Expanding our understanding of polygenic disease comorbidity structure: PRSxPheWAS

Most common diseases including diabetes, hypertension, and coronary artery disease present in a polygenic nature. This means that an individual’s risk for the condition is due to genetic variation across numerous genes. Polygenic risk scores (PRSs) are genetic instruments designed to quantify this genetic liability by summing the effect size estimates for these various risk alleles of a given disease. A great deal of work has gone into developing PRSs for various diseases. As of January 2025, the PGS catalog contains more than 5,000 published PRSs. Just as common diseases present with risk due to variation in multiple genes these conditions also present with a myriad of comorbid conditions. Many of these comorbidities may reflect the underlying genetics with a specific combination of genetic risk alleles included in PRS for a given disease. Therefore, the systematic evaluation of comorbidity patterns associated with a given PRS may improve our understanding of these common complex diseases. Phenome-wide association studies (PheWASs) are one such tool to systematically evaluate clinical disease across multiple biobanks and in various populations. PheWASs use phecodes, aggregates of clinical billing codes, to represent clinical disease. Then the association between a genetic predictor, such as a PRS, and the various phecodes are assessed using regression analyses. In Aim 1 we will perform PheWAS analyses of the published PRSs (PRSxPheWAS) in the PGS catalog in All of US, eMERGE, BioVU, and UK Biobank. These analyses will be adjusted for standard covariates that reflect differences in patient demographics and hospital utilization. The results from these biobanks and others will be meta- analyzed using AnVIL. In Aim 2 the analyses of Aim 1 will be repeated but the population will be separated by electronic medical record reported sex to identify potential differences in clinical disease presentation and risk. All produced workflows, data visuals, and results will be made available for public access via AnVIL. PheWASs of individual PRSs can identify shared comorbidity structures and risk patterns that may reflect underlying biology, environmental/behavioral patterns, or phenotypic convergence. Further, the creation of a robust catalog of phenotypic relationships to individual PRSs across multiple biobanks, the end product of this award, can improve our understanding of comorbidity patterns for common polygenic diseases. Project Number: 1R03HG014801-01 | Fiscal Year: 2026 | NIH Institute/Center: National Human Genome Research Institute (NHGRI) | Principal Investigator: Megan Shuey | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $437,500 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 BBBT-U (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11284137