Haplotype Variation and Linkage Disequilibrium in 313 Human Genes

Stephens, Jonathan; Schneider, Julie A.; Tanguay, Debra A.; Choi, Julie; Acharya, Tara; Stanley, Scott E.; Jiang, Rong; Messer, Chad J.; Chew, Anne; Han, Jin Kyu; Duan, Jicheng; Carr, Janet L.; Lee, Min Seob; Koshy, Beena; Kumar, Anil; Zhang, Ge; Newell, William R.; Windemuth, Andreas; Xu, Chao-Jiang; Kalbfleisch, Theodore S.; Shaner, Sandra L.; Arnold, Kevin; Schulz, Volkmar; Drysdale, Connie M.; Nandabalan, Krishnan; Judson, Richard S.; Ruaño, Gualberto; Vovis, Gerald F.

doi:10.1126/science.1059431

Cited by 730 publications

(519 citation statements)

References 24 publications

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“…As a result, a majority of the genes in a large survey of 3899 SNPs in 82 individuals of different origins showed a negative Tajima's D-value. 29 This finding is consistent with growth in the human population. Using simulations 30 to account for the effect of a conservative population growth model, the positive values in Table 3 become highly unexpected and thus constitute strong evidence of balancing selection.…”

Section: Tests Of Neutralitysupporting

confidence: 81%

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci

et al. 2004

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A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (|D 0 |40.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for 480% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F ST statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.

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Section: Tests Of Neutralitysupporting

confidence: 81%

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci

et al. 2004

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“…Nucleotide diversity (p), calculated as the average heterozygosity per site, was 0.00110 for the total sample and did not change significantly after excluding patients with CVID and IgAD from the analysis. Compared to literature available values, such statistic results to be nearly twice the mean value estimated for 292 autosomal genes (p ¼ 0.00058), 16 higher than the mean value calculated from the 320 genes resequenced by the Seattle SNPs project (p ¼ 0.00085) (http://pga.gs.washington. edu/) and also higher than the value obtained as an average for 8 genes from the Innate Immunity Program in Genomics Application database (p ¼ 0.00094) (http:// innateimmunity.net/), recently surveyed for signatures of selection.…”

Section: Polymorphic Variationcontrasting

confidence: 58%

“…The haplotype reconstruction (Table 3) led to the identification of a greater number of haplotypes (64) with respect to that of haplotype-constituting variants (35), emphasizing the considerable level of recombination occurred within the TNFRSF13B gene. 16,23 This was also confirmed by the observed linkage disequilibrium (LD) patterns, which were characterized by low average r 2 values for all SNPs pair-wise comparisons (ZnS), with values ranging from ZnS ¼ 0.06 for the central Asian sample to ZnS ¼ 0.12 for the Val di Scalve sample. This pointed out an overall picture of low LD for the TNFRSF13B region, in which Italian, Middle Eastern and North African healthy samples showed the highest percentages of significant SNPs pair-wise comparisons (19,13 and 12%, respectively).…”

Section: Polymorphic Variationmentioning

confidence: 59%

“…Significant values observed for the total sample may be instead explained by the higher statistical power of tests on such a greater group and by the effect of demographic expansion of anatomically modern humans on the H. sapiens genome, as seen in most of our genes. 16 Finally, even if not significantly different from zero the large positive Tajima's D value for the Val di Scalve sample (Table 2) suggests a condition close to a scarceness of segregating sites and to an excess of intermediate frequency alleles that may be interpreted as a consequence of a founder effect, followed by strong genetic drift.…”

Section: Tnfrsf13b Evolution and Cvidmentioning

confidence: 92%

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An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

et al. 2009

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Coding variants in tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) have been implicated in common variable immunodeficiency (CVID), but the functional effects of such mutations in relation to the development of the disease have not been entirely established. To examine the potential contribution of TNFRSF13B variants to CVID, we have applied an evolutionary approach by sequencing its coding region in 451 individuals belonging to 26 worldwide populations, in addition to controls, patients with CVID and selective IgA deficiency (IgAD) from Italy. The low level of geographical structure for the observed genetic diversity and the several neutrality tests performed confirm the absence of recent population-specific selective pressures, suggesting that TNFRSF13B may be involved also in innate immune functions, rather than in adaptive immunity only. A slight excess of rare derived alleles was found in patients with CVID, and thus some of these variants may contribute to the disease, implying that CVID probably fits the rare variants rather than the common disease/common variant paradigm. This also confirms the previous suggestion that TNFRSF13B defects alone do not cause CVID and that such an extremely heterogeneous immunodeficiency might be more likely related to additional, still unknown environmental and genetic factors.

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“…This population provides a representative sampling of human genetic variation and serves as a comparative baseline for genotypic analysis of the study population. 23,53 CETP SNPs in these individual samples were discovered and the unphased genotypes were determined by sequencing the polymerase chain reaction (PCR) products of the genomic DNA. A total of 66 SNPs were discovered for the CETP gene, but only a subset of nine (SNPs1-9) was selected to represent coverage across the entire gene (Figure 1).…”

Section: Determination Of Genetic Variationmentioning

confidence: 99%

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

Winkelmann¹,

Hoffmann

Nauck

et al. 2003

Pharmacogenomics J

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Cholesteryl ester transfer protein (CETP) plays a central role in high-density lipoprotein (HDL) metabolism. Single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were determined in 98 patients with untreated dyslipidemias and analyzed for associations with plasma CETP and plasma lipids before and during statin treatment. Individual CETP SNPs and haplotypes were both significantly associated with CETP enzyme mass and activity. However, only certain CETP haplotypes, but not individual SNPs, significantly predicted the magnitude of change in HDL cholesterol (HDL-C) and triglycerides. After adjusting for covariates and multiple testing, the TTCAAA haplotype showed a gene-dose effect in predicting the HDL-C increase (P¼0.03), while the TTCAAAGGG and AAAGGG haplotypes predicted a decrease in triglycerides (P¼0.04 both). This is the first study to demonstrate that SNP haplotypes derived from allelic SNP combinations in the CETP gene were more informative than single SNPs in predicting the response to lipid-modifying therapy with statins. The Pharmacogenomics Journal (2003) 3, 284-296, doi:10.1038/sj.tpj.6500195Keywords: cholesteryl ester transfer protein; HDL-cholesterol; triglycerides; haplotype; single nucleotide polymorphism; statin INTRODUCTION Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and plays a central role in high-density lipoprotein (HDL) metabolism. CETP transfers cholesteryl esters associated with HDL to triglyceride-rich lipoproteins, facilitating the clearance of cholesteryl esters from plasma. 1 Although the potential contribution of CETP to reverse cholesterol transport suggests an antiatherogenic mode of action, knowledge of the physiologic role of CETP in lipoprotein metabolism remains incomplete. The overall effect of CETP on atherogenesis may vary depending on both metabolic context and molecular variation in the CETP gene. 2 Investigations of associations between genetic variants in CETP and cardiovascular phenotypes are numerous, but often conflicting in their findings. The Taq1B polymorphism of the CETP gene has been associated with plasma levels of CETP and HDL cholesterol (HDL-C) and with the risk of coronary heart disease (CHD). 3,4 The Taq1B polymorphism has also been shown to serve as a marker of lipoprotein response to dietary intervention. 5,6 Other studies have demonstrated a link between the CETP I405V gene polymorphism and HDL-C, but not with response to diet. 7,8 Several other single nucleotide polymorphisms (SNPs) in the

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Haplotype Variation and Linkage Disequilibrium in 313 Human Genes

Cited by 730 publications

References 24 publications

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci

Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy

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