Chowdari Kodavali V, Mirnics Karoly, Semwal Prachi, Wood Joel, Lawrence Elizabeth, Bhatia Triptish, Deshpande Smita N, B K Thelma, Ferrell Robert E, Middleton Frank A, Devlin Bernie, Levitt Pat, Lewis David A, Nimgaonkar Vishwajit L
Department of Psychiatry, University of Pittsburgh, School of Medicine and Graduate School of Public Health, Western Psychiatric Institute and Clinic, PA 15213, USA.
Hum Mol Genet. 2002 Jun 1;11(12):1373-80. doi: 10.1093/hmg/11.12.1373.
Gene expression analyses of postmortem cerebral cortex suggest that transcription of the regulator of G-protein signaling 4 (RGS4) is decreased in a diagnosis-specific manner in subjects with schizophrenia. To evaluate the possible role of RGS4 in the pathogenesis of schizophrenia, we conducted genetic association and linkage studies using samples ascertained independently in Pittsburgh and New Delhi and by the NIMH Collaborative Genetics Initiative. Using the transmission disequilibrium test, significant transmission distortion was observed in the Pittsburgh and NIMH samples. Among single-nucleotide polymorphisms (SNPs) spanning approximately 300 kb, significant associations involved four SNPs localized to a 10 kb region at RGS4, but the associated haplotypes differed. A trend for transmission distortion was also present in the Indian sample for haplotypes incorporating the same SNPs. Consistent with the linkage/association observed from the family-based tests, samples with affected siblings (NIMH, India) showed higher levels of allele sharing, identical by descent, at RGS4. When the US patients were contrasted to two population-based control samples, however, no significant differences were observed. To check the specificity of the transmission bias, we therefore examined US families with bipolar I disorder (BD1) probands. This sample also showed a trend for transmission distortion, and differed significantly from the population-based controls for the four-SNP haplotypes tested in the other samples. The transmission distortion is unlikely to be due to chance, but its mechanism and specificity require further study. Our results illustrate the potential power of combining gene expression profiling and genomic analyses to identify susceptibility genes for genetically complex disorders.
对死后大脑皮层的基因表达分析表明，精神分裂症患者中G蛋白信号调节因子4（RGS4）的转录以诊断特异性方式降低。为了评估RGS4在精神分裂症发病机制中的可能作用，我们使用在匹兹堡和新德里独立确定的样本以及美国国立精神卫生研究所（NIMH）协作遗传学倡议进行了基因关联和连锁研究。使用传递不平衡检验，在匹兹堡和NIMH样本中观察到显著的传递扭曲。在跨越约300 kb的单核苷酸多态性（SNP）中，显著关联涉及位于RGS4一个10 kb区域的四个SNP，但相关单倍型不同。在印度样本中，包含相同SNP的单倍型也存在传递扭曲趋势。与基于家系检验观察到的连锁/关联一致，有患病兄弟姐妹的样本（NIMH，印度）在RGS4处显示出更高水平的等位基因共享，即同源相同。然而，当将美国患者与两个基于人群的对照样本进行对比时，未观察到显著差异。为了检验传递偏倚的特异性，我们因此检查了以双相I型障碍（BD1）先证者为家系的美国家庭。该样本也显示出传递扭曲趋势，并且与其他样本中测试的四SNP单倍型的基于人群的对照有显著差异。传递扭曲不太可能是偶然的，但其机制和特异性需要进一步研究。我们的结果说明了结合基因表达谱分析和基因组分析来识别遗传复杂疾病易感基因的潜在能力。
