The Gene Expression Landscape of Disease Genes

Abstract

Fine-mapping and gene-prioritisation techniques applied to the latest Genome-Wide Association Study (GWAS) results have prioritised hundreds of genes as causally associated with disease. Here we leverage these recently compiled lists of high-confidence causal genes to interrogate where in the body disease genes operate, which, in previous studies, has mostly been investigated by testing for enrichment of GWAS signal among genes with cell/tissue specific expression. By integrating GWAS summary statistics, gene prioritisation results, and RNA-seq data from 46 tissues and 204 cell types, we directly analyse the gene expression of putative disease genes across the body in relation to 11 major diseases and cancers. In tissues and cell types with established disease relevance, disease genes show higher and more specific gene expression compared to control genes. However, we also detect elevated expression in tissues and cell types without previous links to the corresponding disease. While some of these results may be explained by cell types that span multiple tissues, such as macrophages in brain, blood, lung and spleen in relation to Alzheimers disease (P-values < 10-3), the cause for others is unclear and warrants further investigation. To support functional follow-up studies of disease genes, we identify technical and biological factors influencing their expression, and highlight tissues in which higher expression is associated with increased odds of inclusion in drug development programs. We provide our systematic testing framework as an open-source, publicly available tool that can be utilised to offer novel insights into the genes, tissues and cell types involved in any disease, with the potential for informing drug development and delivery strategies.