Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes

BackgroundIdentification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered GWAS, and therefore few associated loci and causal genes have been identified. ResultsHere, we perform and integrate LD-adjusted colocalization analyses across nine cardiometabolic traits combined with eQTLs and sQTLs from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. To elucidate upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 physiological and pharmacological cardiometabolic regulators in human adipocytes, hepatocytes, and skeletal muscle cells, and map their protein-protein interactions. ConclusionsOur use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our state-of-the-art colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.