Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPRASOOLY, DaniellePELOSO, Gina M.PEREIRA, Alexandre C.DASHTI, HesamGIAMBARTOLOMEI, ClaudiaWHEELER, EleanorAUNG, NayFEROLITO, Brian R.PIETZNER, MaikFARBER-EGER, Eric H.WELLS, Quinn StantonKOSIK, Nicole M.GAZIANO, LiamPOSNER, Daniel C.BENTO, A. PatriciaHUI, QinLIU, ChangARAGAM, KrishnaWANG, ZeyuanCHAREST, BrianHUFFMAN, Jennifer E.WILSON, Peter W. F.PHILLIPS, Lawrence S.WHITTAKER, JohnMUNROE, Patricia B.PETERSEN, Steffen E.CHO, KellyLEACH, Andrew R.MAGARINOS, Maria PaulaGAZIANO, John MichaelLANGENBERG, ClaudiaSUN, Yan V.JOSEPH, JacobCASAS, Juan P.2023-10-302023-10-302023NATURE COMMUNICATIONS, v.14, n.1, 2023https://observatorio.fm.usp.br/handle/OPI/56418We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure. Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.engopenAccessgenetic architectureproteinvolanesorsenarticleCopyright NATURE PORTFOLIO10.1038/s41467-023-39253-3Multidisciplinary Sciences2041-1723