【作者】 孙芸；

【导师】 贺林；

【作者基本信息】 中国科学院研究生院（上海生命科学研究院） ， 神经生物学， 2007， 博士

【摘要】 本论文运用连锁不平衡分析方法研究了两种复杂性遗传疾病(精神发育迟滞和脑卒中)的候选基因。在对精神发育迟滞的研究中,笔者研究了位于下丘脑-垂体-甲状腺轴上的一个重要的转录因子POU1F1基因和神经传递过程中对突触的可塑性起着重要作用的RAB3A基因。笔者在来自秦巴山区的中国汉族人群中对这两个基因展开了病例对照的连锁不平衡分析。结果发现在女性组中,POU1F1基因的rs300996(P=0.0003), snp-7057(P=0.0001)和rs300977(P=0.0005)三个位点的等位基因以及所构成的单倍型频率(global P= 0.0050)相对于总病例和对照组中表现出更强的显著差异;数量性状分析也表明,位点rs300996的等位基因频率(P=0.0301)和由rs300996、snp-7057、rs300977构成的单倍型频率(P=0.0397)分布在女性样本中也表现出显著性差异。在笔者选取的能基本覆盖整个RAB3A基因的遗传标记中,没有发现任何等位基因,基因型以及单倍型频率在病例和对照中有差异。我们的研究结果首次表明POU1F1对精神发育迟滞的作用有性别依赖性,而RAB3A基因在汉族人群中不是精神发育迟滞的易感基因。ALOX5AP和PDE4D基因是在冰岛人群中通过大规模的全基因组连锁分析定位后,进一步通过连锁不平衡分析精细定位找到的脑卒中的候选基因。笔者在来自中国东部地区的汉族人群中开展连锁不平衡分析,旨在研究这两个基因是否是中国人群脑卒中的相关基因。对ALOX5AP的研究发现,在男性病例对照组中,位点SG13S114的频率分布在病例和对照中表现出显著性差异(P= 0.0295),snp-10267, SG13S377, SG13S114和SG13S32构成的整体单倍型(P=0.0239)和单个单倍型(P= 0.0016)的频率分布在病例组和对照组中也有显著性差异。对PDE4D的研究发现,位点SNP83的等位基因频率分布在心源性和颈动脉性脑卒中病例和对照中表现出显著性差异(P=0.0060);在脑内小动脉阻塞性脑卒中组进行研究的时候,由rs152312和SNP56构成的整体单倍型(P = 0.0034)和单个单倍型(P=0.0009)的频率分布在病例组和对照组中表现出显著性差异。我们的研究结果进一步表明,ALOX5AP和PDE4D在中国人群中也是脑卒中的易感基因。更多还原

【Abstract】 This thesis uses the linkage disequilibrium analysis to study the candidate gens of two kinds of common diseases: mental retardation (MR) and stroke. In the study of MR, we investigated the POU1F1 gene, an important transcription factor in the hypothalamus-pituitary-thyroid gland axis and the RAB3A gene, a key molecule in modulating basal neurotransmission and synaptic plasticity. We performed case-control linkage disequilibrium studies in the Chinese Han population from Qin-Ba mountain region. For POU1F1, in females, we found significant differences between cases and controls in the allele frequency distribution of rs300996, snp-7057 (P=0.0001) and rs300977 (P=0.0005) respectively, and their combined haplotype (global P=0.0050). The P-value was 0.0301 for rs300996 and 0.0397 for the haplotype combination of rs300996-snp-7057-rs300977 in the analysis of the quantitative effects of the alleles and haplotypes on IQ in females. However, there were no significant differences with RAB3A detected in the same sample at all. Our data first suggest that POU1F1 may affect MR through a gender specific mechanism, but RAB3A doesn’t.ALOX5AP and PDE4D are promising candidate genes in relation to stroke, given its positional and functional involvement. In the linkage disequilibrium studies, we explored the role of these genes in the incidence of stroke in the Chinese Han population of eastern China. For ALOX5AP, in the analysis of the male group, SG13S114 showed significant differences between cases and controls (P=0.0295); the global P value for the frequencies of the haplotypes in snp-10267, SG13S377 SG13S114 and SG13S32 was 0.0239, and the frequency of haplotype G-G-T-C was higher in cases than in controls (P=0.0016). For PDE4D, in the analysis of the combined cardiogenic and carotid stroke group, both the allele (P=0.0060) and genotype (P=0.0160) frequencies between cases and controls at SNP83 showed significant differences; in the analysis of the small-artery occlusive stroke group, the global haplotype frequency in rs152312 and SNP56 showed significant differences between cases and controls (P=0.0034), and the frequency of haplotype C-A was higher in cases than in controls (P=0.0009). Our findings well support that both ALOX5AP and PDE4D are associated with an increased risk for ischemic stroke in the Chinese population.更多还原