Linkage Disequilibrium

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N.-o. Nilsson - One of the best experts on this subject based on the ideXlab platform.

Andrew Collins - One of the best experts on this subject based on the ideXlab platform.

  • Exome-based Linkage Disequilibrium maps of individual genes: functional clustering and relationship to disease
    Human Genetics, 2013
    Co-Authors: Jane Gibson, William Tapper, Sarah Ennis, Andrew Collins
    Abstract:

    Exome sequencing identifies thousands of DNA variants and a proportion of these are involved in disease. Genotypes derived from exome sequences provide particularly high-resolution coverage enabling study of the Linkage Disequilibrium structure of individual genes. The extent and strength of Linkage Disequilibrium reflects the combined influences of mutation, recombination, selection and population history. By constructing Linkage Disequilibrium maps of individual genes, we show that genes containing OMIM-listed disease variants are significantly under - represented amongst genes with complete or very strong Linkage Disequilibrium ( P  = 0.0004). In contrast, genes with disease variants are significantly over - represented amongst genes with levels of Linkage Disequilibrium close to the average for genes not known to contain disease variants ( P  = 0.0038). Functional clustering reveals, amongst genes with particularly strong Linkage Disequilibrium, significant enrichment of essential biological functions (e.g. phosphorylation, cell division, cellular transport and metabolic processes). Strong Linkage Disequilibrium, corresponding to reduced haplotype diversity, may reflect selection in utero against deleterious mutations which have profound impact on the function of essential genes. Genes with very weak Linkage Disequilibrium show enrichment of functions requiring greater allelic diversity (e.g. sensory perception and immune response). This category is not enriched for genes containing disease variation. In contrast, there is significant enrichment of genes containing disease variants amongst genes with more average levels of Linkage Disequilibrium. Mutations in these genes may less likely lead to in utero lethality and be subject to less intense selection.

  • Linkage Disequilibrium in maps of SNPs and other markers
    GeneScreen, 2008
    Co-Authors: Andrew Collins
    Abstract:

    One strategy for detection of disease genes is to exploit Linkage Disequilibrium in the hope that in candidate regions there will be detectable association between disease and marker alleles. Maps of single nucleotide polymorphisms (SNPs) will be used for this purpose but a recent simulation suggests that a useful level of Linkage Disequilibrium is unlikely to extend beyond an average distance of 3 Kb in the general population. This implies that very high marker densities will be required to detect disease: SNP associations. The evidence from published data comprising 877 SNP pairs is presented. For comparison, associations between other pairs of markers, principally microsatellites, are examined in a large sample of haplotypes from the fragile X (FRAX) region in Xq27–28. Association ρ is estimated from haplotype frequencies and the decline in Linkage Disequilibrium with distance is described using the model originally described by Malecot. The evidence from SNP pairs suggest that Linkage Disequilibrium extends to at least 263 Kb in random haplotypes, but with a considerable amount of variation particularly at small distances. For microsatellites in the FRAX region Disequilibrium extends to at least 435 Kb. This suggests that a genome scan with markers spaced every 100 Kb would be powerful (30 000 markers per genome). Higher densities might be required in some genomic regions and presumably will be required to determine causal SNPs.

  • Linkage Disequilibrium and Association Mapping: Analysis and Applications
    2007
    Co-Authors: Andrew Collins
    Abstract:

    Table of contents Chapter 1. Linkage Disequilibrium and association mapping - an introduction. (Andrew Collins). Chapter 2. A history of association mapping (Newton E Morton) . Chapter 3. Linkage Disequilibrium maps and location databases.(William Tapper). Chapter 4. LDMAP: The construction of high-resolution Linkage Disequilibrium maps of the human genome. (Kuo T-Y, Lau W, Collins A). Chapter 5. Linkage Disequilibrium as a tool for detecting the signatures of selection. (Sarah Ennis) . Chapter 6. The genetic basis of complex traits - rare variants or 'common gene common disease'? (Sudha K Iyengar, Robert C Elston ). Chapter 7. Linkage Disequilibrium Mapping for Complex Disease Genes (Andrew DeWan, Robert J. Klein, Josephine Hoh). Chapter 8. Linkage Disequilibrium maps and disease association mapping (Nik Maniatis). Chapter 9. Coalescent methods for fine-scale disease gene mapping (Andrew P. Morris). Chapter 10. Family Based Linkage Disequilibrium Tests Using general pedigrees (Yin Yao Shugart, Lina Chen, Terri Beaty). Chapter 11. Association studies using familial cases: an efficient strategy for identifying low penetrance disease alleles (Emily L. Webb, Richard S. Houlston). Chapter 12. Association mapping using pooled DNA (Hsin-Chou Yang and Cathy S. J. Fann). Chapter 13. Selecting SNPs for Association Studies with SNPbrowser™ Software (Francisco M. De La Vega) Chapter 14. Avoiding false discoveries in association studies (Chiara Sabatti). Chapter 15. Gene mapping in asthma related traits. (Tarja Laitinen). Chapter 16. Identifying susceptibility variants for type 2 diabetes. (Eleftheria Zeggini and Mark I McCarthy).

  • Linkage Disequilibrium and Association Mapping - Linkage Disequilibrium and Association Mapping
    Methods in molecular biology (Clifton N.J.), 2007
    Co-Authors: Andrew Collins
    Abstract:

    The basis for recent developments on the characterization of the Linkage-Disequilibrium structure of the genome and the application of association mapping to genes for common human diseases is described. Patterns of Linkage Disequilibrium are now understood, for a number of human populations, in unprecedented detail. This information not only provides a vital resource for the design and execution of powerful association-mapping studies, but opens new avenues of research into the genetic history of human populations and the effects of natural selection, mutation, and recombination on the genomic landscape.

  • Properties of Linkage Disequilibrium (LD) maps
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Weilhua Zhang, Andrew Collins, Nikolas Maniatis, William J. Tapper, Newton E. Morton
    Abstract:

    A Linkage Disequilibrium map is expressed in Linkage Disequilibrium (LD) units (LDU) discriminating blocks of conserved LD that have additive distances and locations monotonic with physical (kb) and genetic (cM) maps. There is remarkable agreement between LDU steps and sites of meiotic recombination in the one body of data informative for crossing over, and good agreement with another method that defines blocks without assigning an LD location to each marker. The map may be constructed from haplotypes or diplotypes, and efficiency estimated from the empirical variance of LD is substantially greater for the ρ metric based on evolutionary theory than for the absolute correlation r, and for the LD map compared with its physical counterpart. The empirical variance is nearly three times as great for the worst alternative (r and kb map) as for the most efficient approach (ρ and LD map). According to the empirical variances, blocks are best defined by zero distance between included markers. Because block size is algorithm-dependent and highly variable, the number of markers required for positional cloning is minimized by uniform spacing on the LD map, which is estimated to have ≈1 LDU per locus, but with much variation among regions. No alternative representation of Linkage Disequilibrium (some of which are loosely called maps) has these properties, suggesting that LD maps are optimal for positional cloning of genes determining disease susceptibility.

Carmen Rodríguez - One of the best experts on this subject based on the ideXlab platform.

  • Extent of third-order Linkage Disequilibrium in a composite line of Iberian pigs
    BMC genetics, 2018
    Co-Authors: Luis Gomez-raya, Luis Silió, Wendy M. Rauw, Luis Alberto Gracia-cortés, Carmen Rodríguez
    Abstract:

    Previous studies on Linkage Disequilibrium have investigated second order Linkage Disequilibrium in animal and plant populations. The objective of this paper was to investigate the genome-wide levels of third order Linkage Disequilibrium in a composite line founded by admixture of four Iberian pig strains. A model for the generation of third order Linkage Disequilibrium by population admixture is proposed. A computer Expectation-Maximization algorithm is developed and applied to the estimation of third order Linkage Disequilibrium at inter- and intra-chromosomal level using 26,347 SNPs typed in 306 sows. The relationship of third order Linkage Disequilibrium with physical distance was investigated over 35 million triplets in SSC12. Basic and normalized estimates of inter and intra-chromosomal third order Linkage Disequilibrium are reported. Genome-wide analyses revealed that third order Linkage Disequilibrium is rather common among linked loci in this Iberian pig line. It is shown that population admixture of multiple populations may explain the observed levels of third order Linkage Disequilibrium although it could be generated by genetic drift. Third order Linkage Disequilibrium decreases rapidly up to 4 Mb and then declines slowly. The short distances between consecutive markers explain the maintenance of the observed third order Linkage disequilibria levels when using a model incorporating the break-up of Disequilibrium by recombination. Genome-wide testing also revealed that only 3.6% of the normalized estimates were different from 1, − 1, 0, or from a not well-defined situation in which there is only one possible value for the third order Linkage Disequilibrium parameter, given allele frequencies and pairwise Linkage disequilibria parameters. Third order Linkage Disequilibrium is common among linked markers in the analyzed pig line and may have been generated by population admixture of multiple populations or by genetic drift. As with second order Linkage Disequilibrium, the absolute value of the third order Linkage Disequilibrium decreases with physical distance. Normalization of third order Linkage Disequilibrium should be avoided for closely linked bi-allelic loci.

T. Kraft - One of the best experts on this subject based on the ideXlab platform.

M. Hansen - One of the best experts on this subject based on the ideXlab platform.

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