Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
World J Biol Psychiatry. 2012 Oct;13(7):550-4. doi: 10.3109/15622975.2012.666359. Epub 2012 Mar 5.
SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported. Our objective was to test whether the associated SNP affected CDC42 expression.
Two available SNP × gene expression datasets were accessed to test the effect of rs2473277 on CDC42 expression: (i) the mRNA by SNP Browser, which presents results of a genome-wide linkage study of gene expression, and (ii) the Genevar HapMap expression dataset. rs2473277 is in strong linkage disequilibrium (LD) with the SNP rs2473307 (r(2) =0.96), which is predicted to affect transcription factor binding. rs2473307 was directly tested for allelic effects on gene expression using a gene reporter assay in a human neuronal cell line.
In both datasets, the schizophrenia risk allele at rs2473277 was associated with a reduction in CDC42 mRNA levels. In the reporter gene assay the risk allele at rs2473307 similarly reduced gene expression.
We found evidence that rs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC42.
细胞分裂周期蛋白 42（CDC42）基因上游的 SNP rs2473277 在前不久的全基因组关联研究（GWAS）中与精神分裂症相关联。此前已有报道称，CDC42 在精神分裂症患者中的表达水平降低。本研究旨在检验关联 SNP 是否影响 CDC42 的表达。
我们利用两个可用的 SNP×基因表达数据集来检验 rs2473277 对 CDC42 表达的影响：（i）SNP Browser 中的 mRNA，它提供了全基因组连锁研究中基因表达的结果；（ii）Genevar HapMap 表达数据集。rs2473277 与 SNP rs2473307 强连锁不平衡（r²=0.96），后者被预测会影响转录因子结合。rs2473307 被直接用于在人神经细胞系中的基因报告基因检测，以检验其等位基因对基因表达的影响。
在这两个数据集，rs2473277 的精神分裂症风险等位基因与 CDC42 mRNA 水平的降低相关联。在报告基因检测中，rs2473307 的风险等位基因也同样降低了基因表达。
我们发现了证据表明，rs2473307 与与精神分裂症相关联的 SNP rs2473277 高度连锁，是 CDC42 的功能性变体，通过降低 CDC42 的表达，可能增加精神分裂症的风险。
