The Transmission/Disequilibrium Test: History, Subdivision, and Admixture

W.J. Ewens, R.S. Spielman

Department of Biology, University of Pennsylvania, Philadelphia 19104-6018, USA.

American Journal of Human Genetics , 57(2), 455-64 (Aug 1995)

Abstract

Disease association with a genetic marker is often taken as a preliminary indication of linkage with disease susceptibility. However, population subdivision and admixture may lead to disease association even in the absence of linkage. In a previous paper, we described a test for linkage (and linkage disequilibrium) between a genetic marker and disease susceptibility; linkage is detected by this test only if association is also present. This transmission/disequilibrium test (TDT) is carried out with data on transmission of marker alleles from parents heterozygous for the marker to affected offspring. The TDT is a valid test for linkage and association, even when the association is caused by population subdivision and admixture.

In the previous paper, we did not explicitly consider the effect of recent history on population structure. Here we extend the previous results by examining in detail the effects of subdivision and admixture, viewed as processes in population history. We describe two models for these processes. For both models, we analyze the properties of (a) the TDT as a test for linkage (and association) between marker and disease and (b) the conventional contingency statistic used with family data to test for population association. We show that the contingency test statistic does not have a chi2 distribution if subdivision or admixture is present. In contrast, the TDT remains a valid chi2 statistic for the linkage hypothesis, regardless of population history.

Association Studies