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A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Molecular Psychiatry volume 22, pages 1664–1672 (2017)Cite this article

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Abstract

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

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Acknowledgements

The IBBC is supported by the National Institute of Mental Health grants USA U01MH101719, U01MH0101720, CAN+: U01MH0101723, EUA: U01MH101722, EUB: U01MH101724. Additional support includes: NIH R01MH087626 (REG), R01MH087636 (BSE, DMM-M), R01MH085953 (CEB), Simons Foundation Explorer Award (CEB), RO1MH064824 (WRK), P01HD070454 (BEM, BSE, DMM-M), R01MH107018 (TJS), NIH U54 HD079125 MIND Institute Intellectual and Developmental Disabilities Research Center (TJS), the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities, National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454, RW Woodruff Fund (JFC, OYO), the Canadian Institutes of Health Research (ASB, EWCC, MOP-74631, MOP-97800; ASB, MOP-111238), the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders (ASB), Brain Canada Mental Health Training Award (NJB), Baily Thomas Charitable Trust (2315/1) (MvdB), The Waterloo Foundation (WF918-1234) (MvdB), Wellcome Trust ISSF grant (MvdB), A Medical Research Council (UK) Centre grant G0800509 (MO), CIBERSAM (CA), the Binational Science Foundation, grant number 2011378 (DG), FONDECYT-Chile #1130392 and 1171014 (GMR), Wellcome Trust 110222/Z/15/Z (MN), The FWO grant G.0E11.17 N (JRV), the Brain and Behavior Research Foundation 22597 (AW), the Swiss National Science Foundation (324730_144260) (SE), the EU IMI initiative EU AIMS (DM), the Brain and Behavior Research Foundation (JV), the Brain and Behavior Research Foundation 21278 (MA), the NHMRC 1072593 (AL). We thank the research teams across the international sites and the individuals and family members who have enabled the establishment of the Consortium and have contributed to advancing the understanding and treatment of 22q11DS.

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Author notes

  1. R E Gur, A S Bassett, D M McDonald-McGinn, C E Bearden, E Chow, B S Emanuel, M Owen, A Swillen, M Van den Bree, J Vermeesch, J A S Vorstman, S Warren, T Lehner and B Morrow: R E Gur and A S Bassett: These authors contributed equally to this work.

  2. List of other members of The International 22q11.2 Deletion Syndrome Brain Behavior Consortium is provided in the Supplemental Material.

Authors and Affiliations

  1. Perelman School of Medicine and Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

    R E Gur

  2. Centre for Addiction and Mental Health, Toronto General Hospital and the University of Toronto, Toronto, ON, Canada

    A S Bassett & E Chow

  3. The Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA

    D M McDonald-McGinn & B S Emanuel

  4. University of California Los Angeles, Los Angeles, CA, USA

    C E Bearden

  5. Cardiff University, Cardiff, UK

    M Owen & M Van den Bree

  6. Katholieke University, Leuven, Belgium

    A Swillen & J Vermeesch

  7. Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    J A S Vorstman

  8. Emory University, Atlanta, GA, USA

    S Warren

  9. National Institute of Mental Health, Bethesda, MD, USA

    T Lehner

  10. Albert Einstein College of Medicine, New York, NY, USA

    B Morrow

Authors
  1. R E Gur
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  9. M Van den Bree
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and The International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Corresponding authors

Correspondence to R E Gur or A S Bassett.

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Competing interests

DMM-M has given lectures on 22q11DS for Natera; CA has been a consultant to or has received honoraria or grants from Abbot, AMGEN, AstraZeneca, CIBERSAM, Dainippon Sumitomo Pharma, Fundación Alicia Koplowitz, Forum, Instituto de Salud Carlos III, Gedeon Richter, Janssen Cilag, Lundbeck, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sunovio and Takeda. DF has been a consultant and/or advisor to or has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Janssen, Lundbeck, Otsuka and Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía. The other authors declare no conflict of interest.

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Gur, R., Bassett, A., McDonald-McGinn, D. et al. A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium. Mol Psychiatry 22, 1664–1672 (2017). https://doi.org/10.1038/mp.2017.161

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