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 - ANZgene
AU - Baxter, Alan
AU - Kermode, Allan
AU - Bahlo, Melanie
AU - Carroll, William
AU - Butzkueven, Helmut
AU - Booth, David
AU - Stewart, Graeme
AU - Wiley, James
AU - Field, Judith
AU - Tajouri, Lotti
AU - Griffiths, Lyn
AU - Barnett, Michael
AU - Moscato, Pablo
AU - Heard, Robert
AU - Scott, Rodney
AU - McColl, Shaun
AU - Foote, Simon
AU - Broadley, Simon
AU - Slee, Mark
AU - Vucic, Steve
AU - Kilpatrick, Trevor
AU - Taylor, Bruce V.
N1 - Unless otherwise indicated, articles and accompanying materials published by PLOS on the PLOS Sites, including peer reviews, are licensed by the respective authors for use and distribution by you subject to citation of the original source in accordance with the Creative Commons Attribution (CC BY) license.
PY - 2013/3/5
Y1 - 2013/3/5
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84874636721&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0056379
DO - 10.1371/journal.pone.0056379
M3 - Article
C2 - 23472070
AN - SCOPUS:84874636721
SN - 1932-6203
VL - 8
SP - 1
EP - 8
JO - PLoS One
JF - PLoS One
IS - 3
M1 - e56379
ER -