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.