Evidence That Schizophrenia Risk Variation in the ZNF804A Gene Exerts Its Effects During Fetal Brain Development
Evidence That Schizophrenia Risk Variation in the ZNF804A Gene Exerts Its Effects During Fetal Brain Development
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DOI：
10.1176/appi.ajp.2012.11121845
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发表时间：
2012-12-01
影响因子：
17.7
通讯作者：
Bray, Nicholas J.
中科院分区：
文献类型：
--
作者：
Hill, Matthew J.;Bray, Nicholas J.
目的：位于ZNF 804 A基因内含子内的单核苷酸多态性rs 1344706在全基因组范围内与精神分裂症显著相关。尽管rs 1344706基因型与改变的功能性脑连接有关，但介导其与精神分裂症关联的分子机制尚未明确。鉴于其在非编码序列中的位置，作者测试了rs 1344706和ZNF 804 A在成人和胎儿人脑中表达的相关性。使用相对等位基因表达的高度定量测量来评估rs 1344706基因型对ZNF 804 A在背外侧前额叶皮层、海马、结果：rs 1344706位点基因型对ZNF 804 A在成年人脑内的调控无明显影响。与此相反，rs 1344706基因型有显着的影响ZNF 804 A等位基因的表达在中期妊娠胎儿大脑，与精神分裂症的风险（T）等位基因与减少ZNF 804 A expressions.Conclusions：T等位基因rs 1344706与相对减少ZNF 804 A表达在中期妊娠胎儿大脑发育。这些数据为精神分裂症风险机制提供了证据，该机制在胎儿大脑中起作用（可能是特定的）。(Am J Psychiatry 2012; 169：1301-1308）
Objective: The single-nucleotide polymorphism rs1344706, located within an intron of the ZNF804A gene, exhibits genome-wide significant association with schizophrenia. Although genotype at rs1344706 is associated with altered functional brain connectivity, the molecular mechanisms mediating its association with schizophrenia have not been clearly defined. Given its location in noncoding sequence, the authors tested association between rs1344706 and ZNF804A expression in adult and fetal human brain.Method: Highly quantitative measures of relative allelic expression were used to assess the effect of rs1344706 genotype on the mRNA expression of ZNF804A in the dorsolateral prefrontal cortex, hippocampus, and substantia nigra of the adult human brain and in human brain tissue from the first and second trimester of gestation.Results: Genotype at rs1344706 had no significant effect on the regulation of ZNF804A in any of the three adult brain regions examined. In contrast, rs1344706 genotype had a significant effect on ZNF804A allelic expression in second-trimester fetal brain, with the schizophrenia risk (T) allele associated with reduced ZNF804A expression.Conclusions: The T allele of rs1344706 is associated with a relative decrease in ZNF804A expression during the second trimester of fetal brain development. These data provide evidence for a schizophrenia risk mechanism that is operational in (and possibly specific to) the fetal brain. (Am J Psychiatry 2012; 169:1301-1308)