The application of pharmagenic enrichment in precision treatment of complex trait disorders

Complex traits, such as cardiovascular diseases, diabetes mellitus, rheumatology disorders, and mental health disorders, exhibit remarkable heterogeneity. This diversity arises from the intricate interplay of genetic, environmental, and lifestyle factors. Unlike simple Mendelian traits, which are governed by a single gene, complex traits involve multiple genetic variants distributed across the genome. Furthermore, the heterogeneity of these many small effect size variants among individuals contributes to variable responses to genetically targeted treatments when guided by population level data. Precision medicine considers the variability in different individuals’ genetics, environmental factors, and lifestyle. This approach delivers a more personalised strategy to address the unique characteristics of individuals or groups. Genome-wide association studies (GWAS) and polygenic risk scores have provided valuable insights into the common variant architecture and polygenicity of complex disorders. However, translating these findings into clinical practice remains challenging. To address these multifactorial hurdles, I therefore evaluated the utility of the novel pharmagenic enrichment score (PES) framework in this thesis to identify a more tailored treatment opportunities across a range of complex disorders. The PES methodology integrates polygenic risk scores within clinically relevant pathways, enabling prioritisation of new and existing personalised treatment strategies at both the population and individual levels. By optimising therapeutic efficacy through a systematic approach that integrates genetic risks into treatment decisions for complex diseases, this framework contributes to the advancement of precision medicine.