Abstract
Transmission-ratio distortion (TRD) is a phenomenon in which the segregation of alleles does not obey Mendel's laws. As a simple example, a recessive locus that results in fetal lethality will result in live-born individuals sharing more alleles at this locus than expected under Mendel's laws. This could result in apparent linkage of the phenotype of 'being alive' to such a chromosomal regions. Further, this could result in false-positive linkage when 'affected-only' parametric or non-parametric linkage analysis is performed. Similarly, loci demonstrating TRD may be detectable in family-based association tests as deviant transmission of alleles. Therefore, TRD could result in confounding of family-based association studies of diseases. The Framingham Heart Study data available for Genetic Analysis Workshop 16 is a suitable dataset to determine whether there are loci in the genome that reveal TRD because of the large number of individuals from families, the high-resolution genotyping, and the population-based nature of the study. We have used both genome-wide linkage and family-based association methods to determine whether there are loci that demonstrate TRD in the Framingham Heart Study. Family-based association analysis identified thousands of loci with apparent TRD. However, the vast majority of these are likely the result of genotyping errors with application of strict quality control criteria to the genotype data, and automated inspection of the intensity plots, we identify a small number of loci that may show true TRD, including rs1000548 in intron 6 of S-antigen (arrestin, SAG) on chromosome 2 (p = 7 x 10-10).
Highlights
A critical assumption for the majority of genetic mapping approaches is that Mendel's law of segregation is obeyed
A recessive locus that results in fetal lethality will result in live-born individuals sharing more alleles at this locus than expected under Mendel's laws. This could result in apparent linkage of the phenotype of ‘being alive’ to such a chromosomal regions. This could result in false-positive linkage when ‘affected-only’ parametric or nonparametric linkage analysis is performed
We dealt with linkage disequilibrium among the ~500 k singlenucleotide polymorphism (SNP) by selecting a subset of SNPs based on: minor allele frequency (MAF)>45%, Hardy-Weinberg equilibrium (HWE) p-value > 0.05, individual genotype missing rate
Summary
A critical assumption for the majority of genetic mapping approaches (including both linkage and family-based association) is that Mendel's law of segregation is obeyed. Transmission-ratio distortion (TRD) refers to the deviation from the expected Mendelian inheritance of alleles. Violation of this assumption could result in false-positive linkage, within ‘affected-only’ or ‘non-parametric’ linkage analysis frameworks. The presence of TRD in humans has been addressed in only a few studies, using either linkage [1] or family-based association methods [2] These studies had limited sample sizes, which may have resulted in low power. This limitation has recently been emphasized, when it was shown that hundreds or thousands of trios would be needed to detect loci even with large TRD deviations [3]
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