Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.
Authors
Vacic, VladimirMcCarthy, Shane
Malhotra, Dheeraj
Murray, Fiona
Chou, Hsun-Hua
Peoples, Aine
Makarov, Vladimir
Yoon, Seungtai
Bhandari, Abhishek
Corominas, Roser
Iakoucheva, Lilia M
Krastoshevsky, Olga
Krause, Verena
Larach-Walters, Verónica
Welsh, David K
Craig, David
Kelsoe, John R
Gershon, Elliot S
Leal, Suzanne M
Dell Aquila, Marie
Morris, Derek W
Gill, Michael
Corvin, Aiden
Insel, Paul A
McClellan, Jon
King, Mary-Claire
Karayiorgou, Maria
Levy, Deborah L
DeLisi, Lynn E
Sebat, Jonathan
Affiliation
Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 12824, USA.Issue Date
2011-03-24MeSH
Cell LineChromosomes, Human, Pair 7
Cohort Studies
Cyclic AMP
DNA Copy Number Variations
Female
Gene Dosage
Genes, Duplicate
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inheritance Patterns
Male
Pedigree
Receptors, Vasoactive Intestinal Peptide, Type II
Reproducibility of Results
Schizophrenia
Signal Transduction
Transcription, Genetic
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Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. 2011, 471 (7339):499-503 NatureJournal
NatureDOI
10.1038/nature09884PubMed ID
21346763Abstract
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.Item Type
ArticleLanguage
enISSN
1476-4687ae974a485f413a2113503eed53cd6c53
10.1038/nature09884
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