Hukerikar, Nikita;
Hingorani, Aroon D;
Asselbergs, Folkert W;
Finan, Chris;
Schmidt, Amand F;
(2024)
Prioritising genetic findings for drug target identification and validation.
Atherosclerosis
, 390
, Article 117462. 10.1016/j.atherosclerosis.2024.117462.
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Abstract
The decreasing costs of high-throughput genetic sequencing and increasing abundance of sequenced genome data have paved the way for the use of genetic data in identifying and validating potential drug targets. However, the number of identified potential drug targets are often prohibitively large to experimentally evaluate in wet lab experiments, highlighting the need for systematic approaches for target prioritisation. In this review, we discuss principles of genetically guided drug development, specifically addressing loss-of-function analysis, colocalization and Mendelian randomisation (MR), and the contexts in which each may be most suitable. We subsequently present a range of biomedical resources which can be used to annotate and prioritise disease-associated proteins identified by these studies including 1) ontologies to map genes, proteins, and disease, 2) resources for determining the druggability of a potential target, 3) tissue and cell expression of the gene encoding the potential target, and 4) key biological pathways involving the potential target. We illustrate these concepts through a worked example, identifying a prioritised set of plasma proteins associated with non-alcoholic fatty liver disease (NAFLD). We identified five proteins with strong genetic support for involvement with NAFLD: CYB5A, NT5C, NCAN, TGFBI and DAPK2. All of the identified proteins were expressed in both liver and adipose tissues, with TGFBI and DAPK2 being potentially druggable. In conclusion, the current review provides an overview of genetic evidence for drug target identification, and how biomedical databases can be used to provide actionable prioritisation, fully informing downstream experimental validation.
| Type: | Article |
|---|---|
| Title: | Prioritising genetic findings for drug target identification and validation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.atherosclerosis.2024.117462 |
| Publisher version: | https://doi.org/10.1016/j.atherosclerosis.2024.117... |
| Language: | English |
| Additional information: | Copyright © 2024 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Human genetics, Mendelian randomization, Drug development, Bioinformatics, NAFLD, Drug target validation, Colocalization, Loss-of-function |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10186263 |
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