| Title: | Advancing personalised medicine for psychiatric diseases through integrative GPCR pharmacogenomics |
| Lead Institution: | University of Copenhagen |
| Principal investigator: | Dr Alexander Hauser |
Application 55955
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About
Understanding how drug response to a given therapeutic treatment differs in patients is one of the most important and long-standing challenges in personalised medicine. For example, 30 - 50% of patients with major depression do not respond to their first antidepressant drug prescription, and adherence remains often very poor. While a great deal of effort has been placed on linking variation in drug transport and metabolism with treatment responses, very little is known about how genetic variability in receptor drug targets affects treatment response. Elucidating the spectrum and impact of how a genetic receptor variant influences ligand binding and/or signalling and, ultimately, therapeutic effect is vital and would serve as an important step for understanding variability in drug response. The G protein-coupled receptor (GPCR) super-family spanning ~800 members (~4% of the human genome) allows environmental and physiological messages - communicated by distinct signalling molecules - to be relayed into adequate cellular responses. Apart from involvement in almost all physiological processes, GPCRs also mediate the effect of ~34% of drugs (Hauser et al., 2017 Nat Rev Drug Discov). In this project we focus on drugs used to treat schizophrenia, affective disorders and attention deficit hyperactivity disorder (ADHD), which prevalently target GPCRs directly or indirectly. Despite the significance of GPCRs and genetic variations for CNS drug therapies, personalised medicine is yet beyond reach, because we are missing integrated large-scale data showing which genetic missense variants affect the intended therapeutic effects and how. Here, we will employ a unique 'pharmacogenomics' research strategy, which integrates receptor genetic variants with 3D structures, pharmacological experiments, patient registries and literature data. We first map and select genetic variants in GPCR drug targets affecting CNS drug response through computational models. We then determine how psychiatric drug responses are affected by genetic receptor target variations in cell-based assays. Those experiments are labor-intensive, as we need to capture all possible intracellular responses. We hence envisage that the project would approximately take 3 years. We expect to correlate similar molecular receptor phenotypes induced by genetic variation with clusters of prescription changes and reported adverse reactions. To test these hypotheses, we will integrate information on hospitalisation records and prescribed medicines within the UKBioBank cohort. A successful project would provide evidence for genetic variants linked to therapies and would hence allow us to: i) better understand treatment adverse reactions in psychiatric disorders ii) personalise medicine prescriptions based on GPCR genotypes, and iii) prioritise drugs for pharmacovigilance investigations3 Publications
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 11863 | Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes | Hüsün S. Kizilkaya (+34) | 2024 | Nature Metabolism |
| 9749 | Mutational Landscape of the Proglucagon-Derived Peptides | Peter Lindquist (+4) | 2021 | Frontiers in Endocrinology |
| 10346 | The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection | Peter Lindquist (+5) | 2022 | Frontiers in Endocrinology |
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