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

Nature Genetics
Volume 51 Issue 7, July 2019
https://www.nature.com/ng/volumes/51/issues/7

 

Letter | 28 June 2019
A genetics-led approach defines the drug target landscape of 30 immune-related traits
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.
Hai Fang, Georg Beckmann[…] & Julian C. Knight
Abstract
Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. 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 challenging4,5,6. 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.