Transmission/Disequilibrium Test Based on Haplotype Sharing for Tightly Linked Markers

Abstract

Studies using haplotypes of multiple tightly linked markers are more informative than those using a single marker. However, studies based on multimarker haplotypes have some difficulties. First, if we consider each haplotype as an allele and use the conventional single-marker transmission/disequilibrium test (TDT), then the rapid increase in the degrees of freedom with an increasing number of markers means that the statistical power of the conventional tests will be low. Second, the parental haplotypes cannot always be unambiguously reconstructed. In the present article, we propose a haplotype-sharing TDT (HS-TDT) for linkage or association between a disease-susceptibility locus and a chromosome region in which several tightly linked markers have been typed. This method is applicable to both quantitative traits and qualitative traits. It is applicable to any size of nuclear family, with or without ambiguous phase information, and it is applicable to any number of alleles at each of the markers. The degrees of freedom (in a broad sense) of the test increase linearly as the number of markers considered increases but do not increase as the number of alleles at the markers increases. Our simulation results show that the HS-TDT has the correct type I error rate in structured populations and that, in most cases, the power of HS-TDT is higher than the power of the existing single-marker TDTs and haplotype-based TDTs.

Members 6B and 14 of the TNF receptor superfamily in multiple sclerosis predisposition

“…As it has been reported that analyses using haplotypes of multiple tightly linked markers are usually more informative than those using a single marker, 23,24 we decided to perform multimarker transmission disequilibrium tests in the TNFRSF14 and TNFRSF6B loci with 931 family trios from the IMSGC GWAS data (Supplementary Figure 1 and Supplementary Tables 1 and 2). For each locus, we tested the statistical significance of the most common haplotype among the transmitted set.…”

Identification of probable genotyping errors by consideration of haplotypes

“…Therefore, genotyping error rates that are tolerable in the context of single-marker analysis can be unacceptable for analyses based on haplotypes. For example, Knapp and Becker 10 recently observed a dramatic inflation of the type I error rate of the haplotype-sharing transmission/disequilibrium test (HS-TDT) by Zhang et al 11 in the presence of genotyping error rates as small as 0.001. As haplotype analysis requires a higher standard of data integrity, it would be valuable to develop methods for the identification of probable genotyping errors that exploit the kind of data typically available.…”

Accurate Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms Using Sibship Data

“…In the context of association studies, when the disease association of a specific allele is dependent on cis-acting interactions with other loci, the disease association may not be detected by testing a single allele unless the whole functional haplotype itself is analyzed. This has been demonstrated through both empirical studies (Drysdale et al 2000;Martin et al 2000) and simulation studies (Zhang et al 2002(Zhang et al , 2003. Computational algorithms and statistical methods are currently the preferred means, particularly for largescale haplotype determination.…”