Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex.
Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex.
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DOI：
10.1016/j.schres.2013.11.021
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发表时间：
2014-01
影响因子：
4.5
通讯作者：
Vawter MP
中科院分区：
文献类型：
--
作者：
Guella I;Sequeira A;Rollins B;Morgan L;Myers RM;Watson SJ;Akil H;Bunney WE;Delisi LE;Byerley W;Vawter MP
rs1344706是锌指蛋白804A基因（ZNF 804A）内的一个内含子SNP，被鉴定为精神分裂症（SZ）和双相情感障碍（BD）最引人注目的风险SNP之一。然而，尚不清楚ZNF 804A通过何种分子机制增加疾病风险。我们通过对来自哥斯达黎加中央谷隔离人群的428名SZ、385名BD和578名对照样本中最初相关的rs1344706 SNP和位于ZNF 804 A外显子4的外显子SNP（rs12476147）进行基因分型，评估ZNF 804 A在SZ和BD中的作用。我们还研究了46个杂合子死后大脑的背外侧前额叶皮层（DLPFC）中等位基因特异性表达（ASE）不平衡的rs1344706 SNP。虽然在哥斯达黎加样本中未观察到rs1344706与SZ或BD之间的显著关联，但我们观察到外显子rs12476147 SNP的次要等位基因（A）的SZ风险增加（p =0.026）。我们的ASE试验检测到rs1344706杂合子受试者DLPFC中rs12476147 A等位基因的显著过表达。有趣的是，cDNA等位基因比率根据内含子rs1344706基因型显著不同（p值= 0.03），rs1344706 A等位基因与ZNF 804 A rs12476147 A等位基因表达增加相关（平均1.06，p值= 0.02，杂合子受试者与基因组DNA）。总之，我们已经证明了rs12476147与SZ显着相关，并且使用强大的受试者内设计，证明了DLPFC中ZNF 804 A外显子SNP rs12476147的等位基因表达不平衡。虽然这些数据并不排除ZNF 804 A中其他功能变体的可能性，但它提供了证据表明，rs1344706 SZ风险等位基因是直接导致成人皮质中等位基因表达失衡的顺式调节变体。
The rs1344706, an intronic SNP within the zinc-finger protein 804A gene (ZNF804A), was identified as one of the most compelling risk SNPs for schizophrenia (SZ) and bipolar disorder (BD). It is however not clear by which molecular mechanisms ZNF804A increases disease risk. We evaluated the role of ZNF804A in SZ and BD by genotyping the originally associated rs1344706 SNP and an exonic SNP (rs12476147) located in exon four of ZNF804A in a sample of 428 SZ, 385 BD, and 578 controls from the isolated population of the Costa Rica Central Valley. We also investigated the rs1344706 SNP for allelic specific expression (ASE) imbalance in the dorsolateral prefrontal cortex (DLPFC) of 46 heterozygous postmortem brains. While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p =0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value = 0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value = 0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subjects design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex.
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影响因子：
12.3
作者：
Sadee W
通讯作者：
Sadee W
影响因子：
5.3
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
通讯作者：
O'Donovan, MC
影响因子：
6.6
作者：
Donohoe, Gary;Morris, Derek W.;Corvin, Aiden
通讯作者：
Corvin, Aiden
DOI：
10.1002/ajmg.10538
发表时间：
2002-07-08
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
DeLisi, LE;Mesen, A;Sherrington, R
通讯作者：
Sherrington, R
ZNF804A 与亚洲人群的精神分裂症易感性
DOI：
10.1002/ajmg.b.32084
发表时间：
2012-10-01
影响因子：
2.8
作者：
Li, Ming;Shi, Cui-Juan;Su, Bing
通讯作者：
Su, Bing