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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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Change history

  • 02 June 2011

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

References

  1. Sebat, J., Levy, D. L. & McCarthy, S. E. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25, 528–535 (2009)

    Article  CAS  Google Scholar 

  2. The International Schizophrenia Consortium . Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008)

    Article  Google Scholar 

  3. Mulle, J. G. et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am. J. Hum. Genet. 87, 229–236 (2010)

    Article  CAS  Google Scholar 

  4. Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995)

    Article  ADS  CAS  Google Scholar 

  5. McCarthy, S. E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nature Genet. 41, 1223–1227 (2009)

    Article  CAS  Google Scholar 

  6. Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007)

    Article  CAS  Google Scholar 

  7. Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–986 (2008)

    Article  Google Scholar 

  8. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008)

    Article  ADS  CAS  Google Scholar 

  9. Tyson, C. et al. Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH. Am. J. Med. Genet. A. 139A, 173–185 (2005)

    Article  CAS  Google Scholar 

  10. Wu, Y. et al. Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation. BMC Med. Genet. 11, 72 (2010)

    Article  CAS  Google Scholar 

  11. Morava, E. et al. Small inherited terminal duplication of 7q with hydrocephalus, cleft palate, joint contractures, and severe hypotonia. Clin. Dysmorphol. 12, 123–127 (2003)

    Article  Google Scholar 

  12. Bartsch, O. et al. Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 (NF1) microdeletion, in a girl with neurofibromatosis. Cytogenet. Genome Res. 119, 158–164 (2007)

    Article  CAS  Google Scholar 

  13. Sheward, W. J., Lutz, E. M. & Harmar, A. J. The distribution of vasoactive intestinal peptide 2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization. Neuroscience 67, 409–418 (1995)

    Article  CAS  Google Scholar 

  14. Fahrenkrug, J. Transmitter role of vasoactive intestinal peptide. Pharmacol. Toxicol. 72, 354–363 (1993)

    Article  CAS  Google Scholar 

  15. Yang, K. et al. Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission. Hippocampus 19, 779–789 (2009)

    Article  CAS  Google Scholar 

  16. Waschek, J. A. Vasoactive intestinal peptide: an important trophic factor and developmental regulator? Dev. Neurosci. 17, 1–7 (1995)

    Article  CAS  Google Scholar 

  17. Zaben, M. et al. The neurotransmitter VIP expands the pool of symmetrically dividing postnatal dentate gyrus precursors via VPAC2 receptors or directs them toward a neuronal fate via VPAC1 receptors. Stem Cells 27, 2539–2551 (2009)

    Article  CAS  Google Scholar 

  18. Chaudhury, D., Loh, D. H., Dragich, J. M., Hagopian, A. & Colwell, C. S. Select cognitive deficits in vasoactive intestinal peptide deficient mice. BMC Neurosci. 9, 63 (2008)

    Article  Google Scholar 

  19. Brown, T. M., Colwell, C. S., Waschek, J. A. & Piggins, H. D. Disrupted neuronal activity rhythms in the suprachiasmatic nuclei of vasoactive intestinal polypeptide-deficient mice. J. Neurophysiol. 97, 2553–2558 (2007)

    Article  CAS  Google Scholar 

  20. Harmar, A. J. et al. The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109, 497–508 (2002)

    Article  CAS  Google Scholar 

  21. Underhill, P. A. et al. Y chromosome sequence variation and the history of human populations. Nature Genet. 26, 358–361 (2000)

    Article  CAS  Google Scholar 

  22. Millar, J. K. et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310, 1187–1191 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Turetsky, B. I. & Moberg, P. J. An odor-specific threshold deficit implicates abnormal intracellular cyclic AMP signaling in schizophrenia. Am. J. Psychiatry 166, 226–233 (2009)

    Article  Google Scholar 

  24. Gottschling, D. E., Aparicio, O. M., Billington, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990)

    Article  CAS  Google Scholar 

  25. Koering, C. E. et al. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep. 3, 1055–1061 (2002)

    Article  CAS  Google Scholar 

  26. Moreno, D. et al. Development of selective agonists and antagonists for the human vasoactive intestinal polypeptide VPAC2 receptor. Peptides 21, 1543–1549 (2000)

    Article  CAS  Google Scholar 

  27. Chu, A., Caldwell, J. S. & Chen, Y. A. Identification and characterization of a small molecule antagonist of human VPAC2 receptor. Mol. Pharmacol. 77, 95–101 (2009)

    Article  Google Scholar 

  28. Braun, M. M., Farag-El-Massah, S., Xu, K. & Cote, T. R. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nature Rev. Drug Discov. 9, 519–522 (2010)

    Article  CAS  Google Scholar 

  29. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009)

    Article  ADS  CAS  Google Scholar 

  30. Zhang, D. et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol. Psychiatry 14, 376–380 (2008)

    Article  Google Scholar 

Download references

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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The authors declare no competing financial interests.

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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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