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Genome-Wide Analysis Shows Increased Frequency of Copy Number Variation Deletions in Dutch Schizophrenia Patients

  • Jacobine E. Buizer-Voskamp
    Affiliations
    Rudolf Magnus Institute of Neuroscience; Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands

    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Jan-Willem Muntjewerff
    Affiliations
    Department of Psychiatry, University Medical Centre St. Radboud, Nijmegen, the Netherlands
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  • Genetic Risk and Outcome in Psychosis (GROUP) Consortium
    Author Footnotes
    ⁎ The GROUP Consortium members are listed fully in the Acknowledgments section.
  • Eric Strengman
    Affiliations
    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Chiara Sabatti
    Affiliations
    Department of Health Research and Policy, Stanford University School of Medicine, Stanford
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  • Hreinn Stefansson
    Affiliations
    Population genomics, deCODE genetics, Reykjavik, Iceland
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  • Jacob A.S. Vorstman
    Affiliations
    Rudolf Magnus Institute of Neuroscience; Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands
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  • Roel A. Ophoff
    Correspondence
    Address correspondence to Roel A. Ophoff, Ph.D., Center for Neurobehavioral Genetics, University of California, 4357C Gonda, Box 951761, 695 Charles E. Young Drive South, Los Angeles, California 90095-1761
    Affiliations
    Rudolf Magnus Institute of Neuroscience; Department of Psychiatry, University Medical Center Utrecht, Utrecht, the Netherlands

    Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands

    Center for Neurobehavioral Genetics, University of California, Los Angeles, California
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  • Author Footnotes
    ⁎ The GROUP Consortium members are listed fully in the Acknowledgments section.

      Background

      Since 2008, multiple studies have reported on copy number variations (CNVs) in schizophrenia. However, many regions are unique events with minimal overlap between studies. This makes it difficult to gain a comprehensive overview of all CNVs involved in the etiology of schizophrenia. We performed a systematic CNV study on the basis of a homogeneous genome-wide dataset aiming at all CNVs ≥50 kilobase pair. We complemented this analysis with a review of cytogenetic and chromosomal abnormalities for schizophrenia reported in the literature with the purpose of combining classical genetic findings and our current understanding of genomic variation.

      Methods

      We investigated 834 Dutch schizophrenia patients and 672 Dutch control subjects. The CNVs were included if they were detected by QuantiSNP (http://www.well.ox.ac.uk/QuantiSNP/) as well as PennCNV (http://www.neurogenome.org/cnv/penncnv/) and contain known protein coding genes. The integrated identification of CNV regions and cytogenetic loci indicates regions of interest (cytogenetic regions of interest [CROIs]).

      Results

      In total, 2437 CNVs were identified with an average number of 2.1 CNVs/subject for both cases and control subjects. We observed significantly more deletions but not duplications in schizophrenia cases versus control subjects. The CNVs identified coincide with loci previously reported in the literature, confirming well-established schizophrenia CROIs 1q42 and 22q11.2 as well as indicating a potentially novel CROI on chromosome 5q35.1.

      Conclusions

      Chromosomal deletions are more prevalent in schizophrenia patients than in healthy subjects and therefore confer a risk factor for pathogenicity. The combination of our CNV data with previously reported cytogenetic abnormalities in schizophrenia provides an overview of potentially interesting regions for positional candidate genes.

      Key Words

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      References

        • Gottesman I.
        Schizophrenia epigenesis: Past, present, and future.
        Acta Psychiatr Scand. 1994; 90: 26-33
        • Jablensky A.
        Epidemiology of schizophrenia: The global burden of disease and disability.
        Eur Arch Psychiatry Clin Neurosci. 2000; 250: 274-285
        • Andreasen N.
        Symptoms, signs, and diagnosis of schizophrenia.
        Lancet. 1995; 346: 477-481
        • Burmeister M.
        • McInnis M.
        • Zöllner S.
        Psychiatric genetics: Progress amid controversy.
        Nat Rev Genet. 2008; 9: 527-540
        • Tsuang M.
        Schizophrenia: Genes and environment.
        Biol Psychiatry. 2000; 47: 210-220
        • Sullivan P.
        The genetics of schizophrenia.
        PLoS Med. 2005; 2: e212
        • Sullivan P.
        • Kendler K.
        • Neale M.
        Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies.
        Arch Gen Psychiatry. 2003; 60: 1187-1192
        • Tam G.
        • Redon R.
        • Carter N.
        • Grant S.
        The role of DNA copy number variation in schizophrenia.
        Biol Psychiatry. 2009; 66: 1005-1012
        • Purcell S.
        • Wray N.
        • Stone J.
        • Visscher P.
        • O'Donovan M.
        • et al.
        • International Schizophrenia Consortium
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752
        • Kirov G.
        • Grozeva D.
        • Norton N.
        • Ivanov D.
        • Mantripragada K.
        • Holmans P.
        • et al.
        Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.
        Hum Mol Genet. 2009; 18: 1497-1503
        • Stefansson H.
        • Rujescu D.
        • Cichon S.
        • Pietiläinen O.
        • Ingason A.
        • Steinberg S.
        • et al.
        Large recurrent microdeletions associated with schizophrenia.
        Nature. 2008; 455: 232-236
        • The International Schizophrenia Consortium
        Rare chromosomal deletions and duplications increase risk of schizophrenia.
        Nature. 2008; 455: 237-241
        • Vrijenhoek T.
        • Buizer-Voskamp J.E.
        • van der Stelt I.
        • Strengman E.
        • Sabatti C.
        • et al.
        • GROUP Consortium
        Recurrent CNVs disrupt three candidate genes in schizophrenia patients.
        Am J Med Genet Part B. 2008; 83: 504-510
        • Walsh T.
        • McClellan J.
        • McCarthy S.
        • Addington A.
        • Pierce S.
        • Cooper G.
        • et al.
        Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
        Science. 2008; 320: 539-543
        • Xu B.
        • Roos J.
        • Levy S.
        • van Rensburg E.
        • Gogos J.
        • Karayiorgou M.
        Strong association of de novo copy number mutations with sporadic schizophrenia.
        Nat Genet. 2008; 40: 880-885
        • Choy K.
        • Setlur S.
        • Lee C.
        • Lau T.
        The impact of human copy number variation on a new era of genetic testing.
        BJOG. 2010; 117: 391-398
        • Mefford H.
        • Sharp A.
        • Baker C.
        • Itsara A.
        • Jiang Z.
        • Buysse K.
        • et al.
        Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
        N Engl J Med. 2008; 359: 1685-1699
        • Need A.
        • Ge D.
        • Weale M.
        • Maia J.
        • Feng S.
        • Heinzen E.
        • et al.
        A genome-wide investigation of SNPs and CNVs in schizophrenia.
        PLoS Genet. 2009; 5: e1000373
        • Bassett A.
        • Scherer S.W.
        • Brzustowicz L.
        Copy number variations in schizophrenia: Critical review and new perspectives on concepts of genetics and disease.
        Am J Psychiatry. 2010; 167: 899-914
        • Iafrate A.
        • Feuk L.
        • Rivera M.
        • Listewnik M.
        • Donahoe P.
        • Qi Y.
        • et al.
        Detection of large-scale variation in the human genome.
        Nat Genet. 2004; 36: 949-951
        • Vorstman J.A.S.
        • Staal W.G.
        • van Daalen E.
        • van Engeland H.
        • Hochstenbach P.F.R.
        • Franke L.
        Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism.
        Mol Psychiatry. 2006; 11: 18-28
        • Bray N.
        Gene expression in the etiology of schizophrenia.
        Schizophr Bull. 2008; 34: 412-418
        • Moore J.
        • Williams S.
        Epistasis and its implications for personal genetics.
        Am J Med Genet A. 2009; 85: 309-320
        • Colella S.
        • Yau C.
        • Taylor J.
        • Mirza G.
        • Butler H.
        • Clouston P.
        • et al.
        QuantiSNP: An objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data.
        Nucleic Acids Res. 2007; 35: 2013-2025
        • Wang K.
        • Li M.
        • Hadley D.
        • Liu R.
        • Glessner J.
        • Grant S.
        • et al.
        PennCNV: An integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data.
        Genome Res. 2007; 17: 1665-1674
        • Dellinger A.
        • Saw S.
        • Goh L.
        • Seielstad M.
        • Young T.
        • Li Y.
        Comparative analyses of seven algorithms for copy number variant identification from single nucleotide polymorphism arrays.
        Nucleic Acids Res. 2010; 38: e105
        • Winchester L.
        • Yau C.
        • Ragoussis J.
        Comparing CNV detection methods for SNP arrays.
        Brief Funct Genomics Proteomics. 2009; 8: 353-366
        • Lee C.
        • Iafrate A.
        • Brothman A.
        Copy number variations and clinical cytogenetic diagnosis of constitutional disorders.
        Nat Genet. 2007; 39: S48-S54
        • Muir W.
        • Pickard B.
        • Blackwood D.
        Chromosomal abnormalities and psychosis.
        Br J Psychiatry. 2006; 188: 501-503
        • Marenne G.
        • Chanoch S.
        • Rothman N.
        • Rodriguez-Santiago B.
        • Rico D.
        • Pita G.
        • et al.
        CNV assessment using Illumina Infinium 1M platform: Agreement according to algorithm and source of DNA.
        Ann Hum Genet. 2009; 73: 658-669
        • Tsuang D.
        • Millard S.
        • Ely B.
        • Chi P.
        • Wang K.
        • Raskind W.
        • et al.
        The effect of algorithms on copy number variant detection.
        PLoS ONE. 2011; 5: e14456
        • Bailey J.
        • Kidd J.
        • Eichler E.
        Human copy number polymorphic genes.
        Cytogenet Genome Res. 2008; 123: 234-243
        • Freeman J.
        • Perry G.
        • Feuk L.
        • Redon R.
        • McCarroll S.
        • Altshuler D.
        • et al.
        Copy number variation: New insights in genome diversity.
        Genome Res. 2006; 16: 949-961
        • Sharp A.
        • Locke D.
        • McGrath S.
        • Cheng Z.
        • Bailey J.
        • Vallente R.
        • et al.
        Segmental duplications and copy-number variation in the human genome.
        Am J Hum Genet. 2005; 77: 78-88
        • Blackwood D.
        • Fordyce A.
        • Walker M.
        • St. Clair D.
        • Porteous D.
        • Muir W.
        Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family.
        Am J Hum Genet. 2001; 69: 428-433
        • Hoogendoorn M.
        • Vorstman J.
        • Jalali G.
        • Selten J.
        • Sinke R.
        • Emanuel B.
        • Kahn R.S.
        Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia.
        Schizophr Res. 2008; 98: 84-88
        • Karayiorgou M.
        • Gogos J.
        The molecular genetics of the 22q11-associated schizophrenia.
        Mol Brain Res. 2004; 132: 95-104
        • Weksberg R.
        • Stachon A.
        • Squire J.
        • Moldovan L.
        • Bayani J.
        • Meyn S.
        • et al.
        Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome.
        Hum Genet. 2007; 120: 837-845
        • Shaikh T.
        • Kurahashi H.
        • Saitta S.
        • Mizraha O'Hare A.
        • Hu P.
        • Roe B.
        • et al.
        Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis.
        Hum Mol Genet. 2000; 9: 489-501
        • O'Donovan M.
        • Craddock N.
        • Norton N.
        • Williams H.
        • Peirce T.
        • Moskvina V.
        • et al.
        Identification of loci associated with schizophrenia by genome-wide association and follow-up.
        Nat Genet. 2008; 40: 1053-1055
        • Stefansson H.
        • Ophoff R.
        • Steinberg S.
        • Andreassen O.A.
        • Cichon S.
        • Rujescu D.
        • et al.
        Common variants conferring risk of schizophrenia.
        Nature. 2009; 460: 744-747
        • Manolio T.
        • Collins F.
        • Cox N.
        • Goldstein D.
        • Hindorff L.
        • Hunter D.
        • et al.
        Finding the missing heritability of complex diseases.
        Nature. 2009; 461: 747-753
        • Duan J.
        • Sanders A.
        • Gejman P.
        Genome-wide approaches to schizophrenia.
        Brain Res Bull. 2010; 83: 93-102
        • Alkan C.
        • Kidd J.
        • Marques-Bonet T.
        • Aksay G.
        • Antonacci F.
        • Hormozdiari F.
        • et al.
        Personalized copy number and segmental duplication maps using next-generation sequencing.
        Nat Genet. 2009; 41: 1061-1067
        • Riegel M.
        • Baumer A.
        • Jamar M.
        • Delbecque K.
        • Herens C.
        • Verloes A.
        • Schinzel A.
        Submicroscopic terminal deletions and duplications in retarded patients with unclassified malformation syndromes.
        Hum Genet. 2001; 109: 286-294
        • Conrad D.
        • Pinto D.
        • Redon R.
        • Feuk L.
        • Gokcumen O.
        • Zhang Y.
        • et al.
        Origins and functional impact of copy number variation in the human genome.
        Nature. 2010; 464: 704-712
        • Rodriguez-Santiago B.
        • Brunet A.
        • Sobrino B.
        • Serra-Juhé C.
        • Flores R.
        • Armengol L.
        • et al.
        Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia.
        Mol Psychiatry. 2009; 15: 1023-1033
        • Guilmatre A.
        • Dubourg D.
        • Mosca A.
        • Legallic S.
        • Goldenberg A.
        • Drouin-Garraud V.
        • et al.
        Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.
        Arch Gen Psychiatry. 2009; 66: 947-956
        • Kirov G.
        • Gumus D.
        • Chen W.
        • Norton N.
        • Georgieva L.
        • Sari M.
        • et al.
        Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.
        Hum Mol Genet. 2008; 17: 458-465
        • Friedman J.
        • Vrijenhoek T.
        • Markx S.
        • Janssen I.
        • van der Vliet W.
        • Faas B.
        • et al.
        CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy.
        Mol Psychiatry. 2008; 13: 261-266
        • St. Clair D.
        • Blackwood D.
        • Muir W.
        • Carothers A.
        • Walker M.
        • Spowart G.
        • et al.
        Association within a family of a balanced autosomal translocation with major mental illness.
        Lancet. 1990; 336: 13-16
        • Ingason A.
        • Rujescu D.
        • Cichon S.
        • Sigurdsoon E.
        • Sigmundsson T.
        • Pietiläinen O.
        • et al.
        Copy number variations of chromosome 16p13.1 region associated with schizophrenia.
        Mol Psychiatry. 2011; 16: 17-25
        • The International Schizophrenia Consortium
        Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
        Nature. 2009; 460: 748-752
        • Badner J.
        • Gershon E.
        Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
        Mol Psychiatry. 2002; 7: 405-411
        • Lewis C.
        • Levinson D.
        • Wise L.
        • DeLisi L.
        • Straub R.
        • Hovatta I.
        • et al.
        Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.
        Am J Hum Genet. 2003; 73: 34-48
        • Allen N.
        • Bagade S.
        • McQueen M.
        • Ioannidis J.
        • Kavvoura F.
        • Khoury M.
        • et al.
        Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: The SzGene database.
        Nat Genet. 2008; 40: 827-834
        • Wall J.
        • Pritchard J.
        Assessing the performance of the haplotype block model of linkage disequilibrium.
        Am J Hum Genet. 2003; 73: 502-515