TDT-HET: A new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data

Our simulations suggest that, for sufficiently large sample size (1000 trios) our method has good power to detect association even the proportion of unlinked trios is high (75%). While the median difference (TDT-HET empirical power - TDT empirical power) is approximately 0 for all MOI, there are parameter settings for which the power difference can be substantial. Our multi-locus simulations suggest that our method has good power to detect association as long as the markers are reasonably well-correlated and the genotype relative risk are larger. Results of both single-locus and multi-locus simulations suggest our method maintains the correct type I error rate.Finally, the TDT-HET statistic shows highly significant p-values for most of the idiopathic scoliosis candidate loci, and for some loci, the estimated proportion of unlinked trios approaches or exceeds 50%, suggesting the presence of locus heterogeneity.We have developed an extension of the TDT statistic (TDT-HET) that allows for locus heterogeneity among coded trios. Benefits of our method include: estimates of parameters in the presence of heterogeneity, and reasonable power even when the proportion of linked trios is small. Also, we have extended multi-locus methods to TDT-HET and have demonstrated that the empirical power may be high to detect linkage. Last, given that we obtain PPBs, we conjecture that the TDT-HET may be a useful method for correctly identifying linked trios. We anticipate that researchers will find this property increasingly useful as they apply next-generation sequencing data in family based studies.In genetics, heterogeneity is a major feature of human traits. Genetic heterogeneity occurs when the same or clinically indistinguishable phenotypes are caused by different genetic factors. This can be due to multiple variants located in the same locus (allelic heterogeneity) or to mutations located in different loci (locus heterogeneity).The focus of this work is locus heterogeneity, specif