Chen Xiangning, Wang Xu, Chen Qi, Williamson Vernell, van den Oord Edwin, Maher Brion S, O'Neill F Anthony, Walsh Dermot, Kendler Kenneth S
Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Biol Psychiatry. 2008 Mar 1;63(5):441-8. doi: 10.1016/j.biopsych.2007.11.003. Epub 2008 Jan 7.
The 5q21-31 region has been implicated as harboring risk genes for schizophrenia in many linkage studies. In our previous report of stepwise fine mapping of this region, the MEGF10 gene was one of the genes showing consistent associations in our screening subsample. In this study, we carried out independent replication and expression studies of the MEGF10 gene.
Association studies with 8 SNPs in the MEGF10 gene were performed in the Irish case-control study of schizophrenia (ICCSS) sample (652 case and 617 control subjects). The expression of MEGF10 was also compared between healthy control subjects and schizophrenia patients using postmortem brain cDNA libraries.
In the ICCSS sample, associations with the disease were found in the same risk alleles and haplotypes as that observed in our fine-mapping studies. The major allele (A) of rs27388 was overrepresented in affected individuals (p = .0169), which remained significant after correction for multiple testing. In expression studies, MEGF10 had higher expression levels in the affected than the unaffected (p = .015). Schizophrenia patients with a 1/1 genotype at rs27388 had higher expressions than those patients with 1/2 and 2/2 genotypes (p = .0008).
Evidence from both association and expression studies suggests that MEGF10 is likely associated with schizophrenia. The major allele and 1/1 genotype at rs27388 impose higher risks for the disease.
在许多连锁研究中，5q21 - 31区域被认为含有精神分裂症的风险基因。在我们之前关于该区域逐步精细定位的报告中，MEGF10基因是在我们的筛查子样本中显示出一致关联的基因之一。在本研究中，我们对MEGF10基因进行了独立的重复验证和表达研究。
在爱尔兰精神分裂症病例对照研究（ICCSS）样本（652例病例和617例对照）中对MEGF10基因的8个单核苷酸多态性（SNP）进行了关联研究。还使用死后大脑cDNA文库比较了健康对照者和精神分裂症患者之间MEGF10的表达。
在ICCSS样本中，发现与疾病的关联存在于与我们精细定位研究中观察到的相同风险等位基因和单倍型中。rs27388的主要等位基因（A）在受影响个体中过度表达（p = 0.0169），在多重检验校正后仍具有显著性。在表达研究中，MEGF10在受影响者中的表达水平高于未受影响者（p = 0.015）。rs27388基因型为1/1的精神分裂症患者的表达高于基因型为1/2和2/2的患者（p = 0.0008）。
关联研究和表达研究的证据均表明MEGF10可能与精神分裂症相关。rs27388的主要等位基因和1/1基因型使该疾病的风险更高。
