Doi Nagafumi, Itokawa Masanari, Hoshi Yoko, Arai Makoto, Furukawa Aizou, Ujike Hiroshi, Sora Ichiro, Yoshikawa Takeo
Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan.
Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):165-73. doi: 10.1002/ajmg.b.30365.
We examined the hypothesis that -485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case-control association study, 331 unrelated Japanese schizophrenics (S(1): milder cases in the previous study, n = 212; and S(2): additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of -485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene-dose of -485 T, and the severity of chronic outcome in S(2) assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S(1) + S(2) among the three genotypes. -485 T was significantly associated with schizophrenia in S(1) + S(2). Significant negative correlations were observed between the gene-dose and the symptom assessment scores in all items. The homozygote of -485 T showed a second peak frequency in the late-onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early-onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of -485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. -485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested.
神经肽Y基因启动子区域的一种新型多态性位点-485T（在我们之前的论文中显示其与精神分裂症相关）会使人易患该疾病。在一项病例对照关联研究中，招募了331名无亲缘关系的日本精神分裂症患者（S(1)：在之前研究中病情较轻的病例，n = 212；以及S(2)：另外病情较重的病例，n = 119）和199名无亲缘关系的正常对照。通过以下方式检验-485T对疾病风险和严重程度的影响：（1）比较普通人群中各基因型的风险；（2）检测-485T的基因剂量与用阳性和阴性症状量表评估的S(2)中慢性结局严重程度之间的相关性；（3）比较S(1)+S(2)中三种基因型的发病年龄分布。-485T在S(1)+S(2)中与精神分裂症显著相关。在所有项目中，均观察到基因剂量与症状评估得分之间存在显著负相关。-485T的纯合子在男性和女性的晚发组中均显示出第二个峰值频率，而另一个等位基因的纯合子在早发组中显示出一个单一峰值。在普通人群中，杂合子患精神分裂症的风险高于-485T纯合子，这并不支持与易感基因存在连锁不平衡的可能性。-485T最有可能赋予对精神分裂症的抗性而非易感性。提示在线粒体DNA中存在一种核抗性基因与假定致病基因之间的相互作用。
