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

Lam O Huang,Aurélie Labbe,Claire Infante-Rivard

doi:10.3389/fgene.2016.00155

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.

Highlights

Transmission Ratio Distortion (TRD) occurs when the transmission of alleles from a heterozygous parent to the offspring statistically deviates from the Mendelian Law of Inheritance
We previously reviewed a number of human studies on TRD (Naumova et al, 2001; Pardo-Manuel de Villena and Sapienza, 2001; Zöllner et al, 2004; Hanchard et al, 2005; The International HapMap Consortium, 2005; Paterson et al, 2009) and discussed the various methods and study designs in detecting TRD (Huang et al, 2013)
Our simulation study showed that when TRD is unaccounted for as in model 1, the relative risk (RR) is inflated or attenuated exponentially

Summary

Introduction

Transmission Ratio Distortion (TRD) occurs when the transmission of alleles from a heterozygous parent to the offspring statistically deviates from the Mendelian Law of Inheritance. TRD results from disruptive mechanisms occurring during gametic and embryonic development (Huang et al, 2013), including germline selection (Hastings, 1991), meiotic drive (Pardo-Manuel de Villena and Sapienza, 2001), gametic competition (Zöllner et al, 2004), embryo lethality (Zöllner et al, 2004), and imprint resetting error (Naumova et al, 2001; Yang et al, 2008). A recent study uses a Bayesian framework to model TRD in boars and piglets and was shown to achieve appealing statistical performance (Casellas et al, 2014). Individuals unselected for phenotype have been studied to detect TRD in the general population, such as in the Framingham Heart study (Paterson et al, 2009; Meyer et al, 2012), the Centre d’Etude du Polymorphisme Humain (Naumova et al, 2001; Yang et al, 2008), the HapMap project (The International HapMap Consortium, 2005), and the 1000 Genomes Project (Auton et al, 2005).

Methods

Results

Conclusion