Genome-wide association analysis and Mendelian randomization proteomics identify novel protein biomarkers and drug targets for primary prevention of heart failure

We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomization (MR) and colocalization analyses on human proteins to provide causal evidence for the role of druggable proteins in the genesis of HF. We identified 39 genome-wide significant HF risk variants, of which 18 are previously unreported. Using a combination of MR proteomics and genetic cis-only colocalization analyses, we identified 10 additional putatively causal genes for HF. Findings from GWAS and MR-proteomics identified seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of HF.