernandez
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Dean
authors.initials: D
authors.lastname: Palejev
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University School of Medicine, New Haven, Connecticut; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Anita
authors.initials: A
authors.lastname: Huttner
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mihovil
authors.initials: M
authors.lastname: Pletikos
authors.affiliation: Yale Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: James F
authors.initials: JF
authors.lastname: Leckman
authors.affiliation: 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.
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011699:Putamen / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D005879:Tourette Syndrome / Q000235:genetics*; D059467:Transcriptome; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine
keywords: Basal ganglia; Immune system; Interneuron; NOS; Network; Nitric oxide synthase; RNA-Seq