Genome-wide aggregated trans-effects analysis identifies key role in hypertension for proteins involved in clearance of triglyceride-rich lipoproteins

Abstract

Background Genome-wide aggregated trans-effects (GATE) analysis is a novel method in which trans-effects on gene expression (as transcript or protein) are combined with SNP-trait association data to identify core genes that directly influence the trait. The objective of this study was to identify core genes for blood pressure. Methods We undertook GWASs of mean arterial pressure (MAP) and and body mass index (BMI) in 373,882 individuals aged less than 60 in the Our Future Health (OFH) cohort. Using summary statistics from GWASs of circulating proteins on the SomaScan and Olink platforms, we tested for association of GATE scores (predicted levels of each protein based on trans-effects) with MAP. We confirmed replication of top associations in an independent cohort. Results The strongest GATE score association with MAP was for LPL (lipoprotein lipase). Higher genetically predicted circulating levels of LPL were associated with lower MAP but higher BMI. GATE scores for three other proteins involved in lipid handling – CD300LG, ADIPOQ, TIMP4 – were also associated with lower MAP but higher BMI. GATE scores for all four of these proteins were inversely associated with chylomicron triglyceride (measured as XXL-VLDL-TG by NMR spectroscopy). The associations of GATE scores for ANGPTL3 and ANGPTL4, which regulate LPL, were consistent with a causal role of LPL in lowering XXL-VLDL-TG and MAP. Conclusions These results point to a key role in hypertension for proteins that regulate post-prandial clearance of triglyceride-rich lipoproteins, independently of adiposity.