Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Year: 2023
Type: review
Study design: Observational Study
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.
Source: Nature Communications
Authors: Danielle Rasooly, Gina M. Peloso, Alexandre C. Pereira, Hesam Dashti, Claudia Giambartolomei, Eleanor Wheeler, Nay Aung, Brian R. Ferolito, Maik Pietzner, Eric H. Farber-Eger, Quinn Stanton Wells, Nicole M. Kosik, Liam Gaziano, Daniel C. Posner, A. Patrícia Bento, Qin Hui, Chang Liu, Krishna Aragam, Zeyuan Wang, Brian Charest, Jennifer E. Huffman, Peter W. F. Wilson, Lawrence S. Phillips, John Whittaker, Patricia B. Munroe, Steffen E. Petersen, Kelly Cho, Andrew R. Leach, María Paula Magariños, John Michael Gaziano, VA Million Veteran Program, Claudia Langenberg, Yan V. Sun, Jacob Joseph, Juan P. Casas
Institutions: Brigham and Women's Hospital, Harvard University, VA Boston Healthcare System, Boston University, Universidade de São Paulo, Instituto do Coração - HCFMUSP, Broad Institute, Italian Institute of Technology, Human Technopole, University of Cambridge, Wellcome/MRC Institute of Metabolic Science, Addenbrooke's Hospital, MRC Epidemiology Unit, National Health Service, St Bartholomew's Hospital, Queen Mary University of London, Barts Health NHS Trust, William Harvey Research Institute, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité – Universitätsmedizin Berlin, Vanderbilt University Medical Center, Vanderbilt University, European Bioinformatics Institute, Emory University, Atlanta VA Health Care System, Atlanta VA Medical Center, Massachusetts General Hospital, MRC Biostatistics Unit, National Institute for Health and Care Research, Providence VA Medical Center, Brown University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Veterans Affairs, Office of Research and Development, Queen Mary University of London, National Institute for Health and Care Research, Academy of Medical Sciences, University of Cambridge, European Commission, St George's University Hospitals NHS Foundation Trust, Barts Health NHS Trust, National Institutes of Health, Medical Research Council, National Human Genome Research Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Chronic Disease Prevention and Health Promotion, National Center for Advancing Translational Sciences
Awards: Aetiology of type 2 diabetes and related metabolic disorders, High Throughput Science - Investigating pathways to metabolic disease using "omic" approaches, G1300756762, G1799477055, G2137005839, G2464355595, MultIscale precision therapies for NeuroDEvelopmental Disorders, G2753796057, G2762402544, G2892497062, G3112942449, G3812975344, G4234450134, G434337789, G4672149634, G4830252577, G5540849157, G5554709201, G5787426001, G6607318219, G6683797720, G6957823285, G7211668644, G8198795195, G880270018, G8879099116, The Role of Tuberculosis Disease on Non-Communicable Disease Risk: Comparative Analysis of Large Healthcare Databases, G9000145963, G9000203756, Training in Bioinformatics and Integrative Genomics, Georgia Clinical & Translational Science Alliance (Georgia CTSA), CHANGING THE NATURAL HISTORY OF TYPE 2 DIABETES – “CHANGE” STUDY
OpenAlex ID: W4383720502