Identity-by-descent mapping to detect rare variants conferring susceptibility to Multiple Sclerosis

Rui Lin, Jac Charlesworth, Helmut Butzkueven, David Booth, Graeme Stewart, James Wiley, Judith Field, Lotti Tajouri, Lyn Griffiths, Michael Barnett, Pablo Moscato, Robert Heard, Jim Stankovich, Rodney Scott, Shaun McColl, Simon Foote, Simon Broadley, Mark Slee, Steve Vucic, Trevor Kilpatrick & 7 others Victoria M. Perreau, Matthew A. Brown, Bruce V. Taylor, Alan Baxter, Allan Kermode, Melanie Bahlo, William Carroll

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    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 = 1.9x10⁻⁶). 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.
    Original languageEnglish
    Pages (from-to)e56379-1-e56379-8
    Number of pages8
    JournalPLoS ONE
    Volume8
    Issue number3
    DOIs
    Publication statusPublished - 2013

    Bibliographical note

    Copyright the Author(s) 2013. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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