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

ANZgene Consortium

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Article numbere56379
JournalPLoS One
Volume8
Issue number3
DOIs
Publication statusPublished - 5 Mar 2013
Externally publishedYes

Fingerprint

sclerosis
Multiple Sclerosis
Genome-Wide Association Study
Genes
linkage (genetics)
Chromosomes, Human, Pair 19
zinc finger motif
Zinc Fingers
Genome
Haplotypes
genome
haplotypes
heritability
chromosomes
Chromosomes
Transcriptome
transcriptome
Population
etiology
Zinc

Cite this

@article{f944367f052d4a6f9707883a43dd5b62,
title = "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.",
author = "{ANZgene Consortium} and Rui Lin and Jac Charlesworth and Jim Stankovich and Perreau, {Victoria M.} and Brown, {Matthew A.} and Alan Baxter and Allan Kermode and Melanie Bahlo and William Carroll and Helmut Butzkueven and David Booth and Graeme Stewart and James Wiley and Judith Field and Lotti Tajouri and Lyn Griffiths and Michael Barnett and Pablo Moscato and Robert Heard and Rodney Scott and Shaun McColl and Simon Foote and Simon Broadley and Mark Slee and Steve Vucic and Trevor Kilpatrick and Taylor, {Bruce V.}",
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language = "English",
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Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis. / ANZgene Consortium.

In: PLoS One, Vol. 8, No. 3, e56379, 05.03.2013.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis

AU - ANZgene Consortium

AU - Lin, Rui

AU - Charlesworth, Jac

AU - Stankovich, Jim

AU - Perreau, Victoria M.

AU - Brown, Matthew A.

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.

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.

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U2 - 10.1371/journal.pone.0056379

DO - 10.1371/journal.pone.0056379

M3 - Article

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JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

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