S-22-3: UNCOVERING NEW GENES, TISSUES AND THERAPEUTIC TARGETS FOR BLOOD PRESSURE THROUGH LARGE-SCALE TRANSCRIPTOME-WIDE ASSOCIATION STUDIES

Abstract

Objective: Transcriptome-wide association study (TWAS) leverages information from reference panels of human tissues to predict the genetically determined component of expression in much larger datasets for thousands of genes and explore their association with a phenotype/disease of interest in thousands of individuals. Using TWAS, we sought to 1) define contributors to blood pressure (BP) regulation across a panel of 49 human cell-types/tissues 2) detect new kidney genes associated with BP in human kidney samples and 3) identify new pharmacological opportunities for hypertension through TWAS-informed drug repurposing. Design and method: We performed TWAS using PrediXcan across 49 human tissues/cell-types from The Genotype-Tissue Expression project and ranked the overall relevance of tissue of BP according to three independent metrics defining the strength of uncovered tissue-trait associations. We then trained predictors of gene expression from 478 samples from the Human Kidney Tissue Resource by applying a new predictive model which utilises epigenetic and three-dimensional genomic information to prioritise essential genetic variants. The subsequent BP kidney TWAS was conducted in up to ∼750k individuals from UK Biobank and International Consortium for Blood Pressure. Finally, we combined the input from BP kidney TWAS with Connectivity Map to identify drugs capable of inducing or reversing the identified gene expression signatures. Results: We found that fibroblasts, kidney cortex, lymphocytes, brain, thyroid, adrenal glands, aorta and spleen showed the overall strongest associations with BP across 49 human tissues/cell-types. Through TWAS of systolic blood pressure/diastolic blood pressure/pulse pressure we identified 997 kidney genes associated with at least one BP trait. Of these, 562 (56%) have not been reported before. Our computational druggability analysis re-affirmed the potential of several known BP inducers (glucocorticoid receptor agonists, calcineurin inhibitors) to increase BP and uncovered adenylate cyclase system activators to reverse the BP-related changes in the transcriptome. We also found purinergic receptor as a potential gene target for drug repurposing in hypertension. Finally, we found that use of topoisomerase inhibitors, cyclin-dependent kinase inhibitors, inosine monophosphate dehydrogenase inhibitors, and histone deacetylase inhibitors may be associated with hypotension. Conclusion: Our data provided evidence for the role of the kidney as an organ of the key relevance to hypertension and highlighted the importance of immune system in BP regulation. We also identified 997 kidney genes robustly associated with BP. Through TWAS-informed drug repurposing analysis, we uncovered novel targets for drug development in hypertension and highlighted BP drop as a potential side effect of several existing therapeutics.