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, Claudia Langenberg, Yan V. Sun, Jacob Joseph () and Juan P. Casas
Additional contact information
Danielle Rasooly: Harvard Medical School
Gina M. Peloso: VA Boston Healthcare System
Alexandre C. Pereira: University of São Paulo
Hesam Dashti: Harvard Medical School
Claudia Giambartolomei: Health Data Science Centre, Human Technopole
Eleanor Wheeler: University of Cambridge, Addenbrookes Hospital
Nay Aung: Queen Mary University of London
Brian R. Ferolito: VA Boston Healthcare System
Maik Pietzner: University of Cambridge, Addenbrookes Hospital
Eric H. Farber-Eger: Vanderbilt University Medical Center
Quinn Stanton Wells: Biomedical Informatics, and Pharmacology
Nicole M. Kosik: VA Boston Healthcare System
Liam Gaziano: VA Boston Healthcare System
Daniel C. Posner: VA Boston Healthcare System
A. Patrícia Bento: European Bioinformatics Institute, Wellcome Genome Campus
Qin Hui: Emory University Rollins School of Public Health
Chang Liu: Emory University Rollins School of Public Health
Krishna Aragam: VA Boston Healthcare System
Zeyuan Wang: Emory University Rollins School of Public Health
Brian Charest: VA Boston Healthcare System
Jennifer E. Huffman: VA Boston Healthcare System
Peter W. F. Wilson: Atlanta VA Health Care System
Lawrence S. Phillips: Atlanta VA Health Care System
John Whittaker: University of Cambridge
Patricia B. Munroe: Queen Mary University of London, Charterhouse Square
Steffen E. Petersen: St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield
Kelly Cho: Harvard Medical School
Andrew R. Leach: European Bioinformatics Institute, Wellcome Genome Campus
María Paula Magariños: European Bioinformatics Institute, Wellcome Genome Campus
John Michael Gaziano: Harvard Medical School
Claudia Langenberg: University of Cambridge, Addenbrookes Hospital
Yan V. Sun: Emory University Rollins School of Public Health
Jacob Joseph: VA Providence Healthcare System
Juan P. Casas: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-39253-3

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