Abstract
Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35 079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P=0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
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References
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.
Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 2007; 104: 12831–12836.
Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 737–739.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885.
Stefansson H, Rujescu D, Cichon S, Pietiläinen OPH, Ingason A, Fossdal R et al. Large recurrent deletions associated with schizophrenia. Nature 2008; 455: 232–236.
The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 445: 237–241.
Mefford H, Sharp A, Baker C, Itsara Z, Jiang K, Buyysse S et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Eng J Med 2008; 359: 1685–1699.
Cantor RM, Geschwind DH . Schizophrenia: genome, interrupted. Neuron 2008; 58: 165–167.
O’Donovan MC, Kirov G, Owen MJ . Phenotypic variations on the theme of CNVs. Nat Genet 2008; 12: 1392–1393.
St Clair D . Copy number variation and schizophrenia. Schizophr Bull 2009; 35: 9–12.
Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, Rosenberg C et al. Array CGH Identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and /or mental retardation. Hum Mutat 2007; 28: 674–682.
Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 2008; 46: 223–232.
McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci USA 1996; 493: 13060–13065.
Ewald H, Flint T, Kruse TA, Mors O . A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22–21, 4p16, 6q14–22, 10q26 and 16p13.3. Mol Psychiatry 2002; 7: 734–744.
Ekholm JM, Kieseppä T, Hiekkalinna T, Partonen T, Paunio T, Perola M et al. Evidence of susceptibility loci 4q32 and 16p12 for bipolar disorder. Hum Mol Genet 2003; 12: 1907–1915.
Kassem L, Lopez V, Hedeker D, Steele J, Zandi P, Bipolar Disorder Consortium NIMH Genetics Initiative et al. Familiarity of polarity at illness onset in bipolar affective disorder. Am J Psychiatry 2006; 163: 1099–1104.
Jones I, Hamshere M, Nangle JM, Bennett P, Green E, Heron J et al. Bipolar affective puerperal psychosis. Genome wide significant evidence for 16p13 linkage. Am J Psychiatry 2007; 164: 248–258.
Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 2004; 9: 1037–1041.
Hennah W, Tomppo L, Hiekkalinna T, Palo OM, Kilpinen H, Ekelund J et al. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet 2007; 16: 453–462.
Numata S, Ueno S, Iga J, Nakataki M, Ohmori T, Tanahashi T et al. No association between NDE1 gene and schizophrenia in the Japanese population. Schizophr Res 2008; 99: 367–369.
Burdick KE, Kamiya A, Hodgkinson CA, Lencz T, Derosse P, Ishizuka K et al. Elucidating the relationship between DISC1, NDEL1, and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. Hum Mol Genet 2008; 17: 2462–2473.
Need AC, Ge D, Weale ME, Feng S, Heinzen EL, Shianna K et al. A Genome wide investigation of SNPs and CNVs in schizophrenia. PloS Genet 2009; 5: e1000421.
Colella S, Yau C, Taylor JM, 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.
Shaw CJ, Lupski JR . Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet 2004; 13: R57–R64.
Tuzun E, Sharp AJ, Bailey JA, Kaul R, Morrison VA, Pertz LM et al. Fine-scale structural variation of the human genome. Nat Genet 2005; 37: 727–732.
Zhang J, Feuk L, Duggan G, Khaja R, Scherer SW . Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome Cytogen. Genome Res 2006; 115: 205–214.
Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006; 38: 1038–1042.
Kriek M, White SJ, Bouma MC, Dauwerse HG, Hansson KB, Nijhuis JV et al. Genomic imbalances in mental retardation. J Med Genet 2004; 41: 249–255.
Finelli P, Natacci F, Bonati MT, Gottardi G, Engelen JJ, de Die-Smulders CE et al. FISH characterisation of an identical (16) (p11.2p12.2) tandem duplication in two unrelated patients with autistic behaviour. J Med Genet 2004; 41: e90.
Amminger GP, Pape S, Rock D, Roberts SA, Ott SL, Squires-Wheeler E et al. Relationship between childhood behavioural disturbance and later schizophrenia in the New York High-Risk Project. Am J Psychiatry 1999; 156: 525–530.
Keshavan MS, Sujata M, Mehra A, Montrose DM, Sweeney JA . Psychosis proneness and ADHD in young relatives of schizophrenia patients. Schizophr Res 2003; 59: 85–92.
Oner O, Munir K . Attentional and neurocognitive characteristics of high-risk offspring of parents with schizophrenia compared with DSM-IV attention deficit hyperactivity disorder children. Schizophr Res 2005; 76: 293–299.
Kirov G, Groseva D, Norton N, Ivanov D, Mantriparga K, Holmans P et al. Support for involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 2009; 18: 1497–1503.
Whitaker-Azmitia PM, Borella A, Raio N . Serotonin depletion in the adult rat causes loss of the dendritic marker MAP-2. A new animal model of Schizophrenia? Neuropsychopharmacology 1995; 12: 269–272.
Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P . Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. Brain Res 1997; 760: 68–73.
Marx CE, Jarskog LF, Lauder JM, Lieberman JA, Gilmore JH . Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biol Psychiatry 2001; 50: 743–749.
Bouras C, Kovari E, Hof PR, Riederer BM, Giannakopoulos P . Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neuropathol 2001; 102: 373–379.
Kwon YT, Balogh SA, Davydov IV, Kashina AS, Yoon JK, Xie Y et al. Altered activity, social behaviour, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway. Mol Cell Biol 2000; 20: 4135–4148.
Balogh SA, Kwon YT, Denenberg VH . Varying inter-trial intervals reveals temporally defined memory deficits and enhancements in NTAN1-defecient mice. Learn Mem 2000; 7: 279–286.
Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al. A schizophrenia associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 2005; 12: 1167–1178.
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.
Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Sabatti C, Geurts van KA, et al., Genetic Risk and Outcome in Psychosis (GROUP) Consortium. Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet 2008; 83: 504–510.
Acknowledgements
We thank the participating subjects and their relatives, and staff at the recruitment centres. We thank David Goldstein for permission to use the genotype data from the Scottish samples typed at Duke University. This work was sponsored by EU grant LSHM-CT-2006–037761 (Project SGENE). Genotyping of the Dutch samples was sponsored by NIMH funding, R01 MH078075 (to RAO).
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GROUP investigators include: René S Kahn and Wiepke Cahn, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands; Don Linszen and Lieuwe de Haan, Department of Psychiatry, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands; Jim van Os, Lydia Krabbendam and Inez Myin-Germeys, Maastricht University Medical Centre, EURON South Limburg Mental Health Research and Teaching Network, Maastricht, The Netherlands; Durk Wiersma and Richard Bruggeman, Department of Psychiatry, University Medical Centre Groningen, University of Groningen, The Netherlands.
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Ingason, A., Rujescu, D., Cichon, S. et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry 16, 17–25 (2011). https://doi.org/10.1038/mp.2009.101
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DOI: https://doi.org/10.1038/mp.2009.101
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