Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.
Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes.
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综合综合分析确定 GLT8D1 和 CSNK2B 为精神分裂症风险基因
DOI：
10.1038/s41467-018-03247-3
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发表时间：
2018-02-26
影响因子：
16.6
通讯作者：
Luo XJ
中科院分区：
文献类型：
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作者：
Yang CP;Li X;Wu Y;Shen Q;Zeng Y;Xiong Q;Wei M;Chen C;Liu J;Huo Y;Li K;Xue G;Yao YG;Zhang C;Li M;Chen Y;Luo XJ
最近的全基因组关联研究（GWAS）已经确定了多个风险基因座，这些基因座与精神分裂症有很强的关联。然而，在已报道的基因座上精确定位潜在的致病基因仍然是一个重大挑战。在这里，我们确定候选致病基因的精神分裂症使用整合基因组学的方法。Sherlock整合分析表明，ALMS 1、GLT 8D1和CSNK 2B是精神分裂症的危险基因，利用独立的脑表达数量性状基因座（eQTL）数据和整合分析方法（SMR）验证了这3个基因的有效性。因此，精神分裂症病例和对照的基因表达分析进一步支持这三个基因在精神分裂症发病机制中的潜在作用。最后，我们发现GLT8D1和CSNK2B基因敲低促进神经干细胞的增殖，抑制其分化能力，并改变神经元的形态和突触传递。这些证据表明，ALMS 1，CSNK2B和GLT8D1基因可能参与精神分裂症的病理生理学。
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.