TY - JOUR
T1 - DASH
T2 - A method for identical-by-descent haplotype mapping uncovers association with recent variation
AU - Gusev, Alexander
AU - Kenny, Eimear E.
AU - Lowe, Jennifer K.
AU - Salit, Jaqueline
AU - Saxena, Richa
AU - Kathiresan, Sekar
AU - Altshuler, David M.
AU - Friedman, Jeffrey M.
AU - Breslow, Jan L.
AU - Pe'er, Itsik
N1 - Funding Information:
We thank the reviewers for comments and suggestions that have greatly improved this manuscript. This study makes use of genotype data from the WTCCC as well as genotype and sequence data from the island of Kosrae, Federated States of Micronesia. This work has been supported by National Science Foundation grants 0845677 and 0829882, National Institutes of Health award U54-CA121852 and the National Science Foundation Graduate Research Fellowship Program.
PY - 2011/6/10
Y1 - 2011/6/10
N2 - Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers.
AB - Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers.
UR - http://www.scopus.com/inward/record.url?scp=79958863532&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.04.023
DO - 10.1016/j.ajhg.2011.04.023
M3 - Article
C2 - 21620352
AN - SCOPUS:79958863532
SN - 0002-9297
VL - 88
SP - 706
EP - 717
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -