A Test for Linkage and Association in General Pedigrees: The Pedigree Disequilibrium Test

Abstract

Family-based tests of linkage disequilibrium typically are based on nuclear-family data including affected individuals and their parents or their unaffected siblings. A limitation of such tests is that they generally are not valid tests of association when data from related nuclear families from larger pedigrees are used. Standard methods require selection of a single nuclear family from any extended pedigrees when testing for linkage disequilibrium. Often data are available for larger pedigrees, and it would be desirable to have a valid test of linkage disequilibrium that can use all potentially informative data. In this study, we present the pedigree disequilibrium test (PDT) for analysis of linkage disequilibrium in general pedigrees. The PDT can use data from related nuclear families from extended pedigrees and is valid even when there is population substructure. Using computer simulations, we demonstrated validity of the test when the asymptotic distribution is used to assess the significance, and examined statistical power. Power simulations demonstrate that, when extended pedigree data are available, substantial gains in power can be attained by use of the PDT rather than existing methods that use only a subset of the data. Furthermore, the PDT remains more powerful even when there is misclassification of unaffected individuals. Our simulations suggest that there may be advantages to using the PDT even if the data consist of independent families without extended family information. Thus, the PDT provides a general test of linkage disequilibrium that can be widely applied to different data structures.

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…27 Family-based analyses of single NOS2A SNPs were performed using the pedigree disequilibrium test or PDT (v.5.1). 51,52 The PDT is a powerful analytical method that uses genetic data from related nuclear families and discordant sibships within extended pedigrees. Two PDT statistics were used: the PDT-sum statistic, which examines allelic effects, and the genotype-PDT that examines genotypic effects.…”

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

“…The TDT 41 and PDT 42 were used to assess possible association of the FAS and FASL polymorphisms with SLE. Haplotypes were generated and analyzed from GENEHUNTER-PLUS.…”

Preferential transmission and association of the −403 G → A promoter RANTES polymorphism with atopic asthma

“…In order to assess familial transmission of the alleles, the pedigree disequilibrium test (PDT) was used as this test has advantages over the classical transmission/disequilibrium test (TDT). 32,33 TDT is not a valid test of association if related nuclear families and/or siblings from larger pedigrees are used. [32][33][34] PDT overcomes these problems by treating triads (parent-child trios) as independent entities in contrast to TDT, which treats the contribution from heterozygous parents as independent, 32,33 and which makes this test susceptible to confounding by phenocopies or heterogeneity.…”