TESTS FOR LINKAGE AND ASSOCIATION IN NUCLEAR FAMILIES

The transmission/disequilibrium test (TDT) originally was introduced t o test for linkage between a genetic marker and a disease-susceptibili ty locus, in the presence of association. Recently, the TDT has been u sed to test for association in the presence of linkage. The motivation for this is that linkage analysis typically identifies large candidat e regions, and further refinement is necessary before a search for the disease gene is begun, on the molecular level. Evidence of associatio n and linkage may indicate which markers in the region are closest to a disease locus. As a test of linkage, transmissions from heterozygous parents to all of their affected children can be included in the TDT; however, the TDT is a valid chi(2) test of association only if transm issions to unrelated affected children are used in the analysis. If th e sample contains independent nuclear families with multiple affected children, then one procedure that has been used to test for associatio n is to select randomly a single affected child from each sibship and to apply the TDT to those data. As an alternative, we propose two stat istics that use data from all of the affected children. The statistics give valid chi(2) tests Of the null hypothesis of no association or n o linkage and generally are more powerful than the TDT with a single, randomly chosen, affected child from each family.