The potential of integrating human and mouse discovery platforms to advance our understanding of cardiometabolic diseases

Abstract

Cardiometabolic diseases encompass a range of interrelated conditions that arise from underlying metabolic perturbations precipitated by genetic, environmental, and lifestyle factors. While obesity, dyslipidaemia, smoking, and insulin resistance are major risk factors for cardiometabolic diseases, individuals still present in the absence of such traditional risk factors, making it difficult to determine those at greatest risk of disease. Thus, it is crucial to elucidate the genetic, environmental, and molecular underpinnings to better understand, diagnose, and treat cardiometabolic diseases. Much of this information can be garnered using systems genetics, which takes population-based approaches to investigate how genetic variance contributes to complex traits. Despite the important advances made by human genome-wide association studies (GWAS) in this space, corroboration of these findings has been hampered by limitations including the inability to control environmental influence, limited access to pertinent metabolic tissues, and often, poor classification of diseases or phenotypes. A complementary approach to human GWAS is the utilisation of model systems such as genetically diverse mouse panels to study natural genetic and phenotypic variation in a controlled environment. Here, we review mouse genetic reference panels and the opportunities they provide for the study of cardiometabolic diseases and related traits. We discuss how the post-GWAS era has prompted a shift in focus from discovery of novel genetic variants to understanding gene function. Finally, we highlight key advantages and challenges of integrating complementary genetic and multi-omics data from human and mouse populations to advance biological discovery.

Keywords: Hybrid Mouse Diversity Panel; atherosclerosis; cardiometabolic disease; computational biology; coronary artery disease; genetic mapping; genetic reference panels; genetics; genome-wide association studies; genomics; multi-omics; non-alcoholic fatty liver disease; systems biology; systems genetics.

Figure 1.. Illustrative overview of Hybrid Mouse Diversity Panel (HMDP) study designs utilised for the investigation of cardiometabolic diseases and related traits.

Interventions include transgenic expression of the human apolipoprotein (APO)E*3-Leiden and the human cholesteryl ester transferase protein (CETP) transgenes with concomitant feeding of an atherosclerosis promoting western diet (Ath-HMDP; red) (Bennett et al., 2015), feeding of a high-fat, high-sucrose diet (HF/HS-HMDP; yellow) (Parks et al., 2013), induction of isoproterenol (iso)-induced HF (HF-HMDP; green) (Rau et al., 2015), and 30 days of voluntary wheel running (Ex-HMDP; blue) (Moore et al., 2019). Created with BioRender.com.

Figure 2.. Benefits of integrating human and mouse datasets for biological discovery.

Created with BioRender.com.