Identification of multi-omic pleiotropy factors for peripheral artery disease

BackgroundPeripheral artery disease (PAD) is prevalent and frequently co-occurs with type 2 diabetes (T2D) and coronary artery disease (CAD). Although shared genetic factors may contribute to these comorbidities, few studies have examined pleiotropy at the transcriptomic and proteomic levels. MethodsWe generated summary statistics for transcriptome-wide (TWAS) and proteome-wide (PWAS) association analyses across PAD, T2D, and CAD. Joint tests for pleiotropy at the variant, transcript, and protein levels were performed using PLACO, and the contributions of these pleiotropic factors to genetic correlations were quantified. Furthermore, we developed pleiotropy models integrating variants, transcripts, and proteins. ResultsIn the PAD-T2D analysis, we identified 5 SNPs, 2 predicted transcripts, and 2 predicted proteins that together contributed 2.8% to the genome-wide genetic covariance. In the PAD-CAD analysis, 33 SNPs, 2 predicted transcripts, and 2 predicted proteins accounted for 9.15% of the genetic covariance. Overall, eight pleiotropy models were established, providing a multi-layered framework for categorizing our findings. ConclusionEmploying a multi-omic framework, this study elucidates the shared genetic architecture of PAD with T2D and CAD. Our findings enhance the understanding of genetic risk factors underlying PAD and its comorbidities, with potential implications for future therapeutic strategies. Lay summaryThis study investigates why peripheral artery disease (PAD) often occurs together with type 2 diabetes (T2D) or coronary artery disease (CAD) by identifying shared genetic risk factors. O_LIWe discovered new PAD-related genetic variants, including rs2138161, which may function through pathways shared between blood vessel function and metabolic processes. C_LIO_LIPAD-T2D comorbidity appears to be closely related to inflammatory pathways, while PAD-CAD comorbidity is more strongly linked to lipid-related pathways, offering insights into disease mechanisms and potential therapeutic targets. C_LI Graphical AbstractPAD: peripheral artery disease; T2D: type 2 diabetes; CAD: coronary artery disease; SNP: single nucleotide polymorphism; mRNA: messenger ribonucleic acid.