Yasuno Katsuhito, Ando Satoshi, Misumi Shinnosuke, Makino Satoshi, Kulski Jerzy K, Muratake Tatsuyuki, Kaneko Naoshi, Amagane Hideki, Someya Toshiyuki, Inoko Hidetoshi, Suga Hidemichi, Kanemoto Kousuke, Tamiya Gen
Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan.
Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):250-3. doi: 10.1002/ajmg.b.30443.
Many studies suggest that mitochondrial dysfunction is involved in the pathophysiology of schizophrenia. We performed a case-control study using tag SNPs in the mitochondrial uncoupling protein genes, UCP2, UCP4, and BMCP1/UCP5, to investigate their association with schizophrenia. These neuronal UCPs are expressed in various brain tissues and may exert a neuroprotective effect against increased oxidative stress. We found modest associations between schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P = 0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR = 0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of which were statistically significant even after correcting for multiple comparisons. Moreover, we found a statistically significant synergistic interaction between UCP2 and UCP4 by using the multifactor dimensionality reduction (MDR) method. The synergistic interaction was also confirmed by the logistic regression analysis, where the maximal OR was obtained when the risk alleles at rs660339 and rs10807344 were simultaneously homozygous. Individuals possessing homozygous risk alleles at these two loci have a 7.6-fold risk of developing schizophrenia compared with those of minimal OR. Our findings suggest that UCP2 and UCP4 have a modest but important involvement in the genetic etiology of schizophrenia. This is the first report of the association between schizophrenia and neuronal UCPs.
许多研究表明，线粒体功能障碍参与了精神分裂症的病理生理过程。我们进行了一项病例对照研究，使用线粒体解偶联蛋白基因UCP2、UCP4和BMCP1/UCP5中的标签单核苷酸多态性（tag SNPs），以研究它们与精神分裂症的关联。这些神经元型解偶联蛋白在各种脑组织中表达，可能对增加的氧化应激发挥神经保护作用。我们发现精神分裂症与UCP2中的四个标签单核苷酸多态性rs660339（优势比（OR）=1.330；P = 0.0043）和rs649446（OR = 0.739；P = 0.0069），以及UCP4中的rs10807344（OR = 0.622；P = 0.0029）和rs2270450（OR = 0.704；P = 0.0043）之间存在适度关联，即使在进行多重比较校正后，所有这些关联在统计学上均具有显著性。此外，我们使用多因素降维（MDR）方法发现UCP2和UCP4之间存在统计学上显著的协同相互作用。逻辑回归分析也证实了这种协同相互作用，当rs660339和rs10807344处的风险等位基因同时为纯合子时，获得最大的OR值。与最小OR值的个体相比，在这两个位点拥有纯合风险等位基因的个体患精神分裂症的风险高7.6倍。我们的研究结果表明，UCP2和UCP4在精神分裂症的遗传病因中具有适度但重要的作用。这是关于精神分裂症与神经元型解偶联蛋白之间关联的首次报道。
