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. 2010 Jul 8:6:40.
doi: 10.1186/1744-9081-6-40.

Copy number variation of the SELENBP1 gene in schizophrenia

Shirly Amar  1 , Ofer Ovadia, Wolfgang Maier, Richard Ebstein, R H Belmaker, Dan Mishmar, Galila Agam
Affiliations

Copy number variation of the SELENBP1 gene in schizophrenia

Shirly Amar et al. Behav Brain Funct. .

Abstract

Background: Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the disorder and that these mutations could alter the gene product's activity in patients.

Methods: We analyzed SELENBP1 CN variation (CNV) in blood DNA from 49 schizophrenia patients and 49 controls (cohort A). Since CN of genes may vary among tissues, we investigated SELENBP1 CN in age- sex- and postmortem interval-matched cerebellar DNA samples from 14 patients and 14 controls (cohort B). Since CNV may either be de-novo or inherited we analyzed CNV of the SELENBP1 locus in blood DNA from 26 trios of schizophrenia probands and their healthy parents (cohort C). SELENBP1 mRNA levels were measured by real-time PCR.

Results: In cohort A reduced CN of the SELENBP1 locus was found in four patients but in none of the controls. In cohort B we found reduced CN of the SELENBP1 locus in two patients but in none of the controls. In cohort C three patients exhibited drastic CN reduction, not present in their parents, indicating de-novo mutation. A reduction in SELENBP1 mRNA levels in the postmortem cerebellar samples of schizophrenia patients was found.

Conclusions: We report a focused study of CN mutations in the selenium binding-protein1 (SELENBP1) locus previously linked with schizophrenia. We provide evidence for recurrence of decreased CN of the SELENBP1 locus in three unrelated patients' cohorts but not in controls, raising the possibility of functional involvement of these mutations in the etiology of the disease.

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Figures

Figure 1
Figure 1
A histogram of normalized cycle number required to reach a particular fluorescence threshold of the SELENBP1 gene in blood DNA of schizophrenia patients and healthy controls. The distribution of the normalized Ct values of SELENBP1 in the patient group is not significantly different from that of the control group (Kolmogorov-Smirnov two-sample test, p = 0.99). Circle denotes reduced copy number.
Figure 2
Figure 2
A histogram of normalized cycle number required to reach a particular fluorescence threshold of the SELENBP1 gene in postmortem cerebellum DNA of schizophrenia patients. The distribution of the normalized Ct values of SELENBP1 in the patient group differed significantly from that of the control group (Kolmogorov-Smirnov two-sample test, p = 0.038). Circle denotes reduced copy number.
Figure 3
Figure 3
A histogram of normalized cycle number required to reach a particular fluorescence threshold of the SELENBP1 gene in blood DNA of schizophrenia probands and their healthy partents. The distribution of the normalized Ct values of SELENBP1 in the patient group differed significantly from that of the mothers (Kolmogorov-Smirnov two-sample test, p = 0.012). Circle denotes reduced copy number.
Figure 4
Figure 4
Two-dimensional representation of non-metric multidimensional scaling (MDS) ordination of the triads cohort. The cohort consisted of 78 samples (26 trios of schizophrenia probands and their health parents X 3 replicates = 78 samples). The analysis is based on the dissimilarity matrix generated by calculating the Euclidian distance between each of the possible pairwise sample comparisons. Stress value: 0.01; A two-dimensional space representation is considered excellent when the stress value is smaller than 0.05 [50]. ANOSIM test, Global r = 0.658, p = 0.001.
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