Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a group of complex neurodevelopment disorders with a strong genetic basis. Large scale sequencing studies have identified over one hundred ASD risk genes. Nevertheless, the vast majority of ASD risk genes remain to be discovered, as it is estimated that more than 1000 genes are likely to be involved in ASD risk. Prioritization of risk genes is an effective strategy to increase the power of identifying novel risk genes in genetics studies of ASD. As ASD risk genes are likely to exhibit distinct properties from multiple angles, we reason that integrating multiple levels of genomic data is a powerful approach to pinpoint genuine ASD risk genes. RESULTS: We present BNScore, a Bayesian model selection framework to probabilistically prioritize ASD risk genes through explicitly integrating evidence from sequencing-identified ASD genes, biological annotations, and gene functional network. We demonstrate the validity of our approach and its improved performance over existing methods by examining the resulting top candidate ASD risk genes against sets of high-confidence benchmark genes and large-scale ASD genome-wide association studies. We assess the tissue-, cell type- and development stage-specific expression properties of top prioritized genes, and find strong expression specificity in brain tissues, striatal medium spiny neurons, and fetal developmental stages. CONCLUSIONS: In summary, we show that by integrating sequencing findings, functional annotation profiles, and gene-gene functional network, our proposed BNScore provides competitive performance compared to current state-of-the-art methods in prioritizing ASD genes. Our method offers a general and flexible strategy to risk gene prioritization that can potentially be applied to other complex traits as well.