Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion

Abstract

Transmission of the two parental alleles to offspring deviating from the Mendelian ratio is termed Transmission Ratio Distortion (TRD), occurs throughout gametic and embryonic development. TRD has been well-studied in animals, but remains largely unknown in humans. The Transmission Disequilibrium Test (TDT) was first proposed to test for association and linkage in case-trios (affected offspring and parents); adjusting for TRD using control-trios was recommended. However, the TDT does not provide risk parameter estimates for different genetic models. A loglinear model was later proposed to provide child and maternal relative risk (RR) estimates of disease, assuming Mendelian transmission. Results from our simulation study showed that case-trios RR estimates using this model are biased in the presence of TRD; power and Type 1 error are compromised. We propose an extended loglinear model adjusting for TRD. Under this extended model, RR estimates, power and Type 1 error are correctly restored. We applied this model to an intrauterine growth restriction dataset, and showed consistent results with a previous approach that adjusted for TRD using control-trios. Our findings suggested the need to adjust for TRD in avoiding spurious results. Documenting TRD in the population is therefore essential for the correct interpretation of genetic association studies.

Maternal Transmission Ratio Distortion in Two Iberian Pig Varieties

“…Unknown parameters (α, π E , π R ) were estimated for each population by maximizing the likelihood function under a three-dimension gradient ascent approach. Statistical significance for α was evaluated through a standard likelihood ratio test [40] under an SNP-by-SNP approach, as other previous TRD models have used [18,26,41,42]. Ad hoc software was written in FORTRAN90 programming language.…”

“…So far, the greatest TRD study in pigs is the mapping of TRD loci (TDRLs) in boars and part of their offspring using a Bayesian approach to detect paternal TRDLs in the pig genome, but no maternal TRDLs [23]. There are no studies in pigs to assess the segregation deviation by standard χ2 [4,24], t-tests [25], or likelihood ratio tests [18,26].…”

Fertility Costs of Meiotic Drivers

“…Humans are not genetically tractable in this way. While the amount of genetic data on humans is nearly limitless, offspring counts are exceedingly small and reliable pedigree data are rare (but see [101][102][103]). Drivers can also be detected via sequencing many gametes, but this is expensive and is, for now, uncommon [5].…”

Genetic Association Family‐Based Studies and Preeclampsia

“…The Mendelian inheritance ratio assumption is the basis of many genetic analyses. It can be adjusted for with a transmission ratio distortion offset or the inclusion of control trios in the log‐linear model . Such adjustment is exceedingly uncommon in genetic association studies possibly because there is scepticism about the existence of these distortions (but, of course, they will not be observed if not investigated).…”

“…It can be adjusted for with a transmission ratio distortion offset or the inclusion of control trios in the log-linear model. 9,10 Such adjustment is exceedingly uncommon in genetic association studies possibly because there is scepticism about the existence of these distortions (but, of course, they will not be observed if not investigated). In this study, control duos were mainly included to increase power and obtain better parameter estimation.…”