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Linkage Disequilibrium Mapping (linkage + disequilibrium_mapping)
Selected AbstractsLinkage Disequilibrium Mapping of Disease Susceptibility Genes in Human PopulationsINTERNATIONAL STATISTICAL REVIEW, Issue 1 2000David Clayton Summary The paper reviews recent work on statistical methods for using linkage disequilibrium to locate disease susceptibility genes, given a set of marker genes at known positions in the genome. The paper starts by considering a simple deterministic model for linkage disequilibrium and discusses recent attempts to elaborate it to include the effects of stochastic influences, of "drift", by the use of either Writht-Fisher models or by approaches based on the coalescence of the genealogy of the sample of disease chromosomes. Most of this first part of the paper concerns a series of diallelic markers and, in this case, the models so far proposed are hierarchical probability models for multivariate binary data. Likelihoods are intractable and most approaches to linkage disequilibrium mapping amount to marginal models for pairwise associations between individual markers and the disease susceptibility locus. Approaches to evalutation of a full likelihood require Monte Carlo methods in order to integrate over the large number of unknowns. The fact that the initial state of the stochastic process which has led to present-day allele frequencies is unknown is noted and its implications for the hierarchical probability model is discussed. Difficulties and opportunities arising as a result of more polymorphic markers and extended marker haplotypes are indicated. Connections between the hierarchical modelling approach and methods based upon identity by descent and haplotype sharing by seemingly unrelated case are explored. Finally problems resulting from unknown modes of inheritance, incomplete penetrance, and "phenocopies" are briefly reviewed. Résumé Ce papier est une revue des travaux récents, protant sur les méthodes statistiques qui utilisent I'étude, des liaisons désé, quilib rées, pour identifer les génes, de susceptibilité des maladies,ápartir d'une série, de marqueurs de géncs á des positions définies du génome,. Le papier commence par considérer, un modéle, détéministe, simple pour liaisons déséquilibr,ées, puis nous discutons les améliorations, ré centes proposées, de ce modéle, dans but de tenir compte des effects des influences stochastiques soit en utilisant les modéles, de wright-fisher, soit par des approches basées, sur la coalescence de la géné alogic de I'échantillon, des chromosomes malades. La plupart de cette premiére, partie porte sur une série, de marqueurs dialléliques et, dans ce cas, les modéles, proposés, sont des modéles, hiérerchiques, probabilistes pour dinnées, binaires multivariées. Les viaisemblances n'ont pas de forme analytique et la plupart des approches pour la cartographie des liaisons déséquilibrées, sont équivalentes aux modéles, marginaux pour dinnées, appariées, entre des marqueurs individuels et le géne, de susceptibilité de la maladie.Pour évaluer, la vriausemblance compléte, des méthodes de Monte carlo sont nécessaires, afin d'intégrer, le large nombre d; inconnues. Le fait que l'état, initial du process stochastique qui a conduit éla fré, quence, allélique, actuel soit inconnu est á noter et ses implications pour le modéle, hiérarchique, probabiliste sont discutées.Les difficultés, et implications issues de marqueurs polumorphiques et de marquers haplotypes sont dévéloppées.Les liens entire l'approche de modélisation, hiérerchique, et les méthodes, d'analyse d'identite pardescendance et les haplotypes partagés, par des cas apparement non apparentés, sont explorés. Enfin les problémes, relatifs à des modes de transmission inconnus,à des pénétrances, incomplé, tes, et aux "phénocopies" sont briévenment evoqués. [source] Power of Linkage Disequilibrium Mapping to Detect a Quantitative Trait Locus (QTL) in Selected Samples of Unrelated IndividualsANNALS OF HUMAN GENETICS, Issue 6 2003A. Tenesa Summary We considered a strategy to map quantitative trait loci (QTLs) using linkage disequilibrium (LD) when the QTL and marker locus were multiallelic. The strategy involved phenotyping a large number of unrelated individuals and genotyping only selected individuals from the two tails of the trait distribution. Power to detect trait-marker association was assessed as a function of the number of QTL and marker alleles. Two patterns of LD were used to study their influence on power. When the frequency of the QTL allele with the largest effect and that of the marker allele linked in coupling were equal, power was maximum. In this case, increasing the number of QTL alleles reduced the power. The maximum difference in power between the two LD patterns studied was ,30%. For low QTL heritabilities (h2QTL < 0.1) and single trait studies we recommend selecting around 5% of the upper and lower tails of the trait distribution. [source] Candidate gene studies in the 21st century: meta-analysis, mediation, moderationGENES, BRAIN AND BEHAVIOR, Issue S1 2006M. R. Munafò The results of a large body of candidate gene studies of behavioural and psychiatric phenotypes have been largely inconclusive, with most findings failing to replicate reliably. A variety of approaches that augment the ,traditional' candidate gene approach are discussed, including the use of meta-analysis to combine findings from existing published reports, the investigation of mediating variables (including the use of intermediate phenotypes or endophenotypes) and the awareness of possible moderating influences (such as sex or ethnicity) and gene,environment interactions on genetic associations, possibly via epigenetic mechanisms. Advances in genotyping technology will also allow the routine use of haplotype analysis and linkage disequilibrium mapping. Examples of how these approaches may improve our understanding of how genetic associations with behavioural and psychiatric phenotypes obtain are given. [source] Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traitsGENETIC EPIDEMIOLOGY, Issue 4 2002Fang-Chi Hsu Abstract Rapid development in biotechnology has enhanced the opportunity to deal with multipoint gene mapping for complex diseases, and association studies using quantitative traits have recently generated much attention. Unlike the conventional hypothesis-testing approach for fine mapping, we propose a unified multipoint method to localize a gene controlling a quantitative trait. We first calculate the sample size needed to detect linkage and linkage disequilibrium (LD) for a quantitative trait, categorized by decile, under three different modes of inheritance. Our results show that sampling trios of offspring and their parents from either extremely low (EL) or extremely high (EH) probands provides greater statistical power than sampling in the intermediate range. We next propose a unified sampling approach for multipoint LD mapping, where the goal is to estimate the map position (,) of a trait locus and to calculate a confidence interval along with its sampling uncertainty. Our method builds upon a model for an expected preferential transmission statistic at an arbitrary locus conditional on the sampling scheme, such as sampling from EL and EH probands. This approach is valid regardless of the underlying genetic model. The one major assumption for this model is that no more than one quantitative trait locus (QTL) is linked to the region being mapped. Finally we illustrate the proposed method using family data on total serum IgE levels collected in multiplex asthmatic families from Barbados. An unobserved QTL appears to be located at ,, = 41.93 cM with 95% confidence interval of (40.84, 43.02) through the 20-cM region framed by markers D12S1052 and D12S1064 on chromosome 12. The test statistic shows strong evidence of linkage and LD (chi-square statistic = 18.39 with 2 df, P -value = 0.0001). Genet. Epidemiol. 22:298,312, 2002. © 2002 Wiley-Liss, Inc. [source] Third international meeting on the genetic epidemiology of complex traits, April 4,6, 2002, Cambridge, UKHUMAN MUTATION, Issue 3 2002Sally John Abstract The Third International Meeting on the Genetic Epidemiology of Complex Traits was held at Churchill College, Cambridge, UK on April 4,6, 2002. The event was organized by the Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London and sponsored by Roche Genetics and Insightful. It provided an interactive forum for discussion of topical issues relating to the genetic analysis of complex diseases and traits. Topics discussed included linkage disequilibrium mapping and candidate gene analysis, as well as cutting edge advances in both technologies and statistical analysis methods. Details of the meeting can be found at http://www.twin-research.ac.uk/. Hum Mutat20:227,229, 2002. © 2002 Wiley-Liss, Inc. [source] The genetic differences with whole genome linkage disequilibrium mapping between responder and non-responder in interferon-, and ribavirin combined therapy for chronic hepatitis C patientsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2008P.-J. Chen Summary Interferon-, and ribavirin combined therapy has been a mainstream treatment for hepatitis C infection. The efficacy of this combined treatment is around 30% to 60%, and the factors affecting the responsiveness are still poorly defined. Our study is intended to investigate the genetic differences between responder and non-responder patients. The genome-wide linkage disequilibrium screening for loci associated with genetic difference between two patient groups was conducted by using 382 autosomal short tandem repeat (STR) markers involving 92 patients. We have identified 19 STR markers displaying different allele frequencies between the two patient groups. In addition, based on their genomic location and biological function, we selected the CD81 and IL15 genes to perform single nucleotide polymorphism genotyping. In conclusion, this study may provide a new approach for identifying the associated polymorphisms and the susceptible loci for interferon-, and ribavirin combined therapy in patients with chronic hepatitis C. [source] Fine mapping and detection of the causative mutation underlying Quantitative Trait LociJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 5 2010E. Uleberg Summary The effect on power and precision of including the causative SNP amongst the investigated markers in Quantitative Trait Loci (QTL) mapping experiments was investigated. Three fine mapping methods were tested to see which was most efficient in finding the causative mutation: combined linkage and linkage disequilibrium mapping (LLD); association mapping (MARK); a combination of LLD and association mapping (LLDMARK). Two simulated data sets were analysed: in one set, the causative SNP was included amongst the markers, while in the other set the causative SNP was masked between markers. Including the causative SNP amongst the markers increased both precision and power in the analyses. For the LLD method the number of correctly positioned QTL increased from 17 for the analysis without the causative SNP to 77 for the analysis including the causative SNP. The likelihood of the data analysis increased from 3.4 to 13.3 likelihood units for the MARK method when the causative SNP was included. When the causative SNP was masked between the analysed markers, the LLD method was most efficient in detecting the correct QTL position, while the MARK method was most efficient when the causative SNP was included as a marker in the analysis. The LLDMARK method, combining association mapping and LLD, assumes a QTL as the null hypothesis (using LLD method) and tests whether the ,putative causative SNP' explains significantly more variance than a QTL in the region. Thus, if the putative causative SNP does not only give an Identical-By-Descent (IBD) signal, but also an Alike-In-State (AIS) signal, LLDMARK gives a positive likelihood ratio. LLDMARK detected less than half as many causative SNPs as the other methods, and also had a relatively high false discovery rate when the QTL effect was large. LLDMARK may however be more robust against spurious associations, because the regional IBD is largely corrected for by fitting a QTL effect in the null hypothesis model. [source] | |||||||||||||