Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia.
Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia.
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基因组扫描和基因表达微阵列结合起来识别与精神分裂症相关的基因调控位点。
DOI：
10.1007/s00439-006-0172-7
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发表时间：
2006
期刊：
影响因子：
5.3
通讯作者：
Byerley,WilliamF
中科院分区：
文献类型：
--
作者：
Vawter,MarquisP;Atz,MaryE;Rollins,BrandiL;Cooper-Casey,KathleenM;Shao,Ling;Byerley,WilliamF
据报道，精神分裂症中存在多个连锁区，其中一些似乎含有易感基因，这些易感基因在来自无关个体的死后脑组织中有差异表达。我们结合了多重家族中传统的全基因组连锁分析和全淋巴细胞全基因组表达分析。基因组扫描显示与染色体4Q标记(D4S1530，LOD2.17，θ=0)存在显性连锁。使用侧翼微卫星标记的单倍型分析描绘了一个14 Mb区域，该区域与所有受影响的人共分离。随后对SNP基因的全基因组扫描支持使用显性模式与4q33-35.1(LOD=2.39)连锁的证据。全基因组微阵列分析了5个受影响的家庭成员和5个未受影响的家庭成员，在单倍型AGA和GALNT7(天冬氨酸氨基葡萄糖苷酶和UDP-N-乙酰-α-D-氨基半乳糖：多肽N-乙酰半乳糖胺转移酶7)中发现了两个差异表达的基因，具有标称意义；然而，经过协方差分析，这些基因没有保持显著意义。GALNT7的表达水平与4q28.1(最大LOD=3.15)和4q33-35.1(最大LOD=2.37)单倍型连锁；ADH1B(酒精脱氢酶IB)与4q21-q23(最大LOD=3.08)和4q33-35.1(最大LOD=2.27)单倍型连锁。用RT-PCR验证了7个差异表达基因。4q33-35.1单倍型区域的三个基因在精神分裂症死后背外侧前额叶皮质中也有差异表达：AGA、HMGB2和SCRG1。这些结果表明，将差异基因表达与连锁分析相结合，可能有助于确定候选基因和潜在的调控位点。此外，他们还复制了基因复杂多聚糖和顺式调控的最新发现。
Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, θ=0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33–35.1 (LOD=2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotypeAGAandGALNT7(aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptideN-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers.AGAexpression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD=2.37) but to no other genomic region.GALNT7expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD=3.15) and in the haplotype region at 4q33–35.1 (maximum LOD=2.37).ADH1B(alcohol dehydrogenase IB) was linked to loci at 4q21–q23 (maximum LOD=3.08) and haplotype region at 4q33–35.1 (maximum LOD=2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33–35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex:AGA,HMGB2, andSCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complextrans- andcis- regulation of genes.