Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain (original) (raw)

References

1. Cantor RM, Lange K, Sinsheimer JS . Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am J Hum Genet 2010; 86: 6–22.
   Article CAS PubMed PubMed Central Google Scholar
2. Peltonen L, McKusick VA . Genomics and medicine. Dissecting human disease in the postgenomic era. Science 2001; 291: 1224–1229.
   Article CAS PubMed Google Scholar
3. Bray NJ, Buckland PR, Owen MJ, O’Donovan MC . Cis-acting variation in the expression of a high proportion of genes in human brain. Hum Genet 2003; 113: 149–153.
   PubMed Google Scholar
4. Lander ES . The new genomics: global views of biology. Science 1996; 274: 536–539.
   Article CAS PubMed Google Scholar
5. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.
   Article CAS PubMed PubMed Central Google Scholar
6. Maher B . Personal genomes: The case of the missing heritability. Nature 2008; 456: 18–21.
   Article CAS PubMed Google Scholar
7. Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.
   CAS PubMed Google Scholar
8. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.
   CAS PubMed PubMed Central Google Scholar
9. O’Donovan MC, Craddock NJ, Owen MJ . Genetics of psychosis; insights from views across the genome. Hum Genet 2009; 126: 3–12.
   Article PubMed Google Scholar
10. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.
    CAS PubMed PubMed Central Google Scholar
11. Le-Niculescu H, Balaraman Y, Patel S, Tan J, Sidhu K, Jerome RE et al. Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 129–158.
    Article CAS PubMed Google Scholar
12. Kurian SM, Le-Niculescu H, Patel SD, Bertram D, Davis J, Dike C et al. Identification of blood biomarkers for psychosis using convergent functional genomics. Mol Psychiatry 2011; 16: 37–58.
    Article CAS PubMed Google Scholar
13. Peirce TR, Bray NJ, Williams NM, Norton N, Moskvina V, Preece A et al. Convergent evidence for 2′,3′-cyclic nucleotide 3′-phosphodiesterase as a possible susceptibility gene for schizophrenia. Arch Gen Psychiatry 2006; 63: 18–24.
    Article CAS PubMed Google Scholar
14. Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954.
    Article CAS PubMed Google Scholar
15. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 2006; 103: 6747–6752.
    Article CAS PubMed PubMed Central Google Scholar
16. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M . Mapping complex disease traits with global gene expression. Nat Rev Genet 2009; 10: 184–194.
    Article CAS PubMed PubMed Central Google Scholar
17. Niculescu AB, Le-Niculescu H . The P-value illusion: how to improve (psychiatric) genetic studies. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 847–849.
    Article PubMed Google Scholar
18. Patel SD, Le-Niculescu H, Koller DL, Green SD, Lahiri DK, McMahon FJ et al. Coming to grips with complex disorders: genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 850–877.
    CAS PubMed Google Scholar
19. Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ . Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 2010; 6: e1000888.
    Article PubMed PubMed Central Google Scholar
20. Gilad Y, Rifkin SA, Pritchard JK . Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet 2008; 24: 408–415.
    Article CAS PubMed PubMed Central Google Scholar
21. Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L et al. A survey of genetic human cortical gene expression. Nat Genet 2007; 39: 1494–1499.
    Article CAS PubMed Google Scholar
22. Webster JA, Gibbs JR, Clarke J, Ray M, Zhang W, Holmans P et al. Genetic control of human brain transcript expression in Alzheimer disease. Am J Hum Genet 2009; 84: 445–458.
    Article CAS PubMed PubMed Central Google Scholar
23. Ihaka R, Gentleman R . R: A language for data analysis and graphics. J Comput Graph Stat 1996; 5: 299–314.
    Google Scholar
24. Marangos PJ, Schmechel DE . Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci 1987; 10: 269–295.
    Article CAS PubMed Google Scholar
25. Teepker M, Munk K, Mylius V, Haag A, Moller JC, Oertel WH et al. Serum concentrations of s100b and NSE in migraine. Headache 2009; 49: 245–252.
    Article PubMed Google Scholar
26. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet 2007; 81: 559–575.
    Article CAS PubMed PubMed Central Google Scholar
27. Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol 2008; 6: e107.
    Article PubMed PubMed Central Google Scholar
28. Moskvina V, Smith M, Ivanov D, Blackwood D, StClair D, Hultman C et al. Genetic differences between five European populations. Hum Hered 2010; 70: 141–149.
    Article PubMed Google Scholar
29. Balding DJ . Likelihood-based inference for genetic correlation coefficients. Theor Popul Biol 2003; 63: 221–230.
    Article PubMed Google Scholar
30. Nagelkerke NJD . A Note on a General Definition of the Coefficient of Determination. Biometrika 1991; 78: 691–692.
    Article Google Scholar
31. Mitchell KJ, Porteous DJ . Rethinking the genetic architecture of schizophrenia. Psychol Med 2011; 41: 19–32.
    Article CAS PubMed Google Scholar
32. Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 2003; 73: 152–161.
    Article CAS PubMed PubMed Central Google Scholar
33. Southan C . Has the yo-yo stopped? An assessment of human protein-coding gene number. Proteomics 2004; 4: 1712–1726.
    Article CAS PubMed Google Scholar

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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

Authors

1. A L Richards
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2. L Jones
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3. V Moskvina
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4. G Kirov
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5. P V Gejman
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6. D F Levinson
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7. A R Sanders
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8. S Purcell
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9. P M Visscher
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10. N Craddock
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11. M J Owen
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12. P Holmans
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13. M C O'Donovan
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Molecular Genetics of Schizophrenia Collaboration (MGS)

International Schizophrenia Consortium (ISC)

Corresponding author

Correspondence toM C O'Donovan.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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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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• Received: 14 June 2010
• Revised: 12 January 2011
• Accepted: 19 January 2011
• Published: 22 February 2011
• Issue Date: February 2012
• DOI: https://doi.org/10.1038/mp.2011.11

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