A Sibship Test for Linkage in the Presence of Association: The Sib Transmission/Disequilibrium Test

Abstract

Linkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, tests that rely on linkage disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the transmission/disequilibrium test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT-type procedure that tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non-insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging.

CYP7A1 genotypes and haplotypes associated with hypertension in an obese Han Chinese population

“…It has been suggested that a number of regulatory elements responsive to effectors, such as insulin, glucocorticoids and thyroid hormone, reside within the region that spans from À764 to +46 of the human CYP7A1 promoter. 18 Therefore, we hypothesized that this polymorphism might change the binding site of some regulatory elements that react to insulin or other hormones. However, in the study by Abrahamsson et al, 24 which used transient transfection experiments, no evidence was found for any difference between the À204C and À204A alleles.…”

Characterization of new polymorphisms in the 5′UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level

“…For Sib-TDT a ZЈ-score and corresponding Pvalues were calculated. 28 Linkage disequilibrium was calculated by the method of Devlin and Risch. 22 D-values close to zero indicates no linkage disequilibrium, whereas values approaching −0.25 or +0.25 are suggestive of strong linkage disequilibrium.…”

Transmission/disequilibrium tests of androgen receptor and glutathione S‐transferase pi variants in prostate cancer families

“…20 The sib-TDT, on the other hand, needs genotypes of at least 1 affected offspring and 1 unaffected sibling, rather than genotypes of the parents. 21 The reconstruction combined TDT (RC-TDT), introduced by Knapp, allows parental-genotype reconstruction in the TDT, corrects for the biases resulting from such reconstruction and combines data from the TDT and the sib-TDT. Hence, the RC-TDT utilizes information from families in which parental genotypes are either typed or reconstructed as well as families in which parental genotypes are not available but genotypes of unaffected sibs are available.…”

“…9 For families in category 4, the expectation and variance of the number of M alleles in affected offspring under the null hypothesis of no linkage were computed using the equations for sib-TDT. 21 For families in categories 2 and 3, formulas for the reconstructed TDT, which consider genotype reconstruction, were used. 20 The observed and expected numbers of M alleles were then combined across all families in the test statistics of the RC-TDT.…”