Wang Zhenqi, Wei Jun, Zhang Xuan, Guo Yingjun, Xu Qi, Liu Shuzheng, Shi Jieping, Yu Yaqin, Ju Guizhi, Li Yulin, Shen Yan
Jilin University Research Center for Genomic Medicine, School of Public Health, Jilin University, Changchun, China.
Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):902-6. doi: 10.1002/ajmg.b.30383.
This work reviewed all the reports on the NOTCH4 gene in schizophrenia, which have been published since the gene was found to be associated with illness among a British population in 2000. The results from independent studies were inconsistent. Allelic heterogeneity, clinical diagnosis, ethnical backgrounds, and linkage disequilibrium (LD) structures in the human genome may be major reasons for poor replication. A couple of studies suggested that the NOTCH4 gene could play a role in a subgroup of the disease, such as early-onset schizophrenia and negative symptoms. A single study revealed a weak association of the NOTCH4 gene with frontal lobe brain volumes and a strong association with frontal lobe cognitive performance. A meta-analysis showed stronger evidence of the NOTCH4 association in family-based studies than in case-control studies. In a previous study, we found that rs520692, a single nucleotide polymorphism (SNP) at the NOTCH4 locus, was associated with schizophrenia in a Chinese population. In the present study, we applied a large sample size to re-evaluate our initial findings and then confirmed the rs520692 association with illness. The pairwise measures did not show strong LD between paired SNPs although the SNPs tested are located within a 34-kb region, suggesting that LD within the NOTCH4 gene has been broken rapidly by historical recombination in the Chinese population. Taken together, the NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation.
这项研究回顾了自2000年该基因在英国人群中被发现与精神分裂症相关以来，所有已发表的关于NOTCH4基因与精神分裂症的报告。独立研究的结果并不一致。等位基因异质性、临床诊断、种族背景以及人类基因组中的连锁不平衡（LD）结构可能是导致重复研究结果不佳的主要原因。一些研究表明，NOTCH4基因可能在该疾病的一个亚组中起作用，如早发性精神分裂症和阴性症状。一项单独的研究揭示了NOTCH4基因与额叶脑容量之间存在弱关联，与额叶认知表现存在强关联。一项荟萃分析表明，在基于家系的研究中，NOTCH4关联的证据比病例对照研究中更强。在之前的一项研究中，我们发现NOTCH4基因座处的一个单核苷酸多态性（SNP）rs520692与中国人群中的精神分裂症相关。在本研究中，我们应用大样本量重新评估了我们最初的发现，随后证实了rs520692与疾病的关联。成对测量结果显示，尽管所测试的SNP位于一个34 kb的区域内，但成对SNP之间并未显示出强连锁不平衡，这表明在中国人群中，NOTCH4基因内的连锁不平衡已因历史重组而迅速打破。综上所述，NOTCH4基因可能与精神分裂症相关，但该基因如何导致该疾病的病因仍需进一步研究。
