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Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.

Abstract

Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.

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  • Authors+Show Affiliations

    ,

    Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.

    , , , , ,

    Source

    PloS one 8:3 2013 pg e56379

    MeSH

    Case-Control Studies
    Chromosome Mapping
    Chromosomes, Human, Pair 9
    Databases, Genetic
    Genetic Predisposition to Disease
    Genetic Variation
    Genome-Wide Association Study
    Genotype
    Haplotypes
    Humans
    Lod Score
    Models, Genetic
    Multigene Family
    Multiple Sclerosis
    Principal Component Analysis
    Zinc Fingers

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23472070

    Citation

    Lin, Rui, et al. "Identity-by-descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis." PloS One, vol. 8, no. 3, 2013, pp. e56379.
    Lin R, Charlesworth J, Stankovich J, et al. Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis. PLoS ONE. 2013;8(3):e56379.
    Lin, R., Charlesworth, J., Stankovich, J., Perreau, V. M., Brown, M. A., & Taylor, B. V. (2013). Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis. PloS One, 8(3), pp. e56379. doi:10.1371/journal.pone.0056379.
    Lin R, et al. Identity-by-descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis. PLoS ONE. 2013;8(3):e56379. PubMed PMID: 23472070.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis. AU - Lin,Rui, AU - Charlesworth,Jac, AU - Stankovich,Jim, AU - Perreau,Victoria M, AU - Brown,Matthew A, AU - ,, AU - Taylor,Bruce V, Y1 - 2013/03/05/ PY - 2012/11/07/received PY - 2013/01/08/accepted PY - 2013/3/9/entrez PY - 2013/3/9/pubmed PY - 2013/12/16/medline SP - e56379 EP - e56379 JF - PloS one JO - PLoS ONE VL - 8 IS - 3 N2 - Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. 'Population-based linkage analysis' (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10(-6)). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23472070/Identity_by_descent_mapping_to_detect_rare_variants_conferring_susceptibility_to_multiple_sclerosis_ L2 - http://dx.plos.org/10.1371/journal.pone.0056379 DB - PRIME DP - Unbound Medicine ER -