Nature Communications (Jul 2023)
Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
- 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
Affiliations
- Danielle Rasooly
- Division of Aging, Brigham and Women’s Hospital, Harvard Medical School
- Gina M. Peloso
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Alexandre C. Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo
- Hesam Dashti
- Division of Aging, Brigham and Women’s Hospital, Harvard Medical School
- Claudia Giambartolomei
- Health Data Science Centre, Human Technopole
- Eleanor Wheeler
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital
- Nay Aung
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
- Brian R. Ferolito
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Maik Pietzner
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital
- Eric H. Farber-Eger
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center
- Quinn Stanton Wells
- Vanderbilt University Med. Ctr., Departments of Medicine (Cardiology), Biomedical Informatics, and Pharmacology
- Nicole M. Kosik
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Liam Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Daniel C. Posner
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- A. Patrícia Bento
- Department of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
- Qin Hui
- Department of Epidemiology, Emory University Rollins School of Public Health
- Chang Liu
- Department of Epidemiology, Emory University Rollins School of Public Health
- Krishna Aragam
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Zeyuan Wang
- Department of Epidemiology, Emory University Rollins School of Public Health
- Brian Charest
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Jennifer E. Huffman
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System
- Peter W. F. Wilson
- Atlanta VA Health Care System
- Lawrence S. Phillips
- Atlanta VA Health Care System
- John Whittaker
- MRC Biostatistics Unit, University of Cambridge
- Patricia B. Munroe
- William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square
- Steffen E. Petersen
- Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield
- Kelly Cho
- Division of Aging, Brigham and Women’s Hospital, Harvard Medical School
- Andrew R. Leach
- Department of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
- María Paula Magariños
- Department of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus
- John Michael Gaziano
- Division of Aging, Brigham and Women’s Hospital, Harvard Medical School
- VA Million Veteran Program
- Claudia Langenberg
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital
- Yan V. Sun
- Department of Epidemiology, Emory University Rollins School of Public Health
- Jacob Joseph
- Cardiology Section, VA Providence Healthcare System
- Juan P. Casas
- Division of Aging, Brigham and Women’s Hospital, Harvard Medical School
- DOI
- https://doi.org/10.1038/s41467-023-39253-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 15
Abstract
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.
