A Regularized Regression Approach for Dissecting Genetic Conflicts that Increase Disease Risk in Pregnancy

Abstract

Human diseases developed during pregnancy could be caused by the direct effects of both maternal and fetal genes, and/or by the indirect effects caused by genetic conflicts. Genetic conflicts exist when the effects of fetal genes are opposed by the effects of maternal genes, or when there is a conflict between the maternal and paternal genes within the fetal genome. The two types of genetic conflicts involve the functions of different genes in different genomes and are genetically distinct. Differentiating and further dissecting the two sets of genetic conflict effects that increase disease risk during pregnancy present statistical challenges, and have been traditionally pursued as two separate endeavors. In this article, we develop a unified framework to model and test the two sets of genetic conflicts via a regularized regression approach. Our model is developed considering real situations in which the paternal information is often completely missing; an assumption that fails most of the current family-based studies. A mixture model-based penalized logistic regression is proposed for data sampled from a natural population. We develop a variable selection procedure to select significant genetic features. Simulation studies show that the model has high power and good false positive control under reasonable sample sizes and disease allele frequency. A case study of small for gestational age (SGA) is provided to show the utility of the proposed approach. Our model provides a powerful tool for dissecting genetic conflicts that increase disease risk during pregnancy, and offers a testable framework for the genetic conflict hypothesis previously proposed.