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

两个人群中人类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有关。此外，AGT产物中的T235M多态性与多个人群中原发性高血压的风险增加有关，使AGT成为常见疾病易感性的数量性状位点的一个很好的例子。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，并鉴定出44个单核苷酸多态性（SNPs）。在88名白种人和77名日本人中均观察到42个snp。6个主要的单倍型占了该区域的大部分变异，表明等位基因的复杂性比许多其他基因组区域要低。尽管这两个种群共享所有主要的AGT单倍型，但单倍型频率存在显著差异。通过D′、r^2和D ^2测量的更多平衡（LD）显示出随着距离增加而下降的一般模式，但是，正如预期的那样，在一个小的基因组区域，个体LD值是高度可变的。评估了T235M与其他39个snp之间的LD，以模拟LD对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值为>.1，而在高加索受试者中，这一数字要高得多（39个中的35个，即90%）。还测量了高血压相关启动子突变a - 6g和39个snp之间的LD。类似的结果也得到了，33%的snp在日本受试者中显示为r^2 > 0.1, 92%的snp在高加索受试者中显示为r^2 > 0.1。尽管两个人群的LD模式总体上相似，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。这些结果对LD方法在复杂疾病易感性基因定位中的有用性具有重要意义。人类血管紧张素原基因（AGT）的自然选择和种群历史：全世界染色体中736个完整的AGT序列：几条证据表明，血管紧张素原基因（AGT）的遗传变异模式有助于人类高血压的表型变异。AGT的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提出了“钠潴留假说”，该假说假设生活在热带非洲和温带欧亚环境的人群适应不同水平的盐供应。这一假设预测，A（-6）变异应该在非洲人群中比在非非洲人群中发现更高的频率。为了验证这一假设，我们通过对来自非洲、亚洲和欧洲的736条染色体的整个AGT （14,400bp）测序，研究了群体历史和自然选择在塑造AGT遗传多样性模式中的作用。我们证实A（-6）变异在非洲人群中比在非非洲人群中出现的频率更高。此外，携带G（-6）变异的单倍型显示出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。几个中性试验发现，当整个AGT序列比较时，没有证据表明选择性中性偏离。然而，滑动窗口分析显示AGT启动子附近的变异模式与最近选择性扫描的假设是一致的。在一些（但不是全部）AGT区域偏离中性预期表明，基因多样性模式不能用人类种群历史来解释，这将平等地影响所有区域。综上所述，AGT的遗传多样性模式表明，在某些种群中，自然选择更倾向于G（-6）变体而不是A（-6）变体。少

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