Assessing transmission ratio distortion in extended families: a comparison of analysis methods

A statistical departure from Mendel’s law of segregation is known as transmission ratio distortion. Although well documented in many other organisms, the extent of transmission ratio distortion and its influence in the human genome remains incomplete. Using Genetic Analysis Workshop 19 whole genome sequence data from 20 large Mexican American pedigrees, our goal was to identify potentially distorted regions in the genome using family-based association methods such as the transmission disequilibrium test, the pedigree disequilibrium test, and the family-based association test. Preliminary results showed an unusually high number of transmission ratio distortion signals identified by the transmission disequilibrium test, but this phenomenon could not be replicated by the pedigree disequilibrium test or family-based association test. Applying these tests to different subsets of the data, we found the transmission disequilibrium test to be very sensitive to imputed genotypes. Regression analysis of transmission ratio distortion test p values controlling for minor allele frequency and quality control checks showed that Hardy Weinberg p values are associated with this inflation. Although the transmission disequilibrium test appears confounded by imputation of single nucleotide polymorphisms, the pedigree disequilibrium test and family-based association test seem to offer more robust alternatives when searching for transmission ratio distortion loci in whole genome sequence data from extended families.