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At least 19 recordsLinked to original sources
PubMed2005

Division of linkage disequilibrium between absolute linkage disequilibrium and linkage equilibrium.

Linkage disequilibrium is the association between alleles in the allele distributions across linked loci and is intermediate in character between the dependence and the independence of allele distribution. This ambivalence makes linkage disequilibrium difficult to understand and to treat mathematically. To overcome this difficulty, an attempt was made to divide linkage disequilibrium between absolute linkage disequilibrium, which is a complete dependence of allele distribution, and linkage equilibrium, which is a complete independence. A matrix description of linkage disequilibrium showed that (1) linkage disequilibrium is divided between absolute linkage disequilibrium and linkage equilibrium, (2) a linkage disequilibrium state is characterized by the allele frequency in the first locus p, the relative content of absolute linkage disequilibrium d and the linkage equilibrium variable c, and (3) r is the geometric mean of both orientation's d. Division of linkage disequilibrium may make linkage disequilibrium straightforward to understand and to treat mathematically.

Alleles↗
PubMed1994

Maximum-likelihood estimation of gene location by linkage disequilibrium.

Linkage disequilibrium, D, between a polymorphic disease and mapped markers can, in principle, be used to help find the map position of the disease gene. Likelihoods are therefore derived for the value of D conditional on the observed number of haplotypes in the sample and on the population parameter Nc, where N is the effective population size and c the recombination fraction between the disease and marker loci. The likelihood is computed explicitly for the case of two loci with heterozygote superiority and, more generally, by computer simulations assuming a steady state of constant population size and selective pressures or neutrality. It is found that the likelihood is, in general, not very dependent on the degree of selection at the loci and is very flat. This suggests that precise information on map position will not be obtained from estimates of linkage disequilibrium.

Chromosome Mapping↗
PubMed2004

The impact of SNP density on fine-scale patterns of linkage disequilibrium.

Linkage disequilibrium (LD) is a measure of the degree of association between alleles in a population. The detection of disease-causing variants by association with neighbouring single nucleotide polymorphisms (SNPs) depends on the existence of strong LD between them. Previous studies have indicated that the extent of LD is highly variable in different chromosome regions and different populations, demonstrating the importance of genome-wide accurate measurement of LD at high resolution throughout the human genome. A uniform feature of these studies has been the inability to detect LD in regions of low marker density. To investigate the dependence of LD patterns on marker selection we performed a high-resolution study in African-American, Asian and UK Caucasian populations. We selected over 5000 SNPs with an average spacing of approximately 1 SNP per 2 kb after validating ca 12 000 SNPs derived from a dense SNP collection (1 SNP per 0.3 kb on average). Applications of different statistical methods of LD assessment highlight similar areas of high and low LD. However, at high resolution, features such as overall sequence coverage in LD blocks and block boundaries vary substantially with respect to marker density. Model-based linkage disequilibrium unit (LDU) maps appear robust to marker density and consistently influenced by marker allele frequency. The results suggest that very dense marker sets will be required to yield stable views of fine-scale LD in the human genome.

Black or African American↗
PubMed2005

The role of pedigree information in combined linkage disequilibrium and linkage mapping of quantitative trait loci in a general complex pedigree.

Combined linkage disequilibrium and linkage (LDL) mapping can exploit historical as well as recent and observed recombinations in a recorded pedigree. We investigated the role of pedigree information in LDL mapping and the performance of LDL mapping in general complex pedigrees. We compared using complete and incomplete genotypic data, spanning 5 or 10 generations of known pedigree, and we used bi- or multiallelic markers that were positioned at 1- or 5-cM intervals. Analyses carried out with or without pedigree information were compared. Results were compared with linkage mapping in some of the data sets. Linkage mapping or LDL mapping with sparse marker spacing ( approximately 5 cM) gave a poorer mapping resolution without considering pedigree information compared to that with considering pedigree information. The difference was bigger in a pedigree of more generations. However, LDL mapping with closely linked markers ( approximately 1 cM) gave a much higher mapping resolution regardless of using pedigree information. This study shows that when marker spacing is dense and there is considerable linkage disequilibrium generated from historical recombinations between flanking markers and QTL, the loss of power due to ignoring pedigree information is negligible and mapping resolution is very high.

Alleles↗
PubMed2005

Characterization of multilocus linkage disequilibrium.

Linkage disequilibrium (LD) in the human genome, often measured as pairwise correlation between adjacent markers, shows substantial spatial heterogeneity. Congruent with these results, studies have found that certain regions of the genome have far less haplotype diversity than expected if the alleles at multiple markers were independent, while other sets of adjacent markers behave almost independently. Regions with limited haplotype diversity have been described as "blocked" or "haplotype blocks." In this article, we propose a new method that aims to distinguish between blocked and unblocked regions in the genome. Like some other approaches, the method analyses haplotype diversity. Unlike other methods, it allows for adjacent, distinct blocks and also multiple, independent single nucleotide polymorphisms (SNPs) separating blocks. Based on an approximate likelihood model and a parsimony criterion to penalize for model complexity, the method partitions a genomic region into blocks relatively quickly, and simulations suggest that its partitions are accurate. We also propose a new, efficient method to select SNPs for association analysis, namely tag SNPs. These methods compare favorably to similar blocking and tagging methods using simulations.

Algorithms↗
PubMed1998

Linkage disequilibrium and linkage analysis of the glucose-6-phosphatase gene.

Recent studies have indicated that the four most common mutations account for 78% of mutant alleles in the glucose-6-phosphatase (G6Pase) gene. A significant fraction of mutant alleles remain unidentified. Thus, informative polymorphic markers are necessary for linkage analysis in carrier testing and prenatal diagnosis in families where mutations can not be identified. The common mutations appear to be ethnic-specific, suggesting that the individual mutations may have a common founder. With the recent discovery of the nucleotide 1176 polymorphism, we have studied whether these mutations are in linkage disequilibrium with the polymorphism. The results of polymerase chain reaction/allele-specific oligonucleotide analysis show that nucleotide 1 176 C is in linkage disequilibrium with mutations R83 C and R83H, and with the splicing mutation 727G-->T. The 1176T polymorphism is in linkage disequilibrium with 459insTA. A GT repeat polymorphism has also been found. However, its heterozygosity is low. The 1176 nucleotide polymorphic marker can be used in carrier and prenatal diagnosis of GSD1a families that have unidentified mutations and are informative for this marker.

Female↗
PubMed1991

Linkage disequilibrium and linkage information from one-child families.

In linkage analysis a single-child family is usually considered to be completely uninformative. This article shows that such a family can provide information on linkage disequilibrium, even if it provides no information on linkage equilibrium. A transition matrix consisting of the recombination fraction and the phase proportion is proposed to study the genetic transmission from a pair of parents to their single child. The information about linkage for a single-child family is shown to be confounded by the phase proportion. This explains why such a family used to be considered uninformative under the assumption of linkage equilibrium. By reparametrizing the recombination fraction and the phase proportion into one parameter, it is demonstrated that extracting information on linkage disequilibrium is feasible. The study of power of the testing method proposed here is carried out by simulation.

Child↗
PubMed2003

High-resolution joint linkage disequilibrium and linkage mapping of quantitative trait loci based on sibship data.

This paper proposes variance component models for high resolution joint linkage disequilibrium (LD) and linkage mapping of quantitative trait loci (QTL) based on sibship data; this can include population data if independent individuals are treated as single sibships. One application of these models is late onset complex disease gene mapping, when parental data are not available. The models simultaneously incorporate both LD and linkage information. The LD information is contained in mean coefficients of sibship data. The linkage information is contained in the variance-covariance matrices of trait values for sibships with at least two siblings. We derive formulas for calculating the probability of sharing two trait alleles identical by descent (IBD) for sibpairs in interval mapping of QTL; this is the coefficient of dominant variance of the trait covariance of sibpairs on major QTL. To investigate the performance of the formulas, we calculate the numerical values via the formulas and get satisfactory approximations. We compare the power and sample sizes for both LD and linkage mapping. By simulation and theoretical analysis, we compare the results with those of Fulker and Abecasis "AbAw" approach. It is well known that the resolution of linkage analysis can be low for complex disease gene mapping. LD mapping, on the other hand, can increase mapping precision and is useful in high resolution mapping. Linkage analysis is less sensitive to population subdivisions and admixtures. The level of LD is sensitive to population stratification which may easily lead to spurious association. Performing a joint analysis of LD and linkage mapping can help to overcome the limits of both approaches. Moreover, the advantages of the two complementary strategies can be utilized maximally. In practice, linkage analysis may be performed using pedigree data to identify suggestive linkage between markers and trait loci based on a sparse marker map. In the presence of linkage, joint LD and linkage mapping can be carried out to do fine gene mapping based on a dense genetic map using both pedigree and population data. Population and pedigree data of any type can be combined to perform a joint analysis of high resolution LD and linkage mapping of QTL by generalizing the method.

Alleles↗
PubMed2006

Simultaneous fine mapping of multiple closely linked quantitative trait Loci using combined linkage disequilibrium and linkage with a general pedigree.

Within a small region (e.g., <10 cM), there can be multiple quantitative trait loci (QTL) underlying phenotypes of a trait. Simultaneous fine mapping of closely linked QTL needs an efficient tool to remove confounded shade effects among QTL within such a small region. We propose a variance component method using combined linkage disequilibrium (LD) and linkage information and a reversible jump Markov chain Monte Carlo (MCMC) sampling for model selection. QTL identity-by-descent (IBD) coefficients between individuals are estimated by a hybrid MCMC combining the random walk and the meiosis Gibbs sampler. These coefficients are used in a mixed linear model and an empirical Bayesian procedure combines residual maximum likelihood (REML) to estimate QTL effects and a reversible jump MCMC that samples the number of QTL and the posterior QTL intensities across the tested region. Note that two MCMC processes are used, i.e., an (internal) MCMC for IBD estimation and an (external) MCMC for model selection. In a simulation study, the use of the multiple-QTL model clearly removes the shade effects between three closely linked QTL located at 1.125, 3.875, and 7.875 cM across the region of 10 cM, using 40 markers at 0.25-cM intervals. It is shown that the use of combined LD and linkage information gives much more useful information compared to using linkage information alone for both single- and multiple-QTL analyses. When using a lower marker density (11 markers at 1-cM intervals), the signal of the second QTL can disappear. Extreme values of past effective size (resulting in extreme levels of LD) decrease the mapping accuracy.

Chromosome Mapping↗
PubMed2005

The effect of linkage disequilibrium on linkage analysis of incomplete pedigrees.

Dense SNP maps can be highly informative for linkage studies. But when parental genotypes are missing, multipoint linkage scores can be inflated in regions with substantial marker-marker linkage disequilibrium (LD). Such regions were observed in the Affymetrix SNP genotypes for the Genetic Analysis Workshop 14 (GAW14) Collaborative Study on the Genetics of Alcoholism (COGA) dataset, providing an opportunity to test a novel simulation strategy for studying this problem. First, an inheritance vector (with or without linkage present) is simulated for each replicate, i.e., locations of recombinations and transmission of parental chromosomes are determined for each meiosis. Then, two sets of founder haplotypes are superimposed onto the inheritance vector: one set that is inferred from the actual data and which contains the pattern of LD; and one set created by randomly selecting parental alleles based on the known allele frequencies, with no correlation (LD) between markers. Applying this strategy to a map of 176 SNPs (66 Mb of chromosome 7) for 100 replicates of 116 sibling pairs, significant inflation of multipoint linkage scores was observed in regions of high LD when parental genotypes were set to missing, with no linkage present. Similar inflation was observed in analyses of the COGA data for these affected sib pairs with parental genotypes set to missing, but not after reducing the marker map until r2 between any pair of markers was <or= 0.05. Additional simulation studies of affected sib pairs assuming uniform LD throughout a marker map demonstrated inflation of significance levels at r2 values greater than 0.05. When genotypes are available only from two affected siblings in many families in a sample, trimming SNP maps to limit r2 to 0-0.05 for all marker pairs will prevent inflation of linkage scores without sacrificing substantial linkage information. Simulation studies on the observed pedigree structures and map can also be used to determine the effect of LD on a particular study.

Alcoholism↗
PubMed2006

Using dominance relationship coefficients based on linkage disequilibrium and linkage with a general complex pedigree to increase mapping resolution.

Dominance (intralocus allelic interactions) plays often an important role in quantitative trait variation. However, few studies about dominance in QTL mapping have been reported in outbred animal or human populations. This is because common dominance effects can be predicted mainly for many full sibs, which do not often occur in outbred or natural populations with a general pedigree. Moreover, incomplete genotypes for such a pedigree make it infeasible to estimate dominance relationship coefficients between individuals. In this study, identity-by-descent (IBD) coefficients are estimated on the basis of population-wide linkage disequilibrium (LD), which makes it possible to track dominance relationships between unrelated founders. Therefore, it is possible to use dominance effects in QTL mapping without full sibs. Incomplete genotypes with a complex pedigree and many markers can be efficiently dealt with by a Markov chain Monte Carlo method for estimating IBD and dominance relationship matrices (D(RM)). It is shown by simulation that the use of D(RM) increases the likelihood ratio at the true QTL position and the mapping accuracy and power with complete dominance, overdominance, and recessive inheritance modes when using 200 genotyped and phenotyped individuals.

Chromosome Mapping↗
PubMedDate not supplied

Mapping multiple QTL using linkage disequilibrium and linkage analysis information and multitrait data.

A multi-locus QTL mapping method is presented, which combines linkage and linkage disequilibrium (LD) information and uses multitrait data. The method assumed a putative QTL at the midpoint of each marker bracket. Whether the putative QTL had an effect or not was sampled using Markov chain Monte Carlo (MCMC) methods. The method was tested in dairy cattle data on chromosome 14 where the DGAT1 gene was known to be segregating. The DGAT1 gene was mapped to a region of 0.04 cM, and the effects of the gene were accurately estimated. The fitting of multiple QTL gave a much sharper indication of the QTL position than a single QTL model using multitrait data, probably because the multi-locus QTL mapping reduced the carry over effect of the large DGAT1 gene to adjacent putative QTL positions. This suggests that the method could detect secondary QTL that would, in single point analyses, remain hidden under the broad peak of the dominant QTL. However, no indications for a second QTL affecting dairy traits were found on chromosome 14.

Acyltransferases↗
PubMedDate not supplied

The efficiency of designs for fine-mapping of quantitative trait loci using combined linkage disequilibrium and linkage.

In a simulation study, different designs were compared for efficiency of fine-mapping of QTL. The variance component method for fine-mapping of QTL was used to estimate QTL position and variance components. The design of many families with small size gave a higher mapping resolution than a design with few families of large size. However, the difference is small in half sib designs. The proportion of replicates with the QTL positioned within 3 cM of the true position is 0.71 in the best design, and 0.68 in the worst design applied to 128 animals with a phenotypic record and a QTL explaining 25% of the phenotypic variance. The design of two half sib families each of size 64 was further investigated for a hypothetical population with effective size of 1000 simulated for 6000 generations with a marker density of 0.25 cM and with marker mutation rate 4 x10(-4) per generation. In mapping using bi-allelic markers, 42 approximately 55 of replicated simulations could position QTL within 0.75 cM of the true position whereas this was higher for multi allelic markers (48 approximately 76 ). The accuracy was lowest (48%) when mutation age was 100 generations and increased to 68% and 76% for mutation ages of 200 and 500 generations, respectively, after which it was about 70% for mutation ages of 1000 generations and older. When effective size was linearly decreasing in the last 50 generations, the accuracy was decreased (56 to 70%). We show that half sib designs that have often been used for linkage mapping can have sufficient information for fine-mapping of QTL. It is suggested that the same design with the same animals for linkage mapping should be used for fine-mapping so gene mapping can be cost effective in livestock populations.

Alleles↗
PubMed2005

Disentangling linkage disequilibrium and linkage from dense single-nucleotide polymorphism trio data.

Parent-offspring trios are widely collected for disease gene-mapping studies and are being extensively genotyped as part of the International HapMap Project. With dense maps of markers on trios, the effects of LD and linkage can be separated, allowing estimation of recombination rates in a model-free setting. Here we define a model-free multipoint method on the basis of dense sequence polymorphism data from parent-offspring trios to estimate intermarker recombination rates. We use simulations to show that this method has up to 92% power to detect recombination hotspots of intensity 25 times background over a region of size 10 kb typed at density 1 marker per 2.5 kb and almost 100% power to detect large hotspots of intensity >125 times background over regions of size 10 kb typed with just 1 marker per 5 kb (alpha = 0.05). We found strong agreement at megabase scales between estimates from our method applied to HapMap trio data and estimates from the genetic map. At finer scales, using Centre d'Etude du Polymorphisme Humain (CEPH) pedigree data across a 10-Mb region of chromosome 20, a comparison of population recombination rate estimates obtained from our method with estimates obtained using a coalescent-based approximate-likelihood method implemented in PHASE 2.0 shows detection of the same coldspots and most hotspots: The Spearman rank correlation between the estimates from our method and those from PHASE is 0.58 (p < 2.2(-16)).

Computer Simulation↗
PubMed2006

[Disequilibrium linkage between the polymorphism in exons 2, 3 and 4 of the MICA gene and HLA-B antigen of patient with ankylosing spondylitis].

OBJECTIVE: To investigate the association between the exons 2 to 4 of the MICA gene and ankylosing spondylitis (AS). METHODS: By PCR-SSOP, DNA samples from 56 AS patients and 112 random healthy individuals, as normal control were genotyped to analyse the polymorphism in exons 2, 3, 4 of the MICA alleles. RESULTS: MICA*008 was dominant in MICA allele,accounted for 32.14% and 30.36% in AS patients and normal controls respectively. The frequency of MICA*007 was significantly increased in AS patients, when compared with normal controls (chi-square=10.18, P<0.05, RR=2.50). No difference was found in the other MICA alleles. The haplotype analysis revealed that there were the strong linkage disequilibrium between MICA and HLA-B of AS patients, and normal controls. There was a difference in MICA*007-B27 between two groups (chi-square=18.46, P<0.05, RR=7.47). Both HLA-B27 and MICA*007 were strongly associated with AS. Stratified analysis showed that HLA-B27 was significantly relative to AS,while it was not found between MICA*007 and AS. CONCLUSION: The increased frequency of MICA alleles may be due to its strong linkage disequilibrium with HLA-B27.

Alleles↗
PubMed2004

Linkage disequilibrium testing when linkage phase is unknown.

Linkage disequilibrium, the nonrandom association of alleles from different loci, can provide valuable information on the structure of haplotypes in the human genome and is often the basis for evaluating the association of genomic variation with human traits among unrelated subjects. But, linkage phase of genetic markers measured on unrelated subjects is typically unknown, and so measurement of linkage disequilibrium, and testing whether it differs significantly from the null value of zero, requires statistical methods that can account for the ambiguity of unobserved haplotypes. A common method to test whether linkage disequilibrium differs significantly from zero is the likelihood-ratio statistic, which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We show, by simulations, that this approach can be grossly biased, with either extremely conservative or liberal type I error rates. In contrast, we use simulations to show that a composite statistic, proposed by Weir and Cockerham, maintains the correct type I error rates, and, when comparisons are appropriate, has similar power as the likelihood-ratio statistic. We extend the composite statistic to allow for more than two alleles per locus, providing a global composite statistic, which is a strong competitor to the usual likelihood-ratio statistic.

Alleles↗
PubMed2006

The admixture linkage disequilibrium and genetic linkage inference on the gradual admixture population.

Through the theoretical analysis of the admixture linkage disequilibrium (ALD) in the gradual admixture (GA) model, in which admixture occurs in every generation, the ALD is found to be proportional to the difference in marker allele frequencies, P1 - P2, between two subpopulations. Based on this property, we can employ a strict monotonic function (delta(ker) = delta/(P1-P2), where delta denotes the linkage disequilibrium (LD)) of the recombination fraction between the marker locus and the disease locus to infer the true genetic linkage. We construct a quasi likelihood ratio test (LRT) for the case-only data utilizing the information of unlinked markers in the human genome. The simulation results show that our tests can be used to fine map a disease locus. The effects of parameter values in the ALD mapping are also discussed.

Black or African American↗
PubMed2003

Multipoint linkage disequilibrium mapping approach: incorporating evidence of linkage and linkage disequilibrium from unlinked region.

Gene mapping for complex diseases is still a challenge in genetic studies. For family-based studies, the single-locus methods for detecting linkage and linkage disequilibrium (LD) one at a time may not capture the assumed interaction between multiple causal genes efficiently. We propose a multipoint LD approach for assessing the evidence of linkage and LD in a targeted chromosomal region by incorporating evidence from an unlinked region using the case-parent trio design. The paternal and maternal preferential transmission statistics defined in Liang et al. ([2001] Am. J. Hum. Genet. 68:937-950) are the primary statistics for this approach. Our generalized estimating equation (GEE) method builds on a model using the expected preferential transmission statistic from the targeted region conditional on this same statistic from the unlinked region. The major assumption is that there is no more than one trait locus in both the targeted region and unlinked region. The map position of an unobserved trait locus and its confidence interval can be calculated. Finally, we apply this approach to the African-American families drawn from the Collaborative Study on the Genetics of Asthma (CSGA). Previous analysis using this GEE approach developed by Liang et al. ([2001] Am. J. Hum. Genet. 68:937-950) suggested strong evidence of linkage and LD on chromosome 11, but only marginal evidence on chromosome 8. While conditioning on marker D11S937 on chromosome 11, a separate trait locus on chromosome 8 was estimated at tau(2) empty set = 11.67 cM, with a 95% confidence interval of (8.75, 14.59), and the test statistic shows significant evidence of linkage and LD (P-value=0.0198) in this region of chromosome 8.

Black or African American↗