title: 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.
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 12824, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.forename: Hsun-Hua
authors.initials: HH
authors.lastname: Chou
authors.forename: Aine
authors.initials: A
authors.lastname: Peoples
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Seungtai
authors.initials: S
authors.lastname: Yoon
authors.forename: Abhishek
authors.initials: A
authors.lastname: Bhandari
authors.forename: Roser
authors.initials: R
authors.lastname: Corominas
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
authors.forename: Olga
authors.initials: O
authors.lastname: Krastoshevsky
authors.forename: Verena
authors.initials: V
authors.lastname: Krause
authors.forename: Verónica
authors.initials: V
authors.lastname: Larach-Walters
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Gershon
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Marie
authors.initials: M
authors.lastname: Dell Aquila
authors.forename: Derek W
authors.initials: DW
authors.lastname: Morris
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Jon
authors.initials: J
authors.lastname: McClellan
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Levy
authors.forename: Lynn E
authors.initials: LE
authors.lastname: DeLisi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
mesh_terms: D002460:Cell Line; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015331:Cohort Studies; D000242:Cyclic AMP / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D020131:Genes, Duplicate / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D010375:Pedigree; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C495509:VIPR2 protein, human; D000242:Cyclic AMP