Genome-wide landscape of RNA-binding protein target site dysregulation reveals a major impact on psychiatric disorder risk

Abstract

Despite the strong genetic basis of psychiatric disorders, the underlying molecular mechanisms remain largely unmapped. RNA-binding proteins (RBPs) are responsible for most post-transcriptional regulation, from splicing to translational to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. However, quantifying the pathogenic contribution of noncoding variants impacting RBP target sites is challenging. Here, we leverage a deep learning approach that can accurately predict RBP target site dysregulation effects of mutations, and discover that RBP dysregulation is a principal contributor to psychiatric disorder risk. RBP dysregulation explains a substantial amount of heritability not captured by large-scale molecular QTL studies, and has a stronger impact than common coding region variants. We share genome-wide profiles of RBP dysregulation, which we use to identify DDHD2 as a candidate schizophrenia risk gene. This resource provides a novel analytical framework to connect the full range of RNA regulation to complex disease.