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Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain

Molecular Psychiatry volume 17, pages 193–201 (2012)Cite this article

Abstract

It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. As only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among single-nucleotide polymorphisms (SNPs) selected for marginal evidence for association (P<0.5) from genome-wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs, which are also expression quantitative trait loci (eQTLs), should carry more true association signals compared with SNPs that are not marginally associated. To test this, we identified marginally associated (P<0.5) SNPs from two of the largest available schizophrenia GWAS data sets. We assigned eQTL status to those SNPs based upon an eQTL data set derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can, in principle, allow relevant susceptibility eQTLs to be identified.

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Acknowledgements

This work was supported by grants from the MRC and the Wellcome Trust. AR was initially supported by a MRC PhD studentship, and subsequently by NIMH (USA) CONTE Award: 2 P50 MH066392-05A1.

The following authors are included under Molecular Genetics of Schizophrenia Collaboration

PV Gejman (Evanston Northwestern Healthcare and Northwestern University, IL, USA), AR Sanders (Evanston Northwestern Healthcare and Northwestern University, IL, USA), J Duan (Evanston Northwestern Healthcare and Northwestern University, IL, USA), DF Levinson (Stanford University, CA, USA), NG Buccola (Louisiana State University Health Sciences Center, LA, USA), BJ Mowry (Queensland Centre for Mental Health Research, and Queensland Institute for Medical Research, Queensland, Australia), R Freedman (University of Colorado Denver, Colorado, USA), F Amin (Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, USA), DW Black (University of Iowa Carver College of Medicine, IA, USA), JM Silverman (Mount Sinai School of Medicine, New York, USA), WJ Byerley (University of California at San Francisco, California, USA), CR Cloninger (Washington University, Missouri, USA).

The following authors are included under International Schizophrenia Consortium (ISC):

Michael C. O’Donovan (Cardiff University, Cardiff, UK), George K. Kirov (Cardiff University, Cardiff, UK), Nick J. Craddock (Cardiff University, Cardiff, UK), Peter A. Holmans (Cardiff University, Cardiff, UK), Nigel M. Williams (Cardiff University, Cardiff, UK), Lyudmila Georgieva (Cardiff University, Cardiff, UK), Ivan Nikolov (Cardiff University, Cardiff, UK), N. Norton (Cardiff University, Cardiff, UK), H. Williams (Cardiff University, Cardiff, UK), Draga Toncheva (University Hospital Maichin Dom, Sofia, Bulgaria), Vihra Milanova (Alexander University Hospital, Sofia, Bulgaria), Michael J. Owen (Cardiff University, Cardiff, UK), Christina M. Hultman (Karolinska Institutet, Stockholm, Sweden and Uppsala University, Uppsala, Sweden), Paul Lichtenstein (Karolinska Institutet, Stockholm, Sweden), Emma F. Thelander (Karolinska Institutet, Stockholm, Sweden), PatrickSullivan (University of North Carolina at Chapel Hill, North Carolina, USA), Derek W. Morris (Trinity College Dublin, Dublin, Ireland), Colm T. O’Dushlaine (Trinity College Dublin, Dublin, Ireland), Elaine Kenny (Trinity College Dublin, Dublin, Ireland), Emma M. Quinn (Trinity College Dublin, Dublin, Ireland), Michael Gill (Trinity College Dublin, Dublin, Ireland), Aiden Corvin (Trinity College Dublin, Dublin, Ireland), Andrew McQuillin (University College London, London, UK), Khalid Choudhury (University College London, London, UK), Susmita Datta (University College London, London, UK), Jonathan Pimm (University College London, London, UK), Srinivasa Thirumalai (West Berkshire NHS Trust, Reading, UK), Vinay Puri (University College London, London, UK), Robert Krasucki (University College London, London, UK), Jacob Lawrence (University College London, London, UK), Digby Quested (University of Oxford, Oxford, UK), Nicholas Bass (University College London, London, UK), Hugh Gurling (University College London, London, UK), Caroline Crombie (University of Aberdeen, Aberdeen, UK), GillianFraser (University of Aberdeen, Aberdeen, UK), Soh Leh Kuan (University of Aberdeen, Aberdeen, UK), Nicholas Walker (Ravenscraig Hospital, Greenock, UK), David St Clair (University of Aberdeen, Aberdeen, UK), Douglas H. R. Blackwood (University of Edinburgh, Edinburgh, UK), Walter J. Muir (University of Edinburgh, Edinburgh, UK), Kevin A. McGhee (University of Edinburgh, Edinburgh, UK), Ben Pickard (University of Edinburgh, Edinburgh, UK), Pat Malloy (University of Edinburgh, Edinburgh, UK), Alan W. Maclean (University of Edinburgh, Edinburgh, UK), Margaret Van Beck (University of Edinburgh, Edinburgh, UK), Naomi R. Wray (Queensland Institute of Medical Research, Queensland, Australia), Stuart Macgregor (Queensland Institute of Medical Research, Queensland, Australia), Peter M. Visscher (Queensland Institute of Medical Research, Queensland, Australia), Michele T. Pato (University of Southern California, California, USA), Helena Medeiros (University of Southern California, California, USA), Frank Middleton (Upstate Medical University, New York, USA), Celia Carvalho (University of Southern California, California, USA), Christopher Morley (Upstate Medical University, New York, USA), Ayman Fanous (University of Southern California, California, USA and Washington VA Medical Center, Washington, USA and Georgetown University School of Medicine, Washington DC, USA and Virginia Commonwealth University, Virginia, USA), David Conti (University of Southern California, California, USA), James A.Knowles (University of Southern California, California, USA), Carlos Paz Ferreira (Department of Psychiatry, Azores, Portugal), Antonio Macedo (University of Coimbra, Coimbra, Portugal), M. Helena Azevedo (University of Coimbra, Coimbra, Portugal), Carlos N.Pato (University of Southern California, California, USA); Massachusetts General Hospital Jennifer L. Stone (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Andrew N. Kirby (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Manuel A. R. Ferreira (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Mark J. Daly (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), ShaunM. Purcell (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Jennifer L Stone (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Kimberly Chambert (The Broad Institute of Harvard and MIT, Massachusetts, USA), Douglas M Ruderfer (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA), Finny Kuruvilla (The Broad Institute of Harvard and MIT, Massachusetts, USA), Stacey B. Gabriel (The Broad Institute of Harvard and MIT, Massachusetts, USA), Kristin Ardlie (The Broad Institute of Harvard and MIT, Massachusetts, USA), Jennifer L. Moran (The Broad Institute of Harvard and MIT, Massachusetts, USA), Edward M. Scolnick (The Broad Institute of Harvard and MIT, Massachusetts, USA), Pamela Sklar (Massachusetts General Hospital, Massachusetts, USA and The Broad Institute of Harvard and MIT, Massachusetts, USA).

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Authors and Affiliations

  1. Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK

    A L Richards, L Jones, V Moskvina, G Kirov, N Craddock, M J Owen, P Holmans & M C O'Donovan

  2. Department of Psychiatry and Behavioral Sciences, Center for Psychiatric Genetics, Northshore University Health System Research Institute, Evanston, IL, USA

    P V Gejman & A R Sanders

  3. Department of Psychiatry, Stanford University, Stanford, CA, USA

    D F Levinson

  4. Psychiatric and Neurodevelopmental Genetics Unit, Boston, MA, USA

    S Purcell

  5. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    S Purcell

  6. Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    S Purcell

  7. The Broad Institute of Harvard and MIT, Cambridge, MA, USA

    S Purcell

  8. Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Brisbane, QLD, Australia

    P M Visscher

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  1. A L Richards
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International Schizophrenia Consortium (ISC)

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Correspondence to M C O'Donovan.

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Richards, A., Jones, L., Moskvina, V. et al. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain. Mol Psychiatry 17, 193–201 (2012). https://doi.org/10.1038/mp.2011.11

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