Journal Article

A genetics-led approach defines the drug target landscape of 30 immune-related traits

Damerell, David, McCann, Fiona E., Brennan, Paul E., Sundström, Michael, Burnham, Katie L., Chen, Liye, Bountra, Chas, Berg, Louise, Osgood, Julie, Göhlmann, Hinrich W., Kasela, Silva, Peeters, Pieter J., Fang, Hai, Knezevic, Bogdan, Knight, Julian C., Bowness, Paul, Marsden, Brian D., Handunnetthi, Lahiru, Fairfax, Benjamin P., O’Callaghan, Chris A., Sundström, Yvonne, Sekine, Takuya, Milani, Lili, Wegner, Jörg K., De Cesco, Stephane, De Wolf, Hans, Lledó Lara, Alicia, Sanniti, Anna

2019

Overview

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection 1 . Drug targets with genetic support are more likely to be therapeutically valid 2 , 3 , but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging 4 – 6 . Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease. A genetics-led translational approach integrating functional genomic predictors, knowledge of network connectivity and immune ontologies defines the drug target prioritization landscape for 30 immune traits at the gene and pathway level.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 631/154 / 631/208 / 631/250 / 692/699/249 / Acids / Agriculture / Animal Genetics and Genomics / Annotations / Arthritis, Rheumatoid - drug therapy / Arthritis, Rheumatoid - genetics / Arthritis, Rheumatoid - immunology / Binding sites / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Clinical trials / CRISPR / Cytokines / Disease / Drug development / Drug Discovery / Drug targeting / Drugs / Gene expression / Gene Expression Regulation / Gene Function / Gene Regulatory Networks / Genetic aspects / Genetics / Genome, Human / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genotype & phenotype / Human Genetics / Humans / Immunity, Innate - genetics / Immunologic diseases / Immunosuppressive agents / Knowledge management / Letter / Medical research / Mutagenesis / Ontology / Polymorphism, Single Nucleotide / Proteins / Quantitative Trait Loci / Rheumatoid arthritis / Selection, Genetic / Signal transduction / Tumor necrosis factor-TNF