Spatio-Temporal Gene Discovery For Autism Spectrum Disorder

Abstract

Whole exome sequencing (WES) studies for Autism Spectrum Disorder (ASD) could identify only around six dozen risk genes to date because the genetic architecture of the disorder is highly complex. To speed the gene discovery process up, a few network-based ASD gene discovery algorithms were proposed. Although these methods use static gene interaction networks, functional clustering of genes is bound to evolve during neurodevelopment and disruptions are likely to have a cascading effect on the future associations. Thus, approaches that disregard the dynamic nature of neurodevelopment are limited in power. Here, we present a spatio-temporal gene discovery algorithm for ASD, which leverages information from evolving gene coexpression networks of neurodevelopment. The algorithm solves a variant of prize-collecting Steiner forest-based problem on coexpression networks to model neurodevelopment and transfer information from precursor neurodevelopmental windows. The decisions made by the algorithm can be traced back, adding interpretability to the results. We apply the algorithm on WES data of 3,871 samples and identify risk clusters using BrainSpan coexpression networks of earlyand mid-fetal periods. On an independent dataset, we show that incorporation of the temporal dimension increases the prediction power: Predicted clusters are hit more and show higher enrichment in ASD-related functions compared to the state-of-the-art. Code is available at http://ciceklab.cs.bilkent.edu.tr/ST-Steiner/.