Network-guided search for genetic heterogeneity between gene pairs

Abstract

Motivation Correlating genetic loci with a disease phenotype is a common approach to improve our understanding of the genetics underlying complex diseases. Standard analyses mostly ignore two aspects, namely genetic heterogeneity and interactions between loci. Genetic heterogeneity, the phenomenon that different genetic markers lead to the same phenotype, promises to increase statistical power by aggregating low-signal variants. Incorporating interactions between loci results in a computational and statistical bottleneck due to the vast amount of candidate interactions. Results We propose a novel method SiNIMin that addresses these two aspects by finding pairs of interacting genes that are, upon combination, associated with a phenotype of interest under a model of genetic heterogeneity. We guide the interaction search using biological prior knowledge in the form of protein-protein interaction networks. Our method controls type I error and outperforms state-of-the-art methods with respect to statistical power. Additionally, we find novel associations for multiple A. thaliana phenotypes, and for a study of rare variants in migraine patients. Availability Code available at https://github.com/BorgwardtLab/SiNIMin.