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A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population.
Journal of Genetics and Genomics ( IF 5.9 ) Pub Date : 2020-05-06 , DOI: 10.1016/j.jgg.2020.04.001
Kaiqin Li 1 , Yifan Li 1 , Junyang Wang 1 , Yongxia Huo 2 , Di Huang 2 , Shiwu Li 1 , Jiewei Liu 2 , Xiaoyan Li 1 , Rong Liu 3 , Xiaogang Chen 4 , Yong-Gang Yao 5 , Ceshi Chen 2 , Xiao Xiao 2 , Ming Li 5 , Xiong-Jian Luo 6
Affiliation  

The Psychiatric Genomics Consortium (PGC) has recently identified 10 potential functional coding variants for schizophrenia. However, how these coding variants confer schizophrenia risk remains largely unknown. Here, we investigate the associations between eight potential functional coding variants identified by PGC and schizophrenia in a large Han Chinese sample (n = 4022 cases and 9270 controls). Among the eight tested single nucelotide polymorphisms (SNPs), rs3617 (a missense variant, p.K315Q in the ITIH3 gene) showed genome-wide significant association with schizophrenia in the Han Chinese population (P = 8.36 × 10−16), with the same risk allele as in PGC. Interestingly, rs3617 is located in a genomic region that is highly evolutionarily conserved, and its schizophrenia risk allele (C allele) was associated with lower ITIH3 mRNA and protein expression. Intriguingly, mouse neural stem cells stably overexpressing ITIH3 with different alleles of rs3617 exhibited significant differences in proliferation, migration, and differentiation, suggesting the impact of rs3617 on neurodevelopment. Subsequent transcriptome analysis found that the differentially expressed genes in neural stem cells stably overexpressing different alleles of rs3617 were significantly enriched in schizophrenia-related pathways, including cell adhesion, synapse assembly, MAPK and PI3K-AKT pathways. Our study provides convergent lines of evidence suggesting that rs3617 in ITIH3 likely affects protein function and neurodevelopment and thereby confers risk of schizophrenia.



中文翻译:

ITIH3的功能性错义变异会影响汉族人群的蛋白质表达和神经发育,并赋予精神分裂症风险。

精神病基因组学联盟(PGC)最近确定了10种潜在的精神分裂症功能性编码变体。但是,这些编码变体如何导致精神分裂症的风险仍然未知。在这里,我们调查了一个汉族大样本(n  = 4022例和9270个对照)中由PGC和精神分裂症鉴定出的八个潜在功能性编码变异之间的关联。在八种测试的单核苷酸多态性(SNP)中,rs3617(一种错义变体,ITIH3基因中的p.K315Q)在汉族人群中显示出与精神分裂症相关的全基因组显着关联(P  = 8.36×10 -16),其风险等位基因与PGC中相同。有趣的是,rs3617位于高度进化保守的基因组区域,其精神分裂症风险等位基因(C等位基因)与较低的ITIH3 mRNA和蛋白质表达相关。有趣的是,小鼠神经干细胞稳定表达ITIH3rs3617不同等位基因的人在增殖,迁移和分化方面表现出显着差异,表明rs3617对神经发育的影响。随后的转录组分析发现,稳定表达过rs3617不同等位基因的神经干细胞中差异表达的基因在精神分裂症相关途径(包括细胞粘附,突触组装,MAPK和PI3K-AKT途径)中显着丰富。我们的研究提供了趋同的证据,表明ITIH3中的rs3617可能影响蛋白质功能和神经发育,从而带来精神分裂症的风险。

更新日期:2020-05-06
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