Leveraging trans-gene regulation prioritizes central genes and pathways in asthma [CRISPR Screen]

While genome-wide association studies have cataloged thousands of variants, it’s been proposed that most are indirect regulators of a limited, currently unidentified set of central disease-driving genes, defined here as disease-proximal genes (DPGs). Here, we introduce DANDELION, a mediation-based statistical framework that prioritizes DPGs by integrating trans-regulatory effects from disease-relevant tissues with gene-level burden from whole-exome sequencing.

Applying DANDELION to asthma uncovers novel DPGs that escape detection by conventional methods. CRISPR screens in epithelial and T cells find that most DPGs mediate key asthma-related cellular phenotypes. We also demonstrate that loss of a lipid transporter involved in protein palmitoylation encoded by DPG SLC27A3 ameliorates inflammation and airway remodeling in a mouse model of allergic asthma.