Abstract
Genome-wide association studies have demonstrated that most traits are highly polygenic; however, translating these polygenic signals into biological insights remains difficult. A lack of satisfactory methods for translating polygenic results across species has precluded the use of model organisms to address this problem. Here we explore the use of polygenic transcriptomic risk scores (PTRS) for translating polygenic results across species. Unlike polygenic risk scores (PRS), which rely on SNPs for predicting traits, PTRS use imputed gene expression for prediction, which allows cross-species translation to orthologous genes. We first developed RatXcan, which is a framework for transcriptome-wide association studies (TWAS) in outbred rats. Leveraging predicted transcriptome and genotype data from UK Biobank, and the genetically trained gene expression models from RatXcan, we scored more than 3,000 rats using a human-derived PTRS for height. Strikingly, we found that human-derived height PTRS significantly predicted body length in rats (P<0.013). The genes included in the PTRS were enriched for biological pathways including skeletal growth and metabolism and were over-represented in tissues including pancreas and brain. This approach facilitates experimental studies in model organisms that examine the polygenic basis of human complex traits and provides an empirical metric by which to evaluate the suitability of specific animal models and identify their shared biological underpinnings.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Additional analyses were performed to ensure better calibrated significance estimates and additional authors were added.