Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure

• Type of Material: Article
• Authors: Danielle Rasooly, Harvard Medical School; Gina M Peloso, Boston University; Alexandre C Pereira, University of São Paulo; Hesam Dashti, Harvard Medical School; Claudia Giambartolomei, Human Technopole, V.le Rita Levi-Montalcini; Eleanor Wheeler, University of Cambridge; Nay Aung, Queen Mary University London; Brian R Ferolito, VA Boston Healthcare System; Maik Pietzner, University of Cambridge; Eric H Farber-Eger, Vanderbilt University; Quinn Stanton Wells, Vanderbilt University; Nicole M Kosik, VA Boston Healthcare System; Liam Gaziano, VA Boston Healthcare System; Daniel C Posner, VA Boston Healthcare System; A. Patrícia Bento, Wellcome Genome Campus, Hinxton; Qin Hui, Emory University; Chang Liu, Emory University; Krishna Aragam, VA Boston Healthcare System; Zeyuan Wang, Emory University; Brian Charest, VA Boston Healthcare System; Jennifer E Huffman, VA Boston Healthcare System; Peter W. F Wilson, Emory University; Lawrence S Phillips, Emory University; John Whittaker, University of Cambridge; Patricia B Munroe, Queen Mary University London; Steffen E Petersen, Barts Health NHS Trust, West Smithfield; Kelly Cho, Harvard Medical School; Andrew R Leach, Wellcome Genome Campus, Hinxton; María Paula Magarinos, Wellcome Genome Campus, Hinxton; John Michael Gaziano, Harvard Medical School; Claudia Langenberg, University of Cambridge; Yan V Sun, Emory University; Jacob Joseph, VA Providence Healthcare System, Providence; Juan P Casas, Harvard Medical School
• Language: English
• Date: 2023-07-10
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-39253-3
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 3826
• End Page: 3826
• Grant/Funding Information: This research is supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant I01 CX001737 (PI: Phillips), and I01-BX004821 (PI: Wilson/Cho).
• Keywords: Multidisciplinary Sciences; Science & Technology; VOLANESORSEN; Science & Technology - Other Topics; GENETIC ARCHITECTURE; PROTEIN
• Research Categories: Health Sciences, Pharmacology; Biology, Genetics; Biology, Biostatistics; Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology; Engineering, Biomedical

Abstract

We 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.