Genome-wide detection and characterization of mating asymmetry in human populations

The study of the genetic component of early-onset diseases requires investigation into parental genetic effects, particularly those mediated by the mother who can influence the offspring's risk of disease through the effects of her genes acting directly on the intrauterine milieu or indirectly through maternal-gene child-gene interaction effects. An important source of bias that can arise in feto-maternal association testing is the possibility of confounding due to mating asymmetry (MA). However, there is little information on the levels of MA present in human populations and the impact on maternal association testing. In this study, we developed a novel approach to measuring MA and, using HapMap mate-pairs of European and African descent, carried out a genome-wide investigation and characterization of MA. We further investigated the impact of observed levels of MA on maternal association tests through simulation experiments. For the first time, we showed that non-negligible levels of MA are detected in human populations, such that subtle genotype frequency differences between individuals mating in the population are sufficient to induce spurious maternal genotype associations. Though the underlying mechanisms driving the asymmetry within these populations remain elusive, our findings provide consequential evidence for the occurrence of MA in humans and highlight the importance of controlling for MA in maternal association testing.