title: Association testing by haplotype-sharing methods applicable to whole-genome analysis.
abstract: We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random haplotypes. The significance of the HSS is determined using a variance estimate from the theory of U-statistics, whereas the significance of the CROSS test is estimated from a sequential randomization procedure. Both methods are fast and hence practical, even for whole-genome screens with high marker densities. We analyzed data sets of Problems 2 and 3 of Genetic Analysis Workshop 15 and compared HSS and CROSS to conventional association methods. Problem 2 provided a data set of 2300 single-nucleotide polymorphisms (SNPs) in a 10-Mb region of chromosome 18q, which had shown linkage evidence for rheumatoid arthritis. The CROSS test detected a significant association at approximately position 4407 kb. This was supported by single-marker association and HSS. The CROSS test outperformed them both with respect to significance level and signal-to-noise ratio. A 20-kb candidate region could be identified. Problem 3 provided a simulated 10 k SNP data set covering the whole genome. Three known candidate regions for rheumatoid arthritis were detected. Again, the CROSS test gave the most significant results. Furthermore, both the HSS and the CROSS showed better fine-mapping accuracy than straightforward haplotype association. In conclusion, haplotype sharing methods, particularly the CROSS test, show great promise for identifying disease gene loci.
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
authors.forename: André R
authors.initials: AR
authors.lastname: de Vries
authors.affiliation: Deparment of Dermatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
authors.forename: Geert T
authors.initials: GT
authors.lastname: Spijker
authors.affiliation: Groningen Bioinformatics Center, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, 9751 NN Haren, the Netherlands.
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.affiliation: Department of Computer Science, Georgia State University, 34 Peachtree Street, Atlanta, Georgia 30303-3086, USA.
authors.forename: Dumitru
authors.initials: D
authors.lastname: Brinza
authors.affiliation: Department of Computer Science, Georgia State University, 34 Peachtree Street, Atlanta, Georgia 30303-3086, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zelikovsky
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Te Meerman