Abstract
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.
Highlights
Transmission ratio distortion (TRD) refers to a significant departure from the expected Mendelian transmission of alleles from parents to offspring, which is why it can only be observed in family-based studies
We did not filter for significant departures from Hardy-Weinberg equilibrium (HWE) or small minor allele frequencies (MAFs) because we wanted to see if these features were associated with certain patterns in our results
Discussion and conclusions it is known that small levels of genotyping error can inflate transmission disequilibrium test (TDT) results [3, 6, 11], and that using a modal call as the best guess genotype leads to misclassification errors [12,13,14,15], our analysis shows that recently developed imputation algorithms giving no Mendelian errors [8] can have the same impact
Summary
Transmission ratio distortion (TRD) refers to a significant departure from the expected Mendelian transmission of alleles from parents to offspring, which is why it can only be observed in family-based studies. Across odd-numbered chromosomes, the TDT identified more than 8000 single nucleotide polymorphisms (SNPs) with p values for TRD
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