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Strategies for the identification of susceptibility genes underlying complex diseases through whole-genome linkage disequilibrium (LD) mapping

通过全基因组连锁不平衡（LD）作图鉴定复杂疾病易感基因的策略

基本信息

批准号：
14572141
负责人：
NAKAJIMA Toshiaki
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572141/
关键词：
linkage diseciuilibulium(LD) mapping angiotensinogen common disease 連鎖不平衡マッピング

项目摘要

Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations:Variation in the angiotensinogen gene (AGT) has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential hypertension in multiple populations, making AGT a good example of a quantitative trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4 kb genomic region spanning the entire AGT and identified 44 single nucleotide polymorphisms (SNPs). 42 SNPs were observed in both 88 Caucasian and 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations shared all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pair-wise linkage dise … More quilibrium (LD), measured by the D', r^2, and d^2 demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r^2 values > 0.1, while this figure was substantially higher for the Caucasian subjects (35 of 39, or 90%). LD was also measured between a hypertension-associated promoter mutation, A-6G, and 39 SNPs. Similar results were obtained, with 33% of the SNPs showing r^2 > 0.1 in the Japanese subjects and 92% showing r^2 > 0.1 in the Caucasian subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the Caucasian sample. These results have important implications for the usefulness of LD approaches in the mapping of genes underlying susceptibility to complex diseases.Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in worldwide chromosomes:Several lines of evidence suggest that patterns of genetic variability in the angiotensinogengene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen level and the increased risk of essential hypertension. Geographical variation in susceptibility to hypertension has introduced the "sodium retention hypothesis", which posits that populations living in tropical Africa and temperate Eurasian environments are adapted to different levels of salt availability. This hypothesis predicts that the A(-6) variant should be found at higher frequencies in African populations than in non-African populations. To test this hypothesis, we investigated the roles of population history and, natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT (14,400bp) in 736 chromosomes from Africa, Asia, and Europe. We confirmed that the A(-6) variant is present at higher frequency in African populations than in non-African populations. In addition, haplotypes carrying the G(-6) variant showed elevated levels of linkage disequilibrium, suggesting that they have risen to high frequency recently. Several neutrality tests found no evidence for a departure from selective neutrality when whole AGT sequences were compared. However, sliding-window analyses showed that patterns of variation in the vicinity of the AGT promoter are consistent with the hypothesis of a recent selective sweep. Departures from neutral expectation in some, but not all, regions of AGT indicate that patterns of diversity in the gene cannot be accounted for by human population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has favored the G(-6) variant over the A(-6) variant in some populations. Less

两个人群中人血管紧张素原基因的核苷酸多样性和单倍型结构：血管紧张素原基因（AGT）的变异与血浆血管紧张素原水平的变异相关。此外，AGT产物中的T235 M多态性与多个人群中原发性高血压的风险增加相关，使AGT成为常见疾病易感性的数量性状基因座的一个很好的例子。为了更好地了解AGT的遗传变异，我们对整个AGT的14.4 kb基因组区域进行了测序，并确定了44个单核苷酸多态性（SNP）。在88名高加索人和77名日本人中观察到42个SNP。六个主要的单倍型占该地区的大部分变异，表明等位基因的复杂性比许多其他基因组区域。虽然这两个群体共享所有的主要AGT单倍型，有很大的差异，单倍型频率。成对联动盘 ...更多信息通过D '、r^2和d^2测量的平衡（LD）显示出随距离增加而下降的一般模式，但是，正如在小的基因组区域中所预期的那样，个体LD值是高度可变的。评估了T235 M和其他39个SNP中的每一个之间的LD，以模拟LD检测疾病相关突变的有用性。在日本受试者中，13个（33%）SNP的r^2值> 0.1，而高加索受试者的这一数字明显更高（39个中的35个，或90%）。LD还测量了高血压相关启动子突变A-6 G和39个SNP之间的差异。获得了类似的结果，在日本受试者中有33%的SNP显示r^2 > 0.1，在高加索受试者中有92%的SNP显示r^2 > 0.1。尽管两个人群的LD模式总体相似，但这种差异反映了高加索人样本中M235相关单倍型的频率要高得多。这些结果有重要意义的有用性LD的方法在映射的基因易感性复杂diseases.Natural选择和人口的历史在人类血管紧张素原基因（AGT）：736个完整的AGT序列在世界各地的染色体：几行的证据表明，模式的遗传变异的血管紧张素原基因（AGT）有助于人类高血压的表型变异。AGT A（-6）启动子变异与血浆血管紧张素原水平升高和原发性高血压风险增加有关。高血压易感性的地理差异引入了“钠潴留假说”，该假说假定生活在热带非洲和温带欧亚环境中的人口适应不同水平的盐供应。这一假设预测，A（-6）变异在非洲人群中的频率应该高于非非洲人群。为了验证这一假设，我们通过对来自非洲、亚洲和欧洲的736条染色体中的整个AGT（14,400 bp）进行测序，研究了种群历史和自然选择在AGT遗传多样性形成模式中的作用。我们证实A（-6）变异在非洲人群中的频率高于非非洲人群。此外，携带G（-6）变异的单倍型显示出较高水平的连锁不平衡，这表明它们最近已经上升到很高的频率。几个中性测试发现，没有证据偏离选择性中性时，整个AGT序列进行了比较。然而，滑动窗口分析表明，AGT启动子附近的变化模式与最近的选择性扫描的假设是一致的。在AGT的某些（但不是全部）区域中，中性预期的结果表明，该基因的多样性模式不能由人类人口历史来解释，这将平等地影响所有区域。总的来说，AGT的遗传多样性模式表明，在某些群体中，自然选择倾向于G（-6）变异而不是A（-6）变异。少