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, insulin modulating agents, and protein kinase inhibitors with putative neuroprotective properties. 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 framework can 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: pretreatment 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.…”

Genome-wide meta-analysis of pneumonia suggests a role for mucin biology and provides novel drug repurposing opportunities

“…We implemented the pharmagenic enrichment score (PES) approach to identify drug repurposing candidates that could be targeted more precisely based on genetic risk 23,32 . Briefly, the PES is a genetic risk score specifically within a biological pathway that is targeted by approved drugs.…”

“…The PES framework is based on the postulation that an enrichment of genetic risk within a biologically pathway with known drug targets may be an impetus to repurpose a drug which modulates that pathway for individuals who carry the high genetic load mapped to the pathway, as described elsewhere 23,32 . Specifically, we identify druggable pathways with an enrichment of common variant associations relative to the rest of the genes tested and construct pathway-based risk scores for these gene-sets (Supplementary Methods).…”

Four Actionable Bottlenecks and Potential Solutions to Translating Psychiatric Genetics Research: An Expert Review

“…Yet, there is a higher representation of disorders for which the most known genetic variants have been discovered to date. These include schizophrenia, ASD, and mood disorders [45, 51, 53-56, 60, 64, 69, 71, 73, 75-80, 89, 94-97, 100, 102, 103, 107, 113, 114, 116, 118, 119, 122, 126, 127, 143, 156, 157, 160]. This comes as no surprise, but it must be noted that even for disorders such as schizophrenia and bipolar disorder, the genetic variants known are not clinically actionable due to how little genetic variance they account for [34].…”

“…This might be expected given the long delay between research and practice in linear frameworks such as bench-to-bedside; reviews are easier and faster to generate. To our knowledge, only 14 experimental articles address the translation of psychiatric genetic information [5, 6, 49, 60, 91, 92, 94, 98, 113, 114, 130, 145, 151, 162]. There is heterogeneity among these articles.…”