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

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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