Pharmacological enrichment of polygenic risk for precision medicine in complex disorders

Abstract

Individuals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an individual’s common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for individual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, antioxidants, insulin modulating agents, and cholinergic drugs. Interestingly, elevated PES was also observed in individuals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this gene-set orientated approach could integrate an individual’s common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.

Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders

“…The traditional method of testing for precision medicine in RCTs has been a search for baseline enrichment factors: pre-treatment biobehavioural measurements that predict (or moderate) a treatment outcome. These predictors are called enrichment factors following genetics parlance, 50 , 51 but they can just as easily be neuroimaging, peripheral molecular (e.g., proteomic), symptomatic (e.g., comorbid anxiety) or behavioural. However, this “baseline-only” approach to enrichment factors has been largely unsuccessful in neurobehavioural disorders, as exemplified by the lack of progress in determining genetic predictors of antidepressant response.…”

Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function

“…We aimed to further expand drug-repurposing opportunities for lung function using the PES approach ( Reay et al, 2020 ). Briefly, PES aims to implement genetically informed drug repurposing with PGS calculated using genetic variants specifically within druggable pathways ( Figure 3a ).…”

“…Firstly, we assessed each lung function trait for evidence of genetic correlation with biochemical traits that could be pharmacologically modulated, followed by models to investigate whether there was evidence of causation. The previously developed pharmagenic enrichment score (PES) framework was then implemented to identify druggable pathways enriched with lung function-associated variation and calculate pathway-specific polygenic scores (PGS) to prioritise individuals who may benefit from a repurposed compound which interacts with the pathway ( Reay et al, 2020 ). A transcriptome-wide association study (TWAS) of FEV 1 and FVC was also undertaken to reveal genes which could be targeted by existing drugs that may increase pulmonary function.…”

Integrative Genomic–Epigenomic Analysis of Clozapine-Treated Patients with Refractory Psychosis

“…It is known that individuals with BD and psychosis have an increased risk of diabetes mellitus (i.e., high blood glucose levels) [ 37 , 38 , 39 ]. In fact, it has been reported that CLZ response and diabetes mellitus share genetic mechanisms [ 40 , 41 , 42 ], including recurrent genes such as CACNA1C in common pathways (e.g., insulin secretion). Additionally, it has been documented that hyperglycemia may reduce the response to the mood stabilizer treatments [ 43 ].…”