Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
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 b...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39253-3 |
| _version_ | 1797778745041354752 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Danielle Rasooly |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T23:21:57Z |
| format | Article |
| id | doaj.art-121bbc31eec24459b300c8546850ced3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T23:21:57Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-121bbc31eec24459b300c8546850ced32023-07-16T11:22:34ZengNature PortfolioNature Communications2041-17232023-07-0114111510.1038/s41467-023-39253-3Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failureDanielle Rasooly0Gina M. Peloso1Alexandre C. Pereira2Hesam Dashti3Claudia Giambartolomei4Eleanor Wheeler5Nay Aung6Brian R. Ferolito7Maik Pietzner8Eric H. Farber-Eger9Quinn Stanton Wells10Nicole M. Kosik11Liam Gaziano12Daniel C. Posner13A. Patrícia Bento14Qin Hui15Chang Liu16Krishna Aragam17Zeyuan Wang18Brian Charest19Jennifer E. Huffman20Peter W. F. Wilson21Lawrence S. Phillips22John Whittaker23Patricia B. Munroe24Steffen E. Petersen25Kelly Cho26Andrew R. Leach27María Paula Magariños28John Michael Gaziano29VA Million Veteran ProgramClaudia Langenberg30Yan V. Sun31Jacob Joseph32Juan P. Casas33Division of Aging, Brigham and Women’s Hospital, Harvard Medical SchoolMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemLaboratory of Genetics and Molecular Cardiology, Heart Institute, University of São PauloDivision of Aging, Brigham and Women’s Hospital, Harvard Medical SchoolHealth Data Science Centre, Human TechnopoleMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes HospitalWilliam Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of LondonMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes HospitalVanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical CenterVanderbilt University Med. Ctr., Departments of Medicine (Cardiology), Biomedical Informatics, and PharmacologyMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemDepartment of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome CampusDepartment of Epidemiology, Emory University Rollins School of Public HealthDepartment of Epidemiology, Emory University Rollins School of Public HealthMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemDepartment of Epidemiology, Emory University Rollins School of Public HealthMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemMassachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare SystemAtlanta VA Health Care SystemAtlanta VA Health Care SystemMRC Biostatistics Unit, University of CambridgeWilliam Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse SquareBarts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, West SmithfieldDivision of Aging, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome CampusDepartment of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome CampusDivision of Aging, Brigham and Women’s Hospital, Harvard Medical SchoolMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes HospitalDepartment of Epidemiology, Emory University Rollins School of Public HealthCardiology Section, VA Providence Healthcare SystemDivision of Aging, Brigham and Women’s Hospital, Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-023-39253-3 |
| spellingShingle | 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 Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure Nature Communications |
| title | Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure |
| title_full | Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure |
| title_fullStr | Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure |
| title_full_unstemmed | Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure |
| title_short | Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure |
| title_sort | genome wide association analysis and mendelian randomization proteomics identify drug targets for heart failure |
| url | https://doi.org/10.1038/s41467-023-39253-3 |
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