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Analysis of copy number variations at 15 schizophrenia-associated loci

Abstract
Background

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.

Aims

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.

Method

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.

Results

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).

Conclusions

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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Copyright
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: kirov@cardiff.ac.uk
Footnotes
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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

None.

Footnotes
References
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Analysis of copy number variations at 15 schizophrenia-associated loci

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eLetters

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.

References.

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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Conflict of interest: None declared

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