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Wei Pan - One of the best experts on this subject based on the ideXlab platform.

  • Binomial Mixture Model Based Association Testing to Account for Genetic Heterogeneity for GWAS.
    Genetic epidemiology, 2016
    Co-Authors: Wei Pan
    Abstract:

    Genome-wide association studies (GWAS) have confirmed the ubiquitous existence of Genetic Heterogeneity for common disease: multiple common Genetic variants have been identified to be associated, while many more are yet expected to be uncovered. However, the single SNP (single-nucleotide polymorphism) based trend test (or its variants) that has been dominantly used in GWAS is based on contrasting the allele frequency difference between the case and control groups, completely ignoring possible Genetic Heterogeneity. In spite of the widely accepted notion of Genetic Heterogeneity, we are not aware of any previous attempt to apply Genetic Heterogeneity motivated methods in GWAS. Here, to explicitly account for unknown Genetic Heterogeneity, we applied a mixture model based single-SNP test to the Wellcome Trust Case Control Consortium (WTCCC) GWAS data with traits of Crohn's disease, bipolar disease, coronary artery disease, and type 2 diabetes, identifying much larger numbers of significant SNPs and risk loci for each trait than those of the popular trend test, demonstrating potential power gain of the mixture model based test.

  • binomial mixture model based association tests under Genetic Heterogeneity
    Annals of Human Genetics, 2009
    Co-Authors: Hui Zhou, Wei Pan
    Abstract:

    Most of the existing association tests for population-based case-control studies are based on comparing the mean genotype scores between the case and control groups, which may not be efficient under Genetic Heterogeneity. Given that most common diseases are Genetically heterogeneous, caused by mutations in multiple loci, it may be beneficial to fully account for Genetic Heterogeneity in an association test. Here we first propose a binomial mixture model for such a purpose and develop a corresponding mixture likelihood ratio test (MLRT) for a single locus. We also consider two methods to combine single-locus-based MLRTs across multiple loci in linkage disequilibrium to boost power when causal SNPs are not genotyped. We show with a wide spectrum of numerical examples that under Genetic Heterogeneity the proposed tests are more powerful than some commonly used association tests.

Constantine A Stratakis - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Heterogeneity in peutz jeghers syndrome
    Human Mutation, 2000
    Co-Authors: Lisa A Boardman, Fergus J Couch, Lawrence J Burgart, David A Schwartz, Rebecca Berry, Shannon K Mcdonnell, Daniel J Schaid, Lynn C Hartmann, J J Schroeder, Constantine A Stratakis
    Abstract:

    LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have Genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of Genetic Heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger Genetic insertions or deletions. Mutation analysis revealed Genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant Genetic Heterogeneity for PJS and the involvement of other loci in this syndrome.

  • Genetic Heterogeneity in Peutz‐Jeghers syndrome
    Human mutation, 2000
    Co-Authors: Lisa A Boardman, Fergus J Couch, Lawrence J Burgart, David A Schwartz, Rebecca Berry, Shannon K Mcdonnell, Daniel J Schaid, Lynn C Hartmann, J J Schroeder, Constantine A Stratakis
    Abstract:

    LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have Genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of Genetic Heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger Genetic insertions or deletions. Mutation analysis revealed Genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant Genetic Heterogeneity for PJS and the involvement of other loci in this syndrome.

Johan Paulsson - One of the best experts on this subject based on the ideXlab platform.

  • non Genetic Heterogeneity from stochastic partitioning at cell division
    Nature Genetics, 2011
    Co-Authors: Johan Paulsson
    Abstract:

    Johan Paulsson and Dann Huh report a mathematical modeling analysis proposing that stochastic partitioning errors during cell division contribute to non-Genetic Heterogeneity between cells in a population. They find that fluctuations arising from such partitioning errors are difficult to suppress and can mimic noise in gene expression.

  • Non-Genetic Heterogeneity from stochastic partitioning at cell division
    Nature Genetics, 2011
    Co-Authors: Dann Huh, Johan Paulsson
    Abstract:

    Johan Paulsson and Dann Huh report a mathematical modeling analysis proposing that stochastic partitioning errors during cell division contribute to non-Genetic Heterogeneity between cells in a population. They find that fluctuations arising from such partitioning errors are difficult to suppress and can mimic noise in gene expression. Gene expression involves inherently probabilistic steps that create fluctuations in protein abundances. The results from many in-depth analyses and genome-scale surveys have suggested how such fluctuations arise and spread, often in ways consistent with stochastic models of transcription and translation. But fluctuations also arise during cell division when molecules are partitioned stochastically between the two daughters. Here we mathematically demonstrate how stochastic partitioning contributes to the non-Genetic Heterogeneity. Our results show that partitioning errors are hard to correct, and that the resulting noise profiles are remarkably difficult to separate from gene expression noise. By applying these results to common experimental strategies and distinguishing between creation versus transmission of noise, we hypothesize that much of the cell-to-cell Heterogeneity that has been attributed to various aspects of gene expression instead comes from random segregation at cell division. We propose experiments to separate between these two types of fluctuations and discuss future directions.

Lisa A Boardman - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Heterogeneity in peutz jeghers syndrome
    Human Mutation, 2000
    Co-Authors: Lisa A Boardman, Fergus J Couch, Lawrence J Burgart, David A Schwartz, Rebecca Berry, Shannon K Mcdonnell, Daniel J Schaid, Lynn C Hartmann, J J Schroeder, Constantine A Stratakis
    Abstract:

    LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have Genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of Genetic Heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger Genetic insertions or deletions. Mutation analysis revealed Genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant Genetic Heterogeneity for PJS and the involvement of other loci in this syndrome.

  • Genetic Heterogeneity in Peutz‐Jeghers syndrome
    Human mutation, 2000
    Co-Authors: Lisa A Boardman, Fergus J Couch, Lawrence J Burgart, David A Schwartz, Rebecca Berry, Shannon K Mcdonnell, Daniel J Schaid, Lynn C Hartmann, J J Schroeder, Constantine A Stratakis
    Abstract:

    LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have Genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of Genetic Heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger Genetic insertions or deletions. Mutation analysis revealed Genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant Genetic Heterogeneity for PJS and the involvement of other loci in this syndrome.

A. Besner - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Heterogeneity in spinal muscular atrophy A linkage analysis‐based assessment
    Neurology, 1994
    Co-Authors: Alex Mackenzie, Pierre Jacob, L. Surh, A. Besner
    Abstract:

    Article abstract –The spinal muscular atrophies (SMAs) are among the most common autosomal recessive disorders. The mapping of the gene responsible for SMA to chromosome 5 has allowed the assessment of Genetic Heterogeneity in kindreds with a putative diagnosis of SMA. We report linkage analysis of 71 Canadian SMA families (types 1, 2, and 3) using polymorphisms that both flank and are linked to SMA. Data demonstrating nonlinkage to 5q markers were initially obtained in five kindreds; reexamination of the clinical status of these families showed that one fulfilled all the SMA diagnostic criteria, two showed patterns for which a diagnosis of SMA was possible but not conclusive, and two showed patterns for which the diagnosis of SMA appeared unlikely. This results in a degree of Genetic Heterogeneity between 1.5% and 4.5%. The three kindreds for which SMA appeared either possible or likely were simplex (ie, contained only one affected individual), and therefore the possibility that they represented new mutations could not be discounted. Thus, the significant majority of classic SMA cases are caused by a mutation in the 5q13.1 locus. Low Genetic Heterogeneity has implications for both Genetic counseling and the applicability of conventional and Genetic therapies following cloning of the SMA gene.