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CLUMPHAP: a simple tool for performing haplotype‐based association analysis
Author(s) -
Knight Jo,
Curtis David,
Sham Pak C.
Publication year - 2008
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/gepi.20327
Subject(s) - haplotype , international hapmap project , haplotype estimation , cluster analysis , locus (genetics) , genotyping , genetics , biology , single nucleotide polymorphism , hierarchical clustering , statistical power , statistical hypothesis testing , genetic association , computational biology , allele , statistics , genotype , mathematics , gene
Abstract The completion of the HapMap Project and the development of high‐throughput single nucleotide polymorphism genotyping technologies have greatly enhanced the prospects of identifying and characterizing the genetic variants that influence complex traits. In principle, association analysis of haplotypes rather than single nucleotide polymorphisms may better capture an underlying causal variant, but the multiple haplotypes can lead to reduced statistical power due to the testing of (and need to correct for) a large number of haplotypes. This paper presents a novel method based on clustering similar haplotypes to address this issue. The method, implemented in the CLUMPHAP program, is an extension of the CLUMP program designed for the analysis of multi‐allelic markers (Sham and Curtis [1995] Ann. Hum. Genet. 59(Pt1):97–105). CLUMPHAP performs a hierarchical clustering of the haplotypes and then computes the χ 2 statistic between each haplotype cluster and disease; the statistical significance of the largest of the χ 2 statistics is obtained by permutation testing. A significant result suggests that the presence of a disease‐causing variant in the haplotype cluster is over‐represented in cases. Using simulation studies, we have compared CLUMPHAP and more widely used approaches in terms of their statistical power to identify an untyped susceptibility locus. Our results show that CLUMPHAP tends to have greater power than the omnibus haplotype test and is comparable in power to multiple regression locus‐coding approaches. Genet. Epidemiol . 2008. © 2008 Wiley‐Liss, Inc.