Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients
Novel genetic susceptibility loci identified by family based whole exome sequencing in Han Chinese schizophrenia patients
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基于家系的全外显子组测序在中国汉族精神分裂症患者中鉴定出新的遗传易感位点
DOI：
10.1038/s41398-020-0708-y
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发表时间：
2020-01-16
影响因子：
6.8
通讯作者：
Qin, Shengying
中科院分区：
文献类型：
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作者：
Li, Mo;Shen, Lu;Qin, Shengying
精神分裂症(SCZ)是一种高度可遗传的精神疾病，影响全球约1%的人口。然而，早期的相关研究并没有对SCZ的遗传机制得出明确的结论，这表明对SCZ有显著影响的其他易感基因还没有被揭示。因此，为了找出与SCZ遗传风险相关的新的易感基因，我们对65个汉族家系进行了系统的家系研究。对51个双亲均未发病的SCZ三联体进行分析，共发现23个基因上的22个外显子突变和1个剪接点新生突变，其中12个基因在多个三联体中携带罕见的蛋白改变复合杂合性突变。此外，我们还利用传递不平衡检验在18个有名义意义的基因(P<； 5 × 10−4)上发现了26个外显子或剪接点的单核苷酸多态(SNP)。TDT结果证实SCZ易感基因位于3p21.1，包含多基因区域NEK4-ITIH1-ITIH3-ITIH4。通过几种不同的预测矽肺潜在致病基因的策略，我们发现了4个在中国汉族SCZ患者中已发现的易感基因(TSNARE1、PBRM1、STAB1和OLIG2)和4个新的易感基因(PSEN1、TLR5、MGAT5Band SSPO)。综上所述，我们使用基于家族的WES方法确定了一系列可能的SCZ候选基因，从而提高了我们对SCZ发病机制的理解，并为未来的功能验证提供了关键线索。
Schizophrenia (SCZ) is a highly heritable psychiatric disorder that affects approximately 1% of population around the world. However, early relevant studies did not reach clear conclusions of the genetic mechanisms of SCZ, suggesting that additional susceptibility loci that exert significant influence on SCZ are yet to be revealed. So, in order to identify novel susceptibility genes that account for the genetic risk of SCZ, we performed a systematic family-based study using whole exome sequencing (WES) in 65 Han Chinese families. The analysis of 51 SCZ trios with both unaffected parents identified 22 exonic and 1 splice-site de novo mutations (DNMs) on a total of 23 genes, and showed that 12 genes carried rare protein-altering compound heterozygous mutations in more than one trio. In addition, we identified 26 exonic or splice-site single nucleotide polymorphisms (SNPs) on 18 genes with nominal significance (P< 5 × 10−4) using a transmission disequilibrium test (TDT) in all the families. Moreover, TDT result confirmed a SCZ susceptibility locus on 3p21.1, encompassing the multigenetic regionNEK4-ITIH1-ITIH3-ITIH4. Through several different strategies to predict the potential pathogenic genes in silico, we revealed 4 previous discovered susceptibility genes (TSNARE1,PBRM1,STAB1andOLIG2) and 4 novel susceptibility loci (PSEN1,TLR5,MGAT5BandSSPO) in Han Chinese SCZ patients. In summary, we identified a list of putative candidate genes for SCZ using a family-based WES approach, thus improving our understanding of the pathology of SCZ and providing critical clues to future functional validation.