Skip to main content Accessibility help
×
Home

Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study

  • Claire Foley (a1), Elizabeth A. Heron (a2), Denise Harold (a3), James Walters (a4), Michael Owen (a5), Michael O'Donovan (a4), Jonathan Sebat (a6), Eric Kelleher (a7), Christina Mooney (a8), Amy Durand (a9), Carlos Pinto (a10), Paul Cormican (a11), Derek Morris (a12), Gary Donohoe (a13), Michael Gill (a14), Louise Gallagher (a15) and Aiden Corvin (a16)...

Abstract

Background

Copy number variants (CNVs) play a significant role in disease pathogenesis in a small subset of individuals with schizophrenia (~2.5%). Chromosomal microarray testing is a first-tier genetic test for many neurodevelopmental disorders. Similar testing could be useful in schizophrenia.

Aims

To determine whether clinically identifiable phenotypic features could be used to successfully model schizophrenia-associated (SCZ-associated) CNV carrier status in a large schizophrenia cohort.

Method

Logistic regression and receiver operating characteristic (ROC) curves tested the accuracy of readily identifiable phenotypic features in modelling SCZ-associated CNV status in a discovery data-set of 1215 individuals with psychosis. A replication analysis was undertaken in a second psychosis data-set (n = 479).

Results

In the discovery cohort, specific learning disorder (OR = 8.12; 95% CI 1.16–34.88, P = 0.012), developmental delay (OR = 5.19; 95% CI 1.58–14.76, P = 0.003) and comorbid neurodevelopmental disorder (OR = 5.87; 95% CI 1.28–19.69, P = 0.009) were significant independent variables in modelling positive carrier status for a SCZ-associated CNV, with an area under the ROC (AUROC) of 74.2% (95% CI 61.9–86.4%). A model constructed from the discovery cohort including developmental delay and comorbid neurodevelopmental disorder variables resulted in an AUROC of 83% (95% CI 52.0–100.0%) for the replication cohort.

Conclusions

These findings suggest that careful clinical history taking to document specific neurodevelopmental features may be informative in screening for individuals with schizophrenia who are at higher risk of carrying known SCZ-associated CNVs. Identification of genomic disorders in these individuals is likely to have clinical benefits similar to those demonstrated for other neurodevelopmental disorders.

Copyright

Corresponding author

Correspondence: Professor Aiden Corvin. Email: acorvin@tcd.ie

Footnotes

Hide All

Declaration of interest: None.

Footnotes

References

Hide All
1International Schizophrenia Consortium, Purcell, SM, Wray, NR, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–52.
2Marshall, CR, Howrigan, DP, Merico, D, Thiruvahindrapuram, B, Wu, W, Greer, DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 2017; 49: 2735.
3Kirov, G, Rees, E, Walters, JT, Escott-Price, V, Georgieva, L, Richards, AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry 2014; 75: 378–85.10.1016/j.biopsych.2013.07.022
4Kendall, KM, Rees, E, Escott-Price, V, Einon, M, Thomas, R, Hewitt, J, et al. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects. Biol Psychiatry 2017; 82: 103–10.10.1016/j.biopsych.2016.08.014
5Miller, DT, Adam, MP, Aradhya, S, Biesecker, LG, Brothman, AR, Carter, NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: 749–64.
6Schaefer, GB, Mendelsohn, NJ.Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 2013; 15: 399407.10.1038/gim.2013.32
7Philip, N, Bassett, A.Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behav Genet 2011; 41: 403–12.
8Ahn, K, Gotay, N, Andersen, TM, Anvari, AA, Gochman, P, Lee, Y, et al. High rate of disease-related copy number variations in childhood onset schizophrenia. Mol Psychiatry 2014; 19: 568–72.
9Walsh, 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: 539–43.
10Yeo, RA, Gangestad, SW, Liu, J, Ehrlich, S, Thoma, RJ, Pommy, J, et al. The impact of copy number deletions on general cognitive ability and ventricle size in patients with schizophrenia and healthy control subjects. Biol Psychiatry 2013; 73: 540–5.
11Stefansson, H, Meyer-Lindenberg, A, Steinberg, S, Magnusdottir, B, Morgen, K, Arnarsdottir, S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 2014; 505: 361–6.10.1038/nature12818
12Derks, EM, Ayub, M, Chambert, K, Del Favero, J, Johnstone, M, MacGregor, S, et al. A genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability. Am J Med Genet B Neuropsychiatr Genet 2013; 162B: 847–54.
13Sahoo, T, Theisen, A, Rosenfeld, JA, Lamb, AN, Ravnan, JB, Schultz, RA, et al. Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genet Med 2011; 13: 868–80.
14Wilson, NK, Lee, Y, Long, R, Hermetz, K, Rudd, MK, Miller, R, et al. A novel microduplication in the neurodevelopmental gene SRGAP3 that segregates with psychotic illness in the family of a COS proband. Case Rep Genet 2011; 2011: 585893.
15Costain, G, Lionel, AC, Fu, F, Stavropoulos, DJ, Gazzellone, MJ, Marshall, CR, et al. Adult neuropsychiatric expression and familial segregation of 2q13 duplications. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 337–44.
16Miles, JH, Takahashi, TN, Hong, J, Munden, N, Flournoy, N, Braddock, SR, et al. Development and validation of a measure of dysmorphology: useful for autism subgroup classification. Am J Med Genet A 2008; 146A: 1101–16.10.1002/ajmg.a.32244
17Irish Schizophrenia Genomics Consortium, Wellcome Trust Case Control Consortium 2. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry 2012; 72: 620–8.10.1016/j.biopsych.2012.05.035
18First, MB, Spitzer, RL, Gibbon, M, Williams, JBW.Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, 2002.
19Hamshere, ML, Walters, JT, 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 2013; 18: 708–12.
20Rees, E, Walters, JTR, Georgieva, L, Isles, AR, Chambert, KD, Richards, AL, et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry 2014; 204: 108–14.
21Malhotra, D, Sebat, J.CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148(6): 1223–41.
22Rees, E, Kendall, K, Pardiñas, AF, Legge, SE, Pocklington, A, Escott-Price, V, et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry 2016; 73: 963–9.
23R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, 2013 (http://www.R-project.org/).
24Thygesen, JH, Wolfe, K, McQuillin, A, Viñas-Jornet, M, Baena, N, Brison, N, et al. Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders. Br J Psychiatry 2018; 212: 287–94.
25Lowther, C, Merico, D, Costain, G, Waserman, J, Boyd, K, Noor, A, et al. Impact of IQ on the diagnostic yield of chromosomal microarray in a community sample of adults with schizophrenia. Genome Med 2017; 9(1): 105.10.1186/s13073-017-0488-z

Keywords

Type Description Title
WORD
Supplementary materials

Foley et al. supplementary material
Foley et al. supplementary material

 Word (51 KB)
51 KB

Identifying schizophrenia patients who carry pathogenic genetic copy number variants using standard clinical assessment: retrospective cohort study

  • Claire Foley (a1), Elizabeth A. Heron (a2), Denise Harold (a3), James Walters (a4), Michael Owen (a5), Michael O'Donovan (a4), Jonathan Sebat (a6), Eric Kelleher (a7), Christina Mooney (a8), Amy Durand (a9), Carlos Pinto (a10), Paul Cormican (a11), Derek Morris (a12), Gary Donohoe (a13), Michael Gill (a14), Louise Gallagher (a15) and Aiden Corvin (a16)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.