Extended Transmission Disequilibrium Test Research Articles

Use of siblings as controls in case-control association studies.

The transmission disequilibrium test (TDT) is a simple means to detect association which should only be positive if the marker allele is linked to the disease locus, but it cannot be used if parents of affected subjects are unavailable, as can occur when the disease has a late age of onset. Although one can sometimes deduce parental genotypes using the siblings of affected cases, reliance on this procedure can introduce bias and may also result in discarding many families which could provide useful information. Instead, it is shown that the use of unaffected siblings as controls is, like the TDT, robust against bias due to population stratification and other sources, and is expected only to produce positive results when a marker is both associated and linked with the disease locus. The method can have much less power than a case-control study using unrelated controls, but this can be guarded against by seeking unaffected siblings which are genotypically distinct from cases and by focusing only on alleles which are different within pairs of cases and controls. This yields a pair-wise test for association which can be used for multiallelic markers in a manner exactly analogous to the extended TDT (ETDT). The use of siblings as controls is simple, robust, practical and worthy of further consideration.

Affected-only multiplex pedigree analysis of GAW10 problem 2.

From a single extended pedigree simulation replicate, high density, affected only subpedigrees were isolated, based on the T > 40 affected status for the disease trait, Q1. On this sample of 14 pedigrees, with a range of two to six affected members (48 total), we conducted a haplotype based, multilocus, nonparametric genome-wide search of the provided data (367 markers) using the computer program GENEHUNTER. As with most genome screens in complex diseases, the objective of this strategy was to identify regions (hot-spots) which breached our predetermined threshold (p < 0.05), requiring confirmation by other groups or consortia. Of the six regions with threshold breaching scores (p < 0.05), the most promising, on chromosome 8 and chromosome 4, corresponded to the locations of MG2 and MG3. Both of these regions have multiple, consecutive markers above threshold and contained the only scores that exceeded p < 0.01. In addition, a fourth hot-spot consisting of a single marker above threshold, was less than 15 cM from MG1 on chromosome 5. The positions of the remaining three hot-spots did not correspond to the any of the major genes and are therefore false positives. An additional analysis of a single nuclear pedigree simulation replicate, using the extended transmission disequilibrium test (ETDT), was applied to markers in each of the above hot-spot regions to look for evidence of disequilibrium with the disease trait. This analysis provided weak additional support for the chromosome 8 finding, even though the sample was very small (36 pedigrees containing 44 affected offspring).