215-OR: Polygenic Scores for Metabolic Diseases Are Associated with Gene Expression Networks across Tissues

In type 2 diabetes (T2D), coronary artery disease (CAD) and obesity, disease risk across thousands of genetic variants can be captured with global extended polygenic scores (gePS), yet knowledge of underlying disease pathways remains limited. Expression Quantitative Trait Scores (eQTS) connecting gePS to gene expression could help prioritize disease-causing genes and pathways in specific tissues.

We generated gePS for T2D, CAD, and body mass index (BMI) in the Genotype-Tissue Expression (GTEx) database of 838 individuals and 49 tissues. Associations between gePS and phenotypes were confirmed in a hospital-based biobank. eQTS were calculated using a linear model of association between gePS and tissue transcript expression level, adjusting for age, sex, and 5 PCs. Gene set enrichment was performed using Enrichr with Gene Ontology pathway sets and Fisher’s Exact Test (Q < 0.05). Each gePS was strongly associated with >3,000 strong transcript expression levels (eQTS) across multiple tissues at Q<0.05. T2D and BMI eQTS in multiple tissues were each significantly enriched for pathways related to mitochondrial function (Q<0.01), with the most significant T2D signal in the heart atrial appendage and BMI signal in subcutaneous (SC) and visceral adipose. 3,960 eQTS were shared between T2D and BMI in the heart left ventricle (LV), and 68 were shared in SC adipose (all Q<0.05). Shared pathways in the heart were enriched for processes related to cellular respiration and heart contraction (Q<10^-8). For CAD, cholesterol metabolism pathways were enriched in the coronary artery and visceral adipose (Q<10^-2). In summary, T2D and BMI eQTS share mitochondrial and metabolic transcription mechanisms across several tissues, including SC adipose. Cholesterol metabolism was enriched in multiple tissues in CAD eQTS and also observed in T2D and BMI eQTS in visceral adipose. This study provides novel insight into the shared genetic and transcriptomic architecture of T2D, CAD, and obesity.