Linkage disequilibrium and haplotype analysis of COX-2 and risk of colorectal adenoma development.
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ABSTRACT:
SUBMITTER: Kwagyan J
PROVIDER: S-EPMC3618970 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Eragrostis tef (Zucc.), a member of the Chloridoideae subfamily of grasses, is one of the most important food crops in Ethiopia. Lodging is the most important production problem in tef. The rht1 and sd1 dwarfing genes have been useful for improving lodging resistance in wheat and rice, respectively, in what has been known as the "Green Revolution." All homologs of rht1 and sd1 were cloned and sequenced from 31 tef accessions collected from across Ethiopia. The allotetraploid tef genome was found to carry two rht1 homologs. From sequence variation between these two putative homologs, an approximate ancestral divergence date of 6.4 million years ago was calculated for the two genomes within tef. Three sd1 homologs were identified in tef, with unknown orthologous/paralogous relationships. The genetic diversity in the 31 studied accessions was organized into a relatively small number of haplotypes (2-4) for four of these genes, whereas one rht1 homeologue exhibited 10 haplotypes. A low level of nucleotide diversity was observed at all loci. Linkage disequilibrium analysis demonstrated strong linkage disequilibrium, extending the length of the five genes investigated (2-4 kb), with no significant decline. There was no significant correlation between haplotypes of any of these genes and their recorded site of origin.
| S-EPMC3291510 | biostudies-literature
Project description:The HapMap Project is providing a great deal of new information on high-resolution haplotype structure in various human populations. This information has the potential to greatly increase the power of association mapping for a fixed amount of genotyping. A number of methods have been proposed for the identification of haplotype blocks, common haplotypes, and tagging single-nucleotide polymorphisms. Here, we build on this work by developing novel methods for case-control multipoint linkage-disequilibrium (LD) mapping that gain power and speed by making explicit use of the inferred block structure. Specifically, we developed a virtual-variant approach that uses the haplotype-block information to greatly increase power for detection of untyped common variants associated with a trait. Because full multipoint LD mapping can be slow, we exploited the haplotype-block information to develop a fast single-block multipoint mapping method. Our methods are appropriate for genotype data and take into account the uncertainty in phase. We describe the methods in the context of case-parents trios, although they are also applicable to unrelated cases and controls. Our simulations indicate that the most important gains from taking into account the haplotype-block structure at the analysis stage of multipoint LD mapping come from (1) greatly increased power to detect association with untyped variants and (2) greatly improved localization of untyped variants associated with the trait. More-modest gains are obtained in improving power to detect association with a variant that is typed with a moderate amount of missing data. The methods are applied to a Crohn disease data set.
| S-EPMC1785316 | biostudies-literature
Project description:BackgroundRecent evidence indicates that single nucleotide polymorphisms (SNPs) in the Cox-2 gene may modulate the risk of colorectal adenoma development.Patients and methodsWe explored possible associations between Cox-2 polymorphisms and risk of adenoma development in an African American case-control study comprising 72 cases of advanced adenomas and 146 polyp-free controls. An exhaustive approach of genotyping 13 haplotype-tagging SNPs (ht SNPs) distributed over the entire COX-2 gene was used.ResultsStatistically significant inverse associations were observed between the heterozygous genotypes at the 5229 G>T polymorphism in intron 5 [odds ratio (OR)=0.42; confidence interval (CI)=0.19-0.92; p=0.03] and at the 10935 A>G polymorphism in the 3' flanking region downstream from the poly A signals (OR=0.39; CI=0.18-0.83;p=0.01) and the risk for colorectal adenoma development.ConclusionThe data from our pilot study suggest that allelic variants of the COX-2 gene significantly influence the risk of adenoma development in the African American population.
| S-EPMC6980310 | biostudies-literature
Project description:Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
| S-EPMC3582274 | biostudies-literature
Project description:Linkage disequilibrium (LD) analysis provides information on the evolutionary aspects of populations. Recently, haplotype blocks have been used to increase the power of quantitative trait loci detection in genome-wide association studies and the prediction accuracy of genomic selection. Our objectives were as follows: to compare the degree of LD, LD decay, and LD decay extent in popcorn populations; to characterize the number and length of haplotype blocks in the populations; and to determine whether maize chromosomes also have a pattern of interspaced regions of high and low rates of recombination. We used a biparental population, a synthetic, and a breeding population, genotyped for approximately 75,000 single nucleotide polymorphisms (SNPs). The sample size ranged from 190 to 192 plants. For the whole-genome LD and haplotype block analyses, we assumed a window of 500 kb. To characterize the block and step patterns of LD in the populations, we constructed LD maps by chromosome, defining a cold spot as a chromosome segment including SNPs with the same LDU position. The LD and haplotype block analyses were also performed at the intragenic level, selecting 12 genes related to zein, starch, cellulose, and fatty acid biosynthesis. The populations with the higher and lower frequencies of |D'| values greater than 0.75 were the biparental (65-74%) and the breeding population (26-58%), respectively. There were slight differences between the populations regarding the average distance for SNPs with |D'| values greater than 0.75 (in the range of approximately 207 to 229 kb). The level of LD expressed by the r2 values was low in the populations (0.02, 0.04, and 0.04, on average) but comparable to some non-isolated human populations. The frequency of r2 values greater than 0.75 was lower in the biparental population (0.2-0.5%) and higher in the other populations (0.2-1.6%). The average distance for SNPs with r2 values greater than 0.75 was much higher in the biparental population (approximately 80 to 126 kb). In the other populations, the ranges were approximately 6 to 19 and 6 to 35 kb. The heatmaps for the regions covered by the first 100 SNPs in each chromosome, in each population (1 to 3.3 Mb, approximately), provided evidence that the comparatively few high r2 values (close to 1.0) occurred only for SNPs in close proximity, especially in the synthetic and breeding populations. Due to the reduced number of SNPs in the haplotype blocks (2 to 3) in the populations, it is not expected advantage of a haplotype-based association study as well as genomic selection along generations. The results concerning LD decay (rapid decay after 5-10 kb) and LD decay extent (along up to 300 kb) are in the range observed with maize inbred line panels. The LD maps indicate that maize chromosomes had a pattern of regions of extensive LD interspaced with regions of low LD. However, our simulated LD map provides evidence that this pattern can reflect regions with differences in allele frequencies and LD levels (expressed by |D'|) and not regions with high and low rates of recombination.
| S-EPMC6760792 | biostudies-literature
Project description:To facilitate association-based linkage studies we have studied the linkage disequilibrium (LD) and haplotype architecture around five genes of interest for cancer risk: ATM, BRCA1, BRCA2, RAD51, and TP53. Single nucleotide polymorphisms (SNPs) were identified and used to construct haplotypes that span 93-200 kb per locus with an average SNP density of 12 kb. These markers were genotyped in four ethnically defined populations that contained 48 each of African Americans, Asian Americans, Hispanic Americans, and European Americans. Haplotypes were inferred using an expectation maximization (EM) algorithm, and the data were analyzed using D', R(2), Fisher's exact P-values, and the four-gamete test for recombination. LD levels varied widely between loci from continuously high LD across 200 kb to a virtual absence of LD across a similar length of genome. LD structure also varied at each gene and between populations studied. This variation indicates that the success of linkage-based studies will require a precise description of LD at each locus and in each population to be studied. One striking consistency between genes was that at each locus a modest number of haplotypes present in each population accounted for a high fraction of the total number of chromosomes. We conclude that each locus has its own genomic profile with regard to LD, and despite this there is the widespread trend of relatively low haplotype diversity. As a result, a low marker density should be adequate to identify haplotypes that represent the common variation at a locus, thereby decreasing costs and increasing efficacy of association studies.
| S-EPMC187564 | biostudies-literature
Project description:Marginal tests based on individual SNPs are routinely used in genetic association studies. Studies have shown that haplotype-based methods may provide more power in disease mapping than methods based on single markers when, for example, multiple disease-susceptibility variants occur within the same gene. A limitation of haplotype-based methods is that the number of parameters increases exponentially with the number of SNPs, inducing a commensurate increase in the degrees of freedom and weakening the power to detect associations. To address this limitation, we introduce a hierarchical linkage disequilibrium model for disease mapping, based on a reparametrization of the multinomial haplotype distribution, where every parameter corresponds to the cumulant of each possible subset of a set of loci. This hierarchy present in the parameters enables us to employ flexible testing strategies over a range of parameter sets: from standard single SNP analyses through the full haplotype distribution tests, reducing degrees of freedom and increasing the power to detect associations. We show via extensive simulations that our approach maintains the type I error at nominal level and has increased power under many realistic scenarios, as compared to single SNP and standard haplotype-based studies. To evaluate the performance of our proposed methodology in real data, we analyze genome-wide data from the Wellcome Trust Case-Control Consortium.
| S-EPMC6637384 | biostudies-literature
Project description:The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers.We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen alpha1 (COL1A1), estrogen receptor-alpha (ER-alpha), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-beta1 (TGF-beta1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r2, were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r2 was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene.The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.
| S-EPMC421754 | biostudies-literature
Project description:We compared the accuracy of haplotype inferences at a 6 Mb region on chromosome 7 where significant linkage between a brain oscillation phenotype and a cholinergic muscarinic receptor gene was previously reported. Individual haplotype assignments and haplotype frequencies were estimated using 5, 10, and 14 consecutive Illumina single-nucleotide polymorphisms (SNPs) within the 1-LOD unit support interval of the chromosome 7 linkage peak. Initially, haplotypes were constructed incorporating phase information provided by relatives using the pedigree analysis package MERLIN. Population-based haplotypes were inferred using the haplotype estimation software HAPLO.STATS and PHASE, using unrelated individuals. The 14 SNPs within this region exhibited markedly low linkage disequilibrium, and the average D' estimate between SNPs was 0.18 (range: 0.01-0.97). In comparison to the family-based haplotypes calculated in MERLIN, the computational inferences of individual haplotype assignments were most accurate when considering 5 consecutive SNPs, but decayed dramatically when considering 10 or 14 SNPs in both PHASE and HAPLO.STATS. When comparing the two haplotype inference methods, both PHASE and HAPLO.STATS performed poorly. These analyses underscore the difficulties of haplotype estimation in the presence of low linkage disequilibrium and stress the importance of careful consideration of confidence measures when using estimated haplotype frequencies and individual assignments in biomedical research.
| S-EPMC1866700 | biostudies-literature
Project description:To dissect the haplotype structure of candidate genes for disease association studies, it is important to understand the nature of genetic variation at these loci in different populations. We present a survey of haplotype structure and linkage disequilibrium of chemokine and chemokine receptor genes in 11 geographically-distinct population samples (n=728). Chemokine proteins are involved in intercellular signalling and the immune response. These molecules are important modulators of human immunodeficiency virus (HIV)-1 infection and the progression of the acquired immune deficiency syndrome, tumour development and the metastatic process of cancer. To study the extent of genetic variation in this gene family, single nucleotide polymorphisms (SNPs) from 13 chemokine and chemokine receptor genes were genotyped using the 5' nuclease assay (TaqMan). SNP haplotypes, estimated from unphased genotypes using the Expectation-Maximization-algorithm, are described in a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21, and a cluster of three CC-chemokine genes [MPIF-1 (CCL23), PARC (CCL18) and MIP-1alpha (CCL3)] on chromosome 17q11-12. The 32 base pair (bp) deletion in exon 4 of CCR5 was also included in the haplotype analysis of 3p21. A total of 87.5 per cent of the variation of 14 biallelic loci scattered over 150 kilobases of 3p21 is explained by 11 haplotypes which have a frequency of at least 1 per cent in the total sample. An analysis of haplotype blocks in this region indicates recombination between CCR2 and CCR5, although long-range pairwise linkage disequilibrium across the region appears to remain intact on two common haplotypes. A reduced-median network demonstrates a clear relationship between 3p21 haplotypes, rooted by the putative ancestral haplotype determined by direct sequencing of four primate species. Analysis of six SNPs on 17q11-12 indicates that 97.5 per cent of the variation is explained by 15 haplotypes, representing at least 1 per cent of the total sample. Additionally, a possible signature of selection at a non-synonymous coding SNP (M106V) in the MPIF-1 (CCL23) gene warrants further study. We anticipate that the results of this study of chemokine and chemokine receptor variation will be applicable to more extensive surveys of long-range haplotype structure in these gene regions and to association studies of HIV-1 disease and cancer.
| S-EPMC3525265 | biostudies-literature