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BRIEF ASSOCIATION LETTER

Effect of copy number variant burden on Global Assessment of Functioning in schizophrenia

Heilbronner, Urs; Gade, Katrin; Herms, Stefan; Strohmaier, Jana; Lang, Maren; Nöthen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Degenhardt, Franziska

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doi: 10.1097/YPG.0000000000000135
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Reduced social, occupational, and psychological functioning is a hallmark of schizophrenia (SZ). The Global Assessment of Functioning (GAF) score is a measure of the overall psychosocial functioning of an individual on a scale from 1 (lowest) to 100 (highest). In an Icelandic sample, Stefansson et al. (2014) showed that GAF scores were lower in control individuals carrying copy number variants (CNVs) compared to population-based controls with no CNV. To date no study has investigated a possible correlation between GAF scores and CNV burden in patients with SZ.

The aim of the present pilot study was to determine the influence of CNV burden on GAF scores in patients with a DSM-IV diagnosis of SZ at several points in time of their life (see below). Patients were recruited in Germany using an existing genome-wide CNV dataset (Priebe et al., 2013). Chromosomal regions prone to false-positive CNV calls e.g. telomeric and centromeric regions; see Levinson et al. (2011) were excluded. The analysis was restricted to “high-quality” CNVs (i.e. those spanning ≥30 SNPs and with a confidence value/log Bayes Factor of ≥30) that overlapped with at least one RefSeq gene.

GAF scores (DSM-IV Axis 5) were available for 266 patients (42.1% female) with a mean age [range] of 36.4 years [18–80] recruited from consecutive hospital admissions. To approximate the longitudinal course, we retrospectively collected GAF scores for the following three time-points across the course of the disorder (median [range]): (i) premorbid best functioning (89.5 [58–100]); (ii) “worst ever” (during an illness episode; 25 [5–65]); and (iii) current (at the point in time of remission; 61.5 [30–98]).

Wilcoxon nonparametric rank sum tests were used to compare GAF scores in patients carrying ≥1 CNV and patients with no CNV. To determine potential longitudinal CNV effects, the longitudinal nonparametric test (LNPT; R package nparLD, https://cran.r-project.org/web/packages/nparLD) was used. GAF scores were adjusted for age-at-onset/duration of illness and sex by linear regression (Gade et al., 2015). The average number of CNVs per individual [range] was 0.64 [0–4].

Wilcoxon tests showed a trend toward lower psychosocial functioning at the adjusted “worst ever” GAF scores in patients carrying CNVs compared with those who did not (W=9799.5, P=0.112). Median adjusted GAF scores [range] in patients with CNVs were −3.4 [−21.1 to 24.1] compared with −0.6 [−21.1 to 38.0] in patients with no CNV. No effects of overall CNV burden on best, most impaired, and recovery GAF scores were detected by either LNPT or separate analyses of duplications or deletions.

Our pilot study provides tentative evidence for a negative effect of CNV burden on psychosocial functioning in SZ patients. The use of high-quality CNVs to avoid false-positive findings may have impeded the detection of true effects. Follow-up analysis of the present pilot results is now warranted in a larger sample and should involve the analysis of smaller CNVs.

Acknowledgements

We thank the patients for participating in this study. The study was funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Program. M.M.N. received support from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the Deutsche Forschungsgemeinschaft (DFG)-funded Excellence Cluster ImmunoSensation. M.R. was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257; CRESTAR project, HEALTH-2011-1.1-2) grant 279227. F.D. received support from the BONFOR Programme of the University of Bonn, Germany. T.G.S. received funding from DFG (Klinische Forschergruppe 241: SCHU 1603/5-1), and from the Lisa-Oehler-Foundation.

Conflicts of interest

There are no conflicts of interest.

References

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Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J, et al. (2011). Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 168:302–316.
Priebe L, Degenhardt F, Strohmaier J, Breuer R, Herms S, Witt SH, et al. (2013). Copy number variants in German patients with schizophrenia. PLoS One 8:e64035.
Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, et al. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505:361–366.
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