title: DASH: a method for identical-by-descent haplotype mapping uncovers association with recent variation.
abstract: 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.
authors.affiliation: Department of Computer Science, Columbia University, New York, NY 10027, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gusev
authors.affiliation: Department of Computer Science, Columbia University, New York, NY 10027, USA; Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Eimear E
authors.initials: EE
authors.lastname: Kenny
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.affiliation: Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Salit
authors.affiliation: Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.affiliation: Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
authors.affiliation: Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Jan L
authors.initials: JL
authors.lastname: Breslow
authors.affiliation: Department of Computer Science, Columbia University, New York, NY 10027, USA. Electronic address: itsik@cs.columbia.edu.
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
mesh_terms: D000465:Algorithms; D002874:Chromosome Mapping; D003196:Computer Graphics; D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000706:statistics & numerical data*; D004194:Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006239:Haplotypes; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide