Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.

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TitleRare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism.
Publication TypeJournal Article
Year of Publication2012
AuthorsFernandez, TV, Sanders, SJ, Yurkiewicz, IR, A Ercan-Sencicek, G, Kim, Y-S, Fishman, DO, Raubeson, MJ, Song, Y, Yasuno, K, Ho, WSC, Bilguvar, K, Glessner, J, Chu, SHee, Leckman, JF, King, RA, Gilbert, DL, Heiman, GA, Tischfield, JA, Hoekstra, PJ, Devlin, B, Hakonarson, H, Mane, SM, Günel, M, State, MW
JournalBiol Psychiatry
Volume71
Issue5
Pagination392-402
Date Published2012 Mar 01
ISSN1873-2402
KeywordsAdult, Autistic Disorder, Case-Control Studies, Child, DNA Copy Number Variations, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Intellectual Disability, Receptors, GABA, Receptors, Histamine H1, Receptors, Histamine H2, Schizophrenia, Signal Transduction, Tourette Syndrome
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.

DOI10.1016/j.biopsych.2011.09.034
Alternate JournalBiol. Psychiatry
PubMed ID22169095
PubMed Central IDPMC3282144
Grant ListUL1 RR024139 / RR / NCRR NIH HHS / United States
U24 NS051869 / NS / NINDS NIH HHS / United States
K05MH076273 / MH / NIMH NIH HHS / United States
R01 MH061940 / MH / NIMH NIH HHS / United States
R01MH092520 / MH / NIMH NIH HHS / United States
U24NS051869 / NS / NINDS NIH HHS / United States
R25 MH077823 / MH / NIMH NIH HHS / United States
R01MH092289 / MH / NIMH NIH HHS / United States
UL1 RR024139-06 / RR / NCRR NIH HHS / United States
R01MH061940 / MH / NIMH NIH HHS / United States
R01 NS056276-05 / NS / NINDS NIH HHS / United States
R01 MH078160 / MH / NIMH NIH HHS / United States
R25MH077823 / MH / NIMH NIH HHS / United States
K05 MH076273 / MH / NIMH NIH HHS / United States
R01 MH092520 / MH / NIMH NIH HHS / United States
R01 MH092289 / MH / NIMH NIH HHS / United States
R01MH092293 / MH / NIMH NIH HHS / United States
UL1RR024139 / RR / NCRR NIH HHS / United States
R01 NS056276 / NS / NINDS NIH HHS / United States
U24 MH068457 / MH / NIMH NIH HHS / United States
R01 MH092520-02 / MH / NIMH NIH HHS / United States
R01NS056276 / NS / NINDS NIH HHS / United States
R01 MH092293 / MH / NIMH NIH HHS / United States
NS056276 / NS / NINDS NIH HHS / United States
R01 MH092289-02 / MH / NIMH NIH HHS / United States
R01 MH092293-02 / MH / NIMH NIH HHS / United States
R01 MH08185 / MH / NIMH NIH HHS / United States
U24 NS051869-01 / NS / NINDS NIH HHS / United States
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