Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis

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).

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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 = 1.9×10-6). 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. © 2013 Lin et al.

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ID Code: 87616
Item Type: Journal Article
Refereed: Yes
Keywords: transcriptome, zinc finger protein, article, causal attribution, chromosome 19, computer analysis, controlled study, data analysis, gene cluster, gene identification, gene mapping, gene regulatory network, gene sequence, genetic association, genetic database, genetic susceptibility, genetic variability, genome analysis, geographic distribution, haplotype, human, identity by descent mapping, limit of detection, linkage analysis, major clinical study, multiple sclerosis, nucleotide sequence, population based case control study, signal transduction, single nucleotide polymorphism, zinc finger motif, ZNF274 gene
DOI: 10.1371/journal.pone.0056379
ISSN: 19326203 (ISSN)
Divisions: Current > Schools > School of Biomedical Sciences
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: The authors
Deposited On: 21 Sep 2015 07:02
Last Modified: 22 Feb 2016 04:50

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