The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
John Blangero - One of the best experts on this subject based on the ideXlab platform.
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multipoint quantitative trait Linkage Analysis in general pedigrees
American Journal of Human Genetics, 1998Co-Authors: Laura Almasy, John BlangeroAbstract:Multipoint Linkage Analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component Linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component Linkage Analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint Analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.
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bivariate quantitative trait Linkage Analysis pleiotropy versus co incident Linkages
Genetic Epidemiology, 1997Co-Authors: Laura Almasy, Thomas D. Dyer, John BlangeroAbstract:Power to detect Linkage and localization of a major gene were compared in univariate and bivariate variance components Linkage Analysis of three related quantitative traits in general pedigrees. Although both methods demonstrated adequate power to detect loci of moderate effect, bivariate Analysis improved both power and localization for correlated quantitative traits mapping to the same chromosomal region, regardless of whether co-localization was the result of pleiotropy. Additionally, a test of pleiotropy versus co-incident Linkage was shown to have adequate power and a low error rate. © 1997 Wiley-Liss, Inc.
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statistical properties of a variance components method for quantitative trait Linkage Analysis in nuclear families and extended pedigrees
Genetic Epidemiology, 1997Co-Authors: Jeff T Williams, Ravindranath Duggirala, John BlangeroAbstract:We investigated the statistical properties of a variance components method for quantitative trait Linkage Analysis using nuclear families and extended pedigrees. © 1997 Wiley-Liss, Inc.
Leonid Kruglyak - One of the best experts on this subject based on the ideXlab platform.
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multiple locus Linkage Analysis of genomewide expression in yeast
PLOS Biology, 2005Co-Authors: John D Storey, Joshua M Akey, Leonid KruglyakAbstract:With the ability to measure thousands of related phenotypes from a single biological sample, it is now feasible to genetically dissect systems-level biological phenomena. The genetics of transcriptional regulation and protein abundance are likely to be complex, meaning that genetic variation at multiple loci will influence these phenotypes. Several recent studies have investigated the role of genetic variation in transcription by applying traditional Linkage Analysis methods to genomewide expression data, where each gene expression level was treated as a quantitative trait and analyzed separately from one another. Here, we develop a new, computationally efficient method for simultaneously mapping multiple gene expression quantitative trait loci that directly uses all of the available data. Information shared across gene expression traits is captured in a way that makes minimal assumptions about the statistical properties of the data. The method produces easy-to-interpret measures of statistical significance for both individual loci and the overall joint significance of multiple loci selected for a given expression trait. We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous Linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits. We compare the proposed approach to an exhaustive two-dimensional scan over all pairs of loci. Surprisingly, we demonstrate that an exhaustive two-dimensional scan is less powerful than the sequential search used here. In addition, we show that a two-dimensional scan does not truly allow one to test for simultaneous Linkage, and the statistical significance measured from this existing method cannot be interpreted among many traits.
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efficient multipoint Linkage Analysis through reduction of inheritance space
American Journal of Human Genetics, 2001Co-Authors: Kyriacos Markianos, Leonid Kruglyak, Mark J DalyAbstract:Computational constraints currently limit exact multipoint Linkage Analysis to pedigrees of moderate size. We introduce new algorithms that allow Analysis of larger pedigrees by reducing the time and memory requirements of the computation. We use the observed pedigree genotypes to reduce the number of inheritance patterns that need to be considered. The algorithms are implemented in a new version (version 2.1) of the software package GENEHUNTER. Performance gains depend on marker heterozygosity and on the number of pedigree members available for genotyping, but typically are 10–1,000-fold, compared with the performance of the previous release (version 2.0). As a result, families with up to 30 bits of inheritance information have been analyzed, and further increases in family size are feasible. In addition to computation of Linkage statistics and haplotype determination, GENEHUNTER can also perform single-locus and multilocus transmission/disequilibrium tests. We describe and implement a set of permutation tests that allow determination of empirical significance levels in the presence of Linkage disequilibrium among marker loci.
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exact multipoint quantitative trait Linkage Analysis in pedigrees by variance components
American Journal of Human Genetics, 2000Co-Authors: Stephen C Pratt, Mark J Daly, Leonid KruglyakAbstract:Methods based on variance components are powerful tools for Linkage Analysis of quantitative traits, because they allow simultaneous consideration of all pedigree members. The central idea is to identify loci making a significant contribution to the population variance of a trait, by use of allele-sharing probabilities derived from genotyped marker loci. The technique is only as powerful as the methods used to infer these probabilities, but, to date, no implementation has made full use of the inheritance information in mapping data. Here we present a new implementation that uses an exact multipoint algorithm to extract the full probability distribution of allele sharing at every point in a mapped region. At each locus in the region, the program fits a model that partitions total phenotypic variance into components due to environmental factors, a major gene at the locus, and other unlinked genes. Numerical methods are used to derive maximum-likelihood estimates of the variance components, under the assumption of multivariate normality. A likelihood-ratio test is then applied to detect any significant effect of the hypothesized major gene. Simulations show the method to have greater power than does traditional sib-pair Analysis. The method is freely available in a new release of the software package GENEHUNTER.
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faster multipoint Linkage Analysis using fourier transforms
Journal of Computational Biology, 1998Co-Authors: Leonid Kruglyak, Eric S LanderAbstract:ABSTRACT Genetic Linkage Analysis of human pedigrees using many linked markers simultaneously is a difficult computational problem. We have previously described an approach to this problem that uses hidden Markov models (HMMs) and is quite efficient for pedigrees of moderate size. Here, we describe a new, faster algorithm for the key step in the HMM calculation. The algorithm employs a fast Fourier transform on the group of pedigree inheritance patterns. It substantially improves the overall performance of the software package GENEHUNTER for performing Linkage Analysis. The Fourier representation opens up new research directions for pedigree Analysis.
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parametric and nonparametric Linkage Analysis a unified multipoint approach
American Journal of Human Genetics, 1996Co-Authors: Leonid Kruglyak, Mark J Daly, Mary Pat Reevedaly, Eric S LanderAbstract:In complex disease studies, it is crucial to perform multipoint Linkage Analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of Linkage Analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric Linkage (NPL) Analysis, a powerful new approach to pedigree Analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric Linkage Analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL Analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint Analysis of pedigree data to be performed rapidly in a single user-friendly environment.
Laura Almasy - One of the best experts on this subject based on the ideXlab platform.
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multipoint quantitative trait Linkage Analysis in general pedigrees
American Journal of Human Genetics, 1998Co-Authors: Laura Almasy, John BlangeroAbstract:Multipoint Linkage Analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component Linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component Linkage Analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint Analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.
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bivariate quantitative trait Linkage Analysis pleiotropy versus co incident Linkages
Genetic Epidemiology, 1997Co-Authors: Laura Almasy, Thomas D. Dyer, John BlangeroAbstract:Power to detect Linkage and localization of a major gene were compared in univariate and bivariate variance components Linkage Analysis of three related quantitative traits in general pedigrees. Although both methods demonstrated adequate power to detect loci of moderate effect, bivariate Analysis improved both power and localization for correlated quantitative traits mapping to the same chromosomal region, regardless of whether co-localization was the result of pleiotropy. Additionally, a test of pleiotropy versus co-incident Linkage was shown to have adequate power and a low error rate. © 1997 Wiley-Liss, Inc.
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bivariate quantitative trait Linkage Analysis pleiotropy versus co incident Linkages
Genetic Epidemiology, 1997Co-Authors: Laura Almasy, Thomas D Dye, Joh LangeroAbstract:Power to detect Linkage and localization of a major gene were compared in univariate and bivariate variance components Linkage Analysis of three related quantitative traits in general pedigrees. Although both methods demonstrated adequate power to detect loci of moderate effect, bivariate Analysis improved both power and localization for correlated quantitative traits mapping to the same chromosomal region, regardless of whether co-localization was the result of pleiotropy. Additionally, a test of pleiotropy versus co-incident Linkage was shown to have adequate power and a low error rate.
David Curtis - One of the best experts on this subject based on the ideXlab platform.
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investigation by Linkage Analysis of the xy pseudoautosomal region in the genetic susceptibility to schizophrenia
British Journal of Psychiatry, 1995Co-Authors: Gursharan Kalsi, T Read, J Brynjolfsson, Hannes Petursson, P Murphy, David Curtis, Robert Butler, T Sharma, Hugh GurlingAbstract:BACKGROUND A susceptibility locus for schizophrenia in the pseudoautosomal region has been proposed on the basis of a possible excess of sex chromosome aneuploidies among patients with schizophrenia and an increased sex concordance in affected sib pairs. Several studies investigating this hypothesis have produced conflicting evidence. METHOD In a series of Icelandic and British families, we used lod score and sib pair Linkage analyses with markers for the MIC2 and DXYS14 loci on the pseudoautosomal XY region. RESULTS Lod and sib pair Linkage Analysis with these markers produced strongly negative scores. Heterogeneity testing also produced negative results. CONCLUSION We conclude that the present study provides no support for the involvement of either the pseudoautosomal region or the nearby region of the sex chromosomes in the aetiology of schizophrenia.
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Linkage Analysis of idiopathic generalized epilepsy ige and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy no evidence for an epilepsy locus in the hla region
American Journal of Human Genetics, 1993Co-Authors: William P Whitehouse, David Curtis, M Rees, Anders Sundqvist, K Parker, Eddie M K Chung, Diana Baralle, R M GardinerAbstract:Abstract Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage Analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6S89, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint Linkage Analysis was carried out assuming autosomal dominant and autosomal recessive inheritance and age-dependent high or low penetrance. No significant evidence in favor of Linkage was obtained at any locus. Multipoint Linkage Analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype.
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segregation and Linkage Analysis in five manic depression pedigrees excludes the 5ht1a receptor gene htr1a
Annals of Human Genetics, 1993Co-Authors: David Curtis, J Brynjolfsson, Hannes Petursson, P Murphy, S Holmes, Robin Sherrington, P M Brett, L Rifkin, E Moloney, G MelmerAbstract:Summary Five kindreds selected through probands attending an Icelandic hospital were recruited for Linkage studies of manic depression. The rates of affection were equal for males and females and the age of onset appeared to be predominantly in early adult life, since prevalence did not rise appreciably with age. A complex segregation Analysis was performed using the computer program pointer to obtain maximum likelihood estimates of the contributions to liability from multifactorial transmission and a single major locus. Likelihood ratios between models supported a role for a single major locus which was dominant and had moderately high penetrance with, in the case of unipolar illness, additional multifactorial transmission. The bestfitting parameters were used to devise a transmission model for Linkage Analysis. Three markers on chromosome 5 were studied, at D5S76, D5S6 and D5S39. Strongly negative lod scores were obtained which were less than -2 over a distance of 40 cM, which included the region to which the gene for the 5HT1a receptor has been mapped.
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using a dummy quantitative variable to deal with multiple affection categories in genetic Linkage Analysis
Annals of Human Genetics, 1991Co-Authors: David Curtis, H M D GurlingAbstract:Some diseases which have a genetic contribution to aetiology do not demonstrate a clear correspondence between genotype and phenotype. A variety of different clinical syndromes may be thought to reflect the action of a gene, but the probability of affection conditional on genotype may vary between these different diagnostic categories. The normal approach of repeating Linkage analyses several times using different diagnoses to define individuals as affected loses power in two ways: multiple testing must be allowed for, and the distinction between more and less extreme forms of affection is lost. It is shown that for fully dominant or recessive autosomal diseases it is straightforward to assign a quantitative value to each diagnostic category to obtain the desired ratio of the likelihoods of affection conditional on the three possible genotypes. The increased power provided by using this quantitative value in Linkage Analysis is demonstrated by application to simulated pedigrees containing cases of bipolar and unipolar affective disorder.
Joseph D Terwilliger - One of the best experts on this subject based on the ideXlab platform.
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two trait locus Linkage Analysis a powerful strategy for mapping complex genetic traits
American Journal of Human Genetics, 1993Co-Authors: Nicholas J Schork, Michael Boehnke, Joseph D TerwilligerAbstract:Abstract Recent advances in molecular biology have provided geneticists with ever-increasing numbers of highly polymorphic genetic markers that have made possible Linkage mapping of loci responsible for many human diseases. However, nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, we explore two-trait-locus, two-marker-locus Linkage Analysis in which two trait loci are mapped simultaneously to separate genetic markers. We compare the utility of this approach to standard one-trait-locus, one-marker-locus Linkage Analysis with and without allowance for heterogeneity. We also compare the utility of the two-trait-locus, two-marker-locus Analysis to two-trait-locus, one-marker-locus Linkage Analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in Linkage studies, we also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that we consider, we find that two-trait-locus, two-marker-locus Linkage Analysis can provide substantially more Linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, we also find that bilineal pedigrees provide sufficient Linkage information to warrant their inclusion in such studies. We also discuss strategies for assessing the significance of the two Linkages assumed in two-trait-locus, two-marker-locus models.
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a novel polylocus method for Linkage Analysis using the lod score or affected sib pair method
Genetic Epidemiology, 1993Co-Authors: Joseph D TerwilligerAbstract:A novel approach to combining data from multiple linked loci is proposed that can provide substantial increases in power over normal two-point Linkage Analysis or sib-pair Analysis, with a substantial saving in computing time over traditional multipoint methods
