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Analysis of copy number variations at 15 schizophrenia-associated loci


A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.


To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.


We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.


We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10–4).


We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.

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Corresponding author
George Kirov, MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Hadyn Ellis Building, Cardiff University, Cardiff CF24 4HQ, UK. Email:
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The work at Cardiff University was funded by Medical Research Council (MRC) Centre (G0800509) and Program Grants (G0801418) and the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI), and an MRC PhD Studentship to E.R. M.C.O'D., M.J.O. and G.K. have received funding from the MRC and the Wellcome Trust, UK. A.R.I. has received funding from the Biotechnology and Biological Sciences Research Council (UK), the Wellcome Trust and the Leverhulme Trust. This work was supported by a clinical research fellowship to J.T.R.W. from the MRC/Welsh Assembly Government and the Margaret Temple Award from the British Medical Association. The schizophrenia samples were genotyped at the Broad Institute, USA, and funded by a philanthropic gift to the Stanley Center for Psychiatric Research.

Declaration of interest


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1 Girirajan, S, Rosenfeld, JA, Coe, BP, Parikh, S, Friedman, N, Goldstein, A, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med 2012; 367: 1321–31.
2 Karayiorgou, M, Morris, MA, Morrow, B, Shprintzen, RJ, Goldberg, R, Borrow, J, et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci U S A 1995; 92: 7612–6.
3 Driscoll, DA, Salvin, J, Sellinger, B, Budarf, ML, McDonald-McGinn, DM, Zackai, EH, et al. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J Med Genet 1993; 30: 813–7.
4 Shprintzen, R, Goldberg, R, Lewin, M, Sidoti, E, Berkman, M, Argamaso, R, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J 1978; 15: 5662.
5 Grozeva, D, Conrad, DF, Barnes, CP, Hurles, M, Owen, MJ, O'Donovan, MC, et al. Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr Res 2012; 135: 17.
6 Ingason, A, Kirov, G, Giegling, I, Hansen, T, Isles, AR, Jakobsen, KD, et al. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am J Psychiatry 2011; 168: 408–17.
7 Ingason, A, Rujescu, D, Cichon, S, Sigurdsson, E, Sigmundsson, T, Pietilainen, OPH, et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry 2011; 16: 1725.
8 International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–41.
9 Kirov, G, Rujescu, D, Ingason, A, Collier, DA, O'Donovan, MC, Owen, MJ. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 2009; 35: 851–4.
10 Levinson, DF, Duan, J, Oh, S, Wang, K, Sanders, AR, Shi, J, et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–16.
11 McCarthy, SE, Makarov, V, Kirov, G, Addington, AM, McClellan, J, Yoon, S, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: 1223–7.
12 Mulle, JG, Dodd, AF, McGrath, JA, Wolyniec, PS, Mitchell, AA, Shetty, AC, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet 2010; 87: 229–36.
13 Rujescu, D, Ingason, A, Cichon, S, Pietiläinen, OP, Barnes, MR, Toulopoulou, T, et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 2009; 18: 988–96.
14 Malhotra, D, Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148: 1223–41.
15 Kirov, G, Rees, E, Walters, TJ, Escott-Price, V, Georgieva, L, Richards, AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry 2013; August 27 (Epub ahead of print).
16 Mulle, JG, Pulver, AE, McGrath, JA, Wolyniec, PS, Dodd, AF, Cutler, DJ, et al. Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biol Psychiatry 2013; July 17 (Epub ahead of print).
17 Vacic, V, McCarthy, S, Malhotra, D, Murray, F, Chou, H-H, Peoples, A, et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 2011; 471: 499503.
18 Guha, S, Rees, E, Darvasi, A, Ivanov, D, Ikeda, M, Bergen, SE, et al. Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry 2013; 70: 253–60.
19 Moreno-De-Luca, D, Mulle, JG, Kaminsky, EB, Sanders, SJ, Myers, SM, Adam, MP, et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 2010; 87: 618–30.
20 Kirov, G, Grozeva, D, Norton, N, Ivanov, D, Mantripragada, KK, Holmans, P, et al. Support for the involvement of large CNVS in the pathogenesis of schizophrenia. Hum Mol Genet 2009; 18: 1497–503.
21 Hamshere, ML, Walters, JTR, Smith, R, Richards, AL, Green, E, Grozeva, D, et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 2012; 18: 708–12.
22 Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, et al. SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990; 47: 589–93.
23 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). APA, 1994.
24 Wang, K, Li, M, Hadley, D, Liu, R, Glessner, J, Grant, SFA, 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: 1665–74.
25 Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–75.
26 Kirov, G, Pocklington, AJ, Holmans, P, Ivanov, D, Ikeda, M, Ruderfer, D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 2012; 17: 142–53.
27 Rees, E, Moskvina, V, Owen, MJ, O'Donovan, MC, Kirov, G. De novo rates and selection of schizophrenia-associated copy number variants. Biol Psychiatry 2011; 70: 1109–14.
28 Girirajan, S, Dennis Megan, Y, Baker, C, Malig, M, Coe, Bradley P, Campbell, Catarina D, et al. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 2013; 92: 221–37.
29 Urraca, N, Davis, L, Cook, EH, Schanen, NC, Reiter, LT. A single-tube quantitative high-resolution melting curve method for parent-of-origin determination of 15q duplications. Genet Test Mol Biomarkers 2010; 14: 571–6.
30 Ekholm, B, Ekholm, A, Adolfsson, R, Vares, M, Ösby, U, Sedvall, GC, et al. Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses. Nord J Psychiatry 2005; 59: 457–64.
31 Jakobsen, KD, Frederiksen, JN, Hansen, T, Jansson, LB, Parnas, J, Werge, T. Reliability of clinical ICD-10 schizophrenia diagnoses. Nord J Psychiatry 2005; 59: 209–12.
32 de, Kovel CGF, Trucks, H, Helbig, I, Mefford, HC, Baker, C, Leu, C, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133: 2332.
33 Dibbens, LM, Mullen, S, Helbig, I, Mefford, HC, Bayly, MA, Bellows, S, et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 2009; 18: 3626–31.
34 Christiansen, J, Dyck, JD, Elyas, BG, Lilley, M, Bamforth, JS, Hicks, M, et al. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res 2004; 94: 1429–35.
35 Botto, LD, May, K, Fernhoff, PM, Correa, A, Coleman, K, Rasmussen, SA, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 2003; 112: 101–7.
36 Williams, NM, Zaharieva, I, Martin, A, Langley, K, Mantripragada, K, Fossdal, R, et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. Lancet 2010; 376: 1401–8.
37 Bochukova, EG, Huang, N, Keogh, J, Henning, E, Purmann, C, Blaszczyk, K, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010; 463: 666–70.
38 Stefansson, H, Rujescu, D, Cichon, S, Pietilainen, OPH, Ingason, A, Steinberg, S, et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–6.
39 Südhof, TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 2008; 455: 903–11.
40 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: 458–65.
41 Glessner, JT, Wang, K, Cai, G, Korvatska, O, Kim, CE, Wood, S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009; 459: 569–73.
42 Sanders, SJ, Ercan-Sencicek, AG, Hus, V, Luo, R, Murtha, MT, Moreno-De-Luca, D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–85.
43 Wilkinson, LS, Davies, W, Isles, AR. Genomic imprinting effects on brain development and function. Nat Rev Neurosci 2007; 8: 832–43.
44 Moreno-De-Luca, D, Sanders, SJ, Willsey, AJ, Mulle, JG, Lowe, JK, Geschwind, DH, et al. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol Psychiatry 2012; 18: 1090–5.
45 Helbig, I, Hartmann, C, Mefford, HC. The unexpected role of copy number variations in juvenile myoclonic epilepsy. Epilepsy Behav 2013; 28 (suppl 1): S668.
46 Bachmann-Gagescu, R, Mefford, HC, Cowan, C, Glew, GM, Hing, AV, Wallace, S, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 2010; 12: 641–7.
47 Leadbetter, R, Shutty, M, Pavalonis, D, Vieweg, V, Higgins, P, Downs, M. Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992; 149: 6872.
48 Nielsen, J, Dahm, M, Lublin, H, Taylor, D. Psychiatrists' attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010; 24: 965–71.
49 Shprintzen, RJ, Goldberg, R, Golding-Kushner, KJ, Marion, RW. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 1992; 42: 141–2.
50 Shprintzen, RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev 2008; 14: 310.
51 Mefford, HC, Sharp, AJ, 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: 1685–99.
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Analysis of copy number variations at 15 schizophrenia-associated loci

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The significance of copy number variation in schizophrenia

Paul E Bebbington, Emeritus Professor
28 March 2014

The paper by Rees et al. seeks to replicate the association with schizophrenia of CNV's involving putative schizophrenia loci in a large case-control study. They concluded that 11 of the 15 previously implicatedloci were strongly associated with schizophrenia. The odds ratios of theseCNV's relative to schizophrenia range between around 2 and >50. The authors suggest that the findings now indicate a need for routine screening for CNV's.

However, I think there are grounds for reservations about the implication of these findings for the generality of cases of schizophrenia, both at the population level and in terms of public health initiatives. The authors report that one or more of the identified CNV's was present in 2.5% of the case group, and 0.9% in the control group. Let us assume that the prevalence of schizophrenia in the general population is around 0.5%, as reported in the British National Psychiatric Morbidity Surveys (Meltzer et al., 1994; Singleton et al., 2001; Mc Manus et al., 2009). From this it is possible to calculate that, for every one person with schizophrenia who has one of these CNV's, there would be around 72 inthe unaffected population. The positive predictive value (PPV) is the proportion of positive results of a test that are truly positive, and the PPV equivalent to these data can be calculated at 1.37%: in other words, this is the probability that someone with one of the identified CNV's has schizophrenia. If we change the assumed prevalence of schizophrenia to 1%,the PPV rises to 2.73. The authors say "given their frequency, these findings therefore suggest that routine screening for CNV's should be madeavailable and that the results will have immediate implications for genetic counselling, and given their comorbidity with other medical disorders, for patient management as well". However, in my view, these values for PPVs make this conclusion questionable.

It is also of interest to use the authors' data to calculate the population attributable fraction (PAF): this is the notional amount by which the prevalence of an outcome would be reduced if the particular exposure were completely removed from the population. It reflects both thefrequency of the given exposure, and the strength of its effect. Using these data, and, as before, assuming a prevalence of 0.5%, the PAF is 0.618 %. If we assume a prevalence for schizophrenia of 1%, this index changes very little, to 0.622%. This is not a large value: we found a PAFof 14% for the link between psychosis and non-consensual sexual intercourse before the age of 16 (Bebbington et al., 2011), and the recentmeta-analysis by Varese et al. (2012) suggests that the PAF for all forms of childhood adversity in schizophrenia is 33%.

The practical implications of CNV's in schizophrenia are thus in somedoubt.


Bebbington PE, Jonas S, Kuipers E, King M, Cooper C, Brugha T, Meltzer H, McManus S, Jenkins R. Sexual abuse and psychosis: data from an English National Survey. Br J Psychiatry 2011; 199: 29-37.

McManus S, Meltzer H, Brugha TS, Bebbington PE, Jenkins R (Eds). Adult Psychiatric Morbidity in England, 2007: Results of a Household Survey. NHS Information Centre for Health and Social Care, 2009.

Meltzer H, Gill B, Petticrew M. The prevalence of psychiatric morbidity among adults aged 16-64, living in private households, in Great Britain. Office of Population Censuses and Surveys, Social Surveys Division, 1994.

Rees E, Walters JT, Georgieva L, Isles AR, Chambert KD, Richards AL, Mahoney-Davies G, Legge SE, Moran JL, McCarroll SA, O'Donovan MC, Owen MJ,Kirov G. Analysis of copy number variations at 15 schizophrenia-associatedloci. Br J Psychiatry 2014; 204: 108-14.

Singleton N, Bumpstead R, O'Brien M. Psychiatric morbidity among adults living in private households, 2000. The Stationery Office, 2001.

Varese F, Smeets F, Drukker M, Lieverse R, Lataster T, Viechtbauer W,Read J, van Os J, Bentall RP. Childhood adversities increase the risk of psychosis: a meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophr Bull 2012; 38: 661-71.

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