1. A genetics-led approach defines the drug target landscape of 30 immune-related traits.
- Author
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Fang H, De Wolf H, Knezevic B, Burnham KL, Osgood J, Sanniti A, Lledó Lara A, Kasela S, De Cesco S, Wegner JK, Handunnetthi L, McCann FE, Chen L, Sekine T, Brennan PE, Marsden BD, Damerell D, O'Callaghan CA, Bountra C, Bowness P, Sundström Y, Milani L, Berg L, Göhlmann HW, Peeters PJ, Fairfax BP, Sundström M, and Knight JC
- Subjects
- Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid immunology, Gene Expression Regulation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Arthritis, Rheumatoid genetics, Drug Discovery, Gene Regulatory Networks, Genome, Human, Immunity, Innate genetics, Quantitative Trait Loci, Selection, Genetic
- Abstract
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 valid2,3 , but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4-6 . 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.- Published
- 2019
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