Zhou Xianjin, Tang Wei, Greenwood Tiffany A, Guo Shengzhen, He Lin, Geyer Mark A, Kelsoe John R
Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2009;4(4):e5196. doi: 10.1371/journal.pone.0005196. Epub 2009 Apr 9.
The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018). To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029), and two of them (rs12673091, rs3735440) were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012) also displayed a significant association. The SNP7 (rs12673091) was therefore significantly associated in all three samples, and shared the same susceptibility allele (A) across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these psychiatric disorders.
Sp4转录因子对小鼠海马体的发育和功能起着关键作用。小鼠Sp4基因表达降低会导致多种与人类精神疾病相关的行为异常。因此，分别在欧洲白种人和中国人群中研究了人类SP4基因与双相情感障碍和精神分裂症的关联。从人类SP4基因组位点选择的10个单核苷酸多态性（SNP）中，有4个在欧洲白种人家庭中与双相情感障碍显示出显著关联（rs12668354，p = 0.022；rs12673091，p = 0.0005；rs3735440，p = 0.019；rs11974306，p = 0.018）。为了重复这种遗传关联，在一个中国双相情感障碍病例对照样本中检测了同一组SNP。有4个SNP显示出显著关联（rs40245，p = 0.009；rs12673091，p = 0.002；rs1018954，p = 0.001；rs3735440，p = 0.029），其中两个（rs12673091，rs3735440）与欧洲白种人家庭中的阳性SNP相同。考虑到双相情感障碍和精神分裂症之间的遗传重叠，我们在中国精神分裂症三联体家庭中扩展了研究。SNP7（rs12673091，p = 0.012）也显示出显著关联。因此，SNP7（rs12673091）在所有三个样本中均显著关联，并且在所有三个样本中共享相同的易感等位基因（A）。另一方面，我们发现小鼠Sp4基因在调节感觉运动门控方面存在基因剂量效应，感觉运动门控是精神分裂症和双相情感障碍的一种假定内表型。给予多巴胺D2拮抗剂或心境稳定剂可部分逆转Sp4低表达小鼠中缺陷的感觉运动门控。人类遗传学和小鼠药物遗传学研究均支持Sp4基因为双相情感障碍或精神分裂症的易感基因。对Sp4基因在海马体发育中作用的研究可能为这些精神疾病中海马体异常的贡献提供新的见解。
