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. 2018 Feb 26;9(1):838.
doi: 10.1038/s41467-018-03247-3.

Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes

Cui-Ping Yang  1 , Xiaoyan Li  1 , Yong Wu  1 , Qiushuo Shen  1   2 , Yong Zeng  3 , Qiuxia Xiong  3 , Mengping Wei  4 , Chunhui Chen  5 , Jiewei Liu  1 , Yongxia Huo  1 , Kaiqin Li  1 , Gui Xue  5 , Yong-Gang Yao  1   6 , Chen Zhang  4 , Ming Li  1   6 , Yongbin Chen  7   8 , Xiong-Jian Luo  9   10
Affiliations

Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes

Cui-Ping Yang et al. Nat Commun. .

Erratum in

Abstract

Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Expression patterns of the top predicted risk genes (by Sherlock) in human frontal cortex. Expression level of top predicted risk genes across the entire developing stages (from 8 post-conception weeks (pcw) to 40 years (yrs)) were depicted in the frontal cortex, which was divided into four regions: dorsolateral prefrontal cortex (DFC), medial prefrontal cortex (MFC), orbital prefrontal cortex (OFC), and ventrolateral prefrontal cortex (VFC). Of note, most of the genes showed higher expression level at embryonic and fetal stages (8 pcw to 4 mons) compared with childhood and adulthood stages (8 yrs to 40 yrs), suggesting these genes may have a role in neurodevelopment. The expression data (from frontal cortex of 42 human subjects) were extracted from the BrainSpan
Fig. 2
Fig. 2
Dysregulation of ALMS1, GLT8D1, and CSNK2B in schizophrenia cases vs. healthy controls. a mRNA expression of AMLS1 is significantly upregulated in the hippocampus and striatum (P = 0.006 and 0.041, respectively) of schizophrenia cases (SCZ) compared with healthy subjects (Control) (GSE53987 expression data set, 19 schizophrenia cases, and 19 controls). In the prefrontal cortex, AMLS1 also showed a trend of up-regulation (P = 0.056). b, c Expression of GLT8D1 and CSNK2B is significantly decreased in the hippocampus of schizophrenia cases compared with controls. Left panel, hippocampus, middle panel, prefrontal cortex, right panel, and striatum. Student’s t-test was used to compare whether the expression of ALMS1, GLT8D1, and CSNK2B was significantly different in schizophrenia cases (n = 19) and controls (n = 19)
Fig. 3
Fig. 3
Knockdown of GLT8D1 and CSNK2B promote NSCs proliferation and upregulate the expression of the stemness marker genes. a Real-time PCR showed that the shRNAs significantly reduced the mRNA expression level of GLT8D1 and CSNK2B in NSCs. b Western blotting showed that protein level of GLT8D1 and CSNK2B was also significantly reduced. c, d Knockdown of GLT8D1 and CSNK2B promote the proliferation ability of NSCs by BrdU incorporation assay. d The quantification data for c. e Knockdown of GLT8D1 and CSNK2B increased the expression of stemness (Sox2, Klf4, Nanog, and Nestin) marker genes significantly. GAPDH was used an internal control. *P < 0.05, **P < 0.01, ***P < 0.001, two-tailed Student’s t-test. Data represent mean ± SD from three independent biological replicates
Fig. 4
Fig. 4
Knockdown of GLT8D1 and CSNK2B inhibit the differentiation ability of NSCs. a, b Knockdown of GLT8D1 and CSNK2B inhibited the differentiation of NSCs into neurons. a Representative immunostainings for Tuj1 (a marker for newly generated immature neurons) in indicated cells. b The quantification data for a. c, d Knockdown of GLT8D1 and CSNK2B significantly inhibited the differentiation of NSCs into oligodendrocytes. c Representative immunostainings for O4 (a marker for oligodendrocytes) in indicated cells. d The quantification data for d. e, f Knockdown of GLT8D1 and CSNK2B inhibited the differentiation of NSCs into astrocytes significantly. e Representative immunostainings for GFAP (a marker for astrocytes) in indicated cells. f The quantification data for e. Scale bar: 100 µM. *P < 0.05, **P < 0.01, ***P < 0.001, two-tailed Student’s t-test. Data represent mean ± SD from three independent biological assays
Fig. 5
Fig. 5
Knockdown of GLT8D1 and CSNK2B lead to defects in dendritic morphology. a Representative immunostainings for MAP2 (a marker for neurons) in indicated cells. b Quantification data for a. c–f Knockdown of GLT8D1 and CSNK2B led to defects in dendritic growth. Compared with controls, the number of dendrites, the dendritic length, and branch points were significantly reduced in neurons differentiated from NSCs that stably expressing shRNAs targeting GLT8D1 and CSNK2B. A total of 60 neurons were measured for the control and experimental groups. Data in b represent mean ± SD. Data in d–f represent mean ± SEM. ***P < 0.001, two-tailed Student’s t-test
Fig. 6
Fig. 6
Knockdown of GLT8D1 and CSNK2B alters synaptic transmission. a Compared with control neurons, knockdown of GLT8D1 and CSNK2B affected the frequency of miniature excitatory postsynaptic currents (mEPSCs) significantly. However, the amplitude of mEPSCs was not affected. b Compared with controls neurons, the amplitude of miniature inhibitory postsynaptic currents (mIPSC) was significantly affected in neurons transfected with GLT8D1 and CSNK2B shRNAs. The frequency of mIPSC was also significantly altered in neurons transfected with CSNK2B shRNAs compared with controls. A total of 27 neurons (from three independent groups) were recorded for mEPSC. For mIPSC, 30 neurons (from four independent groups) were recorded for control group, and 33 neurons (from four independent groups) were recorded for GLT8D1 and CSNK2B knockdown groups. *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t-test. Data represent mean ± SD
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