title: Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.
abstract: BACKGROUND
  Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes.
  
  
  METHODS
  We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated.
  
  
  RESULTS
  While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10(-4) - 1.6 × 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes.
  
  
  CONCLUSIONS
  We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Fernandez
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Ilana R
authors.initials: IR
authors.lastname: Yurkiewicz
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Fishman
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Raubeson
authors.forename: Youeun
authors.initials: Y
authors.lastname: Song
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.forename: Winson S C
authors.initials: WS
authors.lastname: Ho
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Su Hee
authors.initials: SH
authors.lastname: Chu
authors.forename: James F
authors.initials: JF
authors.lastname: Leckman
authors.forename: Robert A
authors.initials: RA
authors.lastname: King
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gilbert
authors.forename: Gary A
authors.initials: GA
authors.lastname: Heiman
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Hoekstra
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D056915:DNA Copy Number Variations / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability; D018079:Receptors, GABA / Q000235:genetics*; D011969:Receptors, Histamine H1 / Q000235:genetics*; D011970:Receptors, Histamine H2 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D005879:Tourette Syndrome / Q000235:genetics*
chemical_list: D018079:Receptors, GABA; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2