Abstract

BackgroundSchizophrenia is a severe psychiatric disorder associated with IQ deficits. Rare copy number variations (CNVs) have been established to play an important role in the etiology of schizophrenia. Several of the large rare CNVs associated with schizophrenia have been shown to negatively affect IQ in population-based controls where no major neuropsychiatric disorder is reported. The aim of this study was to examine the diagnostic yield of microarray testing and the functional impact of genome-wide rare CNVs in a community ascertained cohort of adults with schizophrenia and low (< 85) or average (≥ 85) IQ.MethodsWe recruited 546 adults of European ancestry with schizophrenia from six community psychiatric clinics in Canada. Each individual was assigned to the low or average IQ group based on standardized tests and/or educational attainment. We used rigorous methods to detect genome-wide rare CNVs from high-resolution microarray data. We compared the burden of rare CNVs classified as pathogenic or as a variant of unknown significance (VUS) between each of the IQ groups and the genome-wide burden and functional impact of rare CNVs after excluding individuals with a pathogenic CNV.ResultsThere were 39/546 (7.1%; 95% confidence interval [CI] = 5.2–9.7%) schizophrenia participants with at least one pathogenic CNV detected, significantly more of whom were from the low IQ group (odds ratio [OR] = 5.01 [2.28–11.03], p = 0.0001). Secondary analyses revealed that individuals with schizophrenia and average IQ had the lowest yield of pathogenic CNVs (n = 9/325; 2.8%), followed by those with borderline intellectual functioning (n = 9/130; 6.9%), non-verbal learning disability (n = 6/29; 20.7%), and co-morbid intellectual disability (n = 15/62; 24.2%). There was no significant difference in the burden of rare CNVs classified as a VUS between any of the IQ subgroups. There was a significantly (p=0.002) increased burden of rare genic duplications in individuals with schizophrenia and low IQ that persisted after excluding individuals with a pathogenic CNV.ConclusionsUsing high-resolution microarrays we were able to demonstrate for the first time that the burden of pathogenic CNVs in schizophrenia differs significantly between IQ subgroups. The results of this study have implications for clinical practice and may help inform future rare variant studies of schizophrenia using next-generation sequencing technologies.

Highlights

  • Schizophrenia is a severe psychiatric disorder associated with Intelligence quotient (IQ) deficits

  • Consent was obtained from all participants and surrogate consent was provided by an individual with power of attorney or equivalent for health decisions for individuals deemed incapable of providing informed consent

  • Our primary analysis revealed that the burden of pathogenic Copy number variation (CNV) was higher in the schizophrenia-Low IQ (LIQ) group (n = 24/192; 12.5%; 95% confidence intervals (CIs) = 8.3–18.2%) compared to the schizophrenia-average IQ (n = 9/325; 2.8%; 95% CI = 1.3–5.3%) group (OR = 5.01 [2.28-11.03], p = 0.0001)

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Summary

Introduction

Schizophrenia is a severe psychiatric disorder associated with IQ deficits. Rare copy number variations (CNVs) have been established to play an important role in the etiology of schizophrenia. Full scale IQ (FSIQ) is 7–8 points lower in cohorts with schizophrenia compared to general population norms [2] and the risk for schizophrenia has been shown to increase by 3.8% per 1-point decrease in FSIQ [3, 4]. This risk appears to be greatest for individuals with FSIQ < 85, and for those with a significantly lower performance IQ (PIQ) than verbal IQ (VIQ) Given that the IQ deficits in schizophrenia are associated with functional outcome [1], further study of genetic risk variants for schizophrenia in the context of the intellectual profile appears warranted

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