Application and interpretation of transmission/disequilibrium tests: Transmission of HLA-DQ haplotypes to unaffected siblings in 526 families with type 1 diabetes

It is widely believed that, if a genetic marker shows a transmission distor tion in patients by the transmission/ disequilibrium test (TDT), then a tra nsmission distortion in healthy siblings would be seen in the opposite dire ction. This is also the case in a complex disease. Furthermore, it has been suggested that replacing the McNemar statistics of the TDT with a test of heterogeneity between transmissions to affected and unaffected children cou ld increase the power to detect disease association. To test these two hypo theses empirically, we analyzed the transmission of HLA-DQA1-DQB1 haplotype s in 526 Norwegian families with type 1 diabetic children and healthy sibli ngs, since some DQA1-DQB1 haplotypes represent major genetic risk factors f or type 1 diabetes. Despite the strong positive and negative disease associ ations with particular DQ haplotypes, we observed no significant deviation from 50% for transmission to healthy siblings. This could be explained by t he low penetrance of susceptibility alleles, together with the fact that ID DM loci also harbor strongly protective alleles that can override the risk contributed by other loci. Our results suggest that, in genetically complex diseases, detectable distortion in transmission to healthy siblings should not be expected. Furthermore, the original TDT seems more powerful than a heterogeneity test.