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Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
PLoS One 2013; 8(3):e56379Plos

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.

Authors+Show Affiliations

Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -