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Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Abstract
Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.
AuthorsVladimir Vacic, Shane McCarthy, Dheeraj Malhotra, Fiona Murray, Hsun-Hua Chou, Aine Peoples, Vladimir Makarov, Seungtai Yoon, Abhishek Bhandari, Roser Corominas, Lilia M Iakoucheva, Olga Krastoshevsky, Verena Krause, Verónica Larach-Walters, David K Welsh, David Craig, John R Kelsoe, Elliot S Gershon, Suzanne M Leal, Marie Dell Aquila, Derek W Morris, Michael Gill, Aiden Corvin, Paul A Insel, Jon McClellan, Mary-Claire King, Maria Karayiorgou, Deborah L Levy, Lynn E DeLisi, Jonathan Sebat
JournalNature (Nature) Vol. 471 Issue 7339 Pg. 499-503 (Mar 24 2011) ISSN: 1476-4687 [Electronic] England
PMID21346763 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Receptors, Vasoactive Intestinal Peptide, Type II
  • VIPR2 protein, human
  • Cyclic AMP
Topics
  • Cell Line
  • Chromosomes, Human, Pair 7 (genetics)
  • Cohort Studies
  • Cyclic AMP (metabolism)
  • DNA Copy Number Variations (genetics)
  • Female
  • Gene Dosage (genetics)
  • Genes, Duplicate (genetics)
  • Genetic Predisposition to Disease (genetics)
  • Genome-Wide Association Study
  • Humans
  • Inheritance Patterns (genetics)
  • Male
  • Pedigree
  • Receptors, Vasoactive Intestinal Peptide, Type II (genetics, metabolism)
  • Reproducibility of Results
  • Schizophrenia (genetics, metabolism)
  • Signal Transduction
  • Transcription, Genetic (genetics)

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