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

An Erratum to this article was published on 01 June 2011

This article has been updated

Abstract

Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders1. 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.

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Figure 1: Detection and validation of microduplications and triplications of 7q36.3.
Figure 2: Patterns of CNV inheritance in families.
Figure 3: Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cAMP signalling.

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  • 02 June 2011

    Figure 3 was corrected on 02 June 2011. Please see erratum at the end of the PDF for details.

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Acknowledgements

This study was supported by a gift from Ted and Vada Stanley to the Cold Spring Harbor Laboratory, a gift to J.S. from the Beyster family foundation, NIH grants to J.S. (MH076431, HG04222), D.L.L. (MH071523), M.-C.K. (MH083989), P.A.I. (GM66232), F.M. (HL091061), D.K.W. (MH082945), M.K. (MH061399), L.E.D. (MH044245), grants to J.S., D.K.W., D.L.L. and M.-C.K from NARSAD, grants to A.C., M.G., D.M. from the Wellcome Trust (072894/Z/03/Z) and Science Foundation Ireland (08INIB1916), a career development award to D.K.W. by the Veterans Administration, and grants to D.L.L. from the Sidney R. Baer, Jr Foundation and Essel Foundation . We wish to thank the Genetic Association Information Network (GAIN), Molecular Genetics of Schizophrenia (MGS) and the Bipolar Genome Study (BiGS) for providing data for this study (investigators listed in the Supplementary Note). We wish to thank B. Trask, R. Malinow and J. Gleeson for discussions.

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V.V. and J.S. wrote the manuscript. V.V., S.M., D.M., H.-H.C., F.M., V.M., S.Y., S.M.L., P.A.I. and J.S. designed the analytical strategy and analysed the data. M.G., A.C., J.M., M.K., D.L.L., V.L-W. and L.E.D. oversaw the recruitment and clinical assessment of study participants. M.D.A. performed cytogenetic analysis. A.B., A.P. and D.M. designed genotype assays and performed genotyping. H.-H.C. and R.C. performed mRNA studies, F.M. performed biochemical studies. O.K., V.K., D.W.M., V.L.-W., L.E.D. and M.K. contributed to the interpretation of clinical patient data. J.M., M.-C.K., M.K., D.L.L., L.E.D., D.C., J.R.K. and E.S.G. contributed to the interpretation of data from genetic studies. P.A.I., L.M.I. and D.K.W. contributed to the interpretation of data from functional studies. J.S. coordinated the study.

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Correspondence to Jonathan Sebat.

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Supplementary information

Supplementary Information

The file contains Supplementary Methods, Supplementary Tables 1 and 3-7, Supplementary Figures 1-6 with legends and additional references. (PDF 1044 kb)

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Vacic, V., McCarthy, S., Malhotra, D. et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499–503 (2011). https://doi.org/10.1038/nature09884

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