State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, China.
Am J Psychiatry. 2011 Dec;168(12):1318-25. doi: 10.1176/appi.ajp.2011.11030381. Epub 2011 Sep 2.
ZNF804A is a schizophrenia risk gene that was recently identified by genome-wide association studies as well as subsequent replications. Although the results are consistent among studies in European populations, there have been conflicting reports in Chinese populations. The authors conducted both association and functional analyses to test whether ZNF804A is a risk gene for schizophrenia in Chinese populations.
The authors recruited two case-control samples of independent Han Chinese (a total of 2,207 participants) from southwestern China. A total of six single-nucleotide polymorphisms (SNPs), including the key SNP (rs1344706) that showed significant association with schizophrenia in European populations and the other five promoter SNPs of ZNF804A, were tested. Based on the results of the association analysis, the authors performed two functional assays to test the impact of the risk SNP on transcriptional factor binding affinity and promoter activity.
The SNP rs1344706 was not associated with schizophrenia in either of the two Han Chinese groups, and this result was confirmed by meta-analyses in five Han Chinese samples. However, the authors identified two ZNF804A promoter SNPs that were significantly associated with schizophrenia in both samples, and the significance was strengthened in the combined samples and further supported by haplotype analysis. The functional assays demonstrated that the risk SNP (rs359895) can influence Sp1 binding affinity, resulting in a higher promoter activity of the risk allele.
Our results suggest that ZNF804A is a common risk gene for schizophrenia in world populations and that the newly identified functional SNP (rs359895) is likely a risk SNP for schizophrenia.
ZNF804A 是一个精神分裂症风险基因，最近通过全基因组关联研究以及后续的复制研究得到了证实。尽管在欧洲人群中的研究结果是一致的，但在中国人群中却有相互矛盾的报告。作者进行了关联和功能分析，以测试 ZNF804A 是否是中国人群精神分裂症的风险基因。
作者从中国西南部招募了两个独立的汉族病例对照样本（共 2207 名参与者）。共检测了 6 个单核苷酸多态性（SNP），包括在欧洲人群中与精神分裂症显著相关的关键 SNP（rs1344706）和 ZNF804A 的其他 5 个启动子 SNP。基于关联分析的结果，作者进行了两项功能测定，以测试风险 SNP 对转录因子结合亲和力和启动子活性的影响。
SNP rs1344706 与两个汉族群体中的精神分裂症均无关联，这一结果在五个汉族样本的荟萃分析中得到了证实。然而，作者发现了两个 ZNF804A 启动子 SNP 与两个样本中的精神分裂症显著相关，在合并样本中的显著性得到了加强，并进一步得到了单倍型分析的支持。功能测定表明，风险 SNP（rs359895）可以影响 Sp1 结合亲和力，从而导致风险等位基因的启动子活性更高。
我们的研究结果表明，ZNF804A 是世界人群中常见的精神分裂症风险基因，新发现的功能 SNP（rs359895）可能是精神分裂症的风险 SNP。
