Tomasi, Julia, Niemi, Mari, Hajizadeh, Nelly and Xu, Huilei (2024) Using pathway-specific polygenic risk scores to investigate disease mechanisms, biomarkers, and treatment response. This proposal is for submission to FinnGen.

Abstract

Background and Hypothesis: Part of the phenotypic heterogeneity across diseases, such as those in the neuroscience and cardiovascular fields, may be due to genetic heterogeneity. These diseases are not solely elicited by single genes, but instead are polygenic with multiple genetic variants having small effects that combine to contribute to disease. Furthermore, within each disease, there are typically several different biological pathways that can impact onset and progression, and each may carry various biomarkers. The study of complex diseases may thus benefit from the use of polygenic approaches specifically focused on relevant biological pathways to examine utility in disease prediction and biomarker selection. One approach that can function towards this goal is the use of a polygenic risk score (PRS). The creation of a PRS can be curated to select SNPs based on biological information relevant to disease. We hypothesize that biologically informed PRSs will be associated with both disease onset and progression in addition to relevant biomarkers that are measurable in clinical trials.
Aims: Genetic evidence for a particular target increases the likelihood that the target will succeed in clinical trials (Minikel et al., 2024). By investigating evidence of the PRS’s association with both disease status and relevant biomarkers, we would enhance our understanding of disease heterogeneity. Additionally, if a pathway-specific PRS shows association with particular measurable biomarkers, it would be suggested that those biomarkers could inform future clinical trials. Overall, the primary aim for our study is to use pathway-specific PRS analyses to assess patient heterogeneity and markers of disease subgroups.
Analysis Design: We propose to develop and calculate pathway-specific PRSs based on biological pathways of interest for several disease areas such as the neuroscience and cardiovascular fields, among others. Upon calculation of the pathway-specific PRSs using summary statistics for our curated list of SNPs, we will test association with diseases and traits in FinnGen, along with relevant biomarkers. If we identify significant biomarkers associated with any of the PRSs, we will perform follow-up analyses including mendelian randomization (MR) and genetic correlations to determine if the results are complimentary to what we observe for the PRS.
Outcome: Our planned analysis fits to the overall FinnGen Scientific Plan as it promotes the use of genetic methodology to add support to the understanding of the mechanisms behind various heterogeneous diseases that can be targeted with novel medications.

Item Type:	Article
Date Deposited:	19 Nov 2024 00:45
Last Modified:	19 Nov 2024 00:45
URI:	https://oak.novartis.com/id/eprint/55233