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

doi:10.1038/s41467-023-39253-3

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

Nat Commun. 2023 Jul 10;14(1):3826. doi: 10.1038/s41467-023-39253-3.

Authors

Danielle Rasooly^#^{1

2}, Gina M Peloso^#^{3

4}, Alexandre C Pereira^{5

6}, Hesam Dashti^{7

8}, Claudia Giambartolomei^{9

10}, Eleanor Wheeler¹¹, Nay Aung^{12

13}, Brian R Ferolito³, Maik Pietzner^{11

14

15}, Eric H Farber-Eger¹⁶, Quinn Stanton Wells¹⁷, Nicole M Kosik³, Liam Gaziano^{3

18}, Daniel C Posner³, A Patrícia Bento¹⁹, Qin Hui^{20

21}, Chang Liu²⁰, Krishna Aragam^{3

8

22}, Zeyuan Wang²⁰, Brian Charest³, Jennifer E Huffman³, Peter W F Wilson^{21

23}, Lawrence S Phillips^{21

24}, John Whittaker²⁵, Patricia B Munroe^{26

27}, Steffen E Petersen^{13

28}, Kelly Cho^{7

3}, Andrew R Leach¹⁹, María Paula Magariños¹⁹, John Michael Gaziano^{7

3}; VA Million Veteran Program; Claudia Langenberg^{11

14

15}, Yan V Sun^{20

21

29}, Jacob Joseph^{30

31}, Juan P Casas^{7

3}

Affiliations

¹ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02130, USA. drasooly@bwh.harvard.edu.
² Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, 150. S. Huntington Ave, Boston, MA, 02130, USA. drasooly@bwh.harvard.edu.
³ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, 150. S. Huntington Ave, Boston, MA, 02130, USA.
⁴ Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Ave Crosstown Centre, Boston, MA, 02118, USA.
⁵ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo, Av Dr Eneas de Carvalho Aguiar 54, São Paulo, 5403000, Brazil.
⁶ Genetics Department, Harvard Medical School, Harvard University, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.
⁷ Division of Aging, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02130, USA.
⁸ Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA, 02142, USA.
⁹ Health Data Science Centre, Human Technopole, V.le Rita Levi-Montalcini, 1, Milan, 20157, Italy.
¹⁰ Central RNA Lab, Non-coding RNAs and RNA-based Therapeutics, Istituto Italiano di Tecnologia, Via Morego 30, 16163, Genova, Italy.
¹¹ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital, IMS, Box 285, Cambridge, CB2 0QQ, UK.
¹² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
¹³ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK.
¹⁴ Computational Medicine, Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Kapelle Ufer 2, Berlin, 10117, Germany.
¹⁵ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
¹⁶ Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Vanderbilt University Med. Ctr., Departments of Medicine (Cardiology), Biomedical Informatics, and Pharmacology, Nashville, TN, USA.
¹⁸ BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN, UK.
¹⁹ Department of Chemical Biology, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, UK.
²⁰ Department of Epidemiology, Emory University Rollins School of Public Health, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA.
²¹ Atlanta VA Health Care System, 1670 Clairmont Road, Decatur, GA, 30033, USA.
²² Massachusetts General Hospital, Boston, MA, 02114, USA.
²³ Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1639 Pierce Dr NE, Atlanta, GA, 30322, USA.
²⁴ Division of Endocrinology, Emory University, 101 Woodruff Circle, WMRB 1027, Atlanta, GA, 30322, USA.
²⁵ MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, United Kingdom.
²⁶ William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
²⁷ National Institute for Health Research, Barts Biomedical Research Centre, Queen Mary University of London, London, UK.
²⁸ William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London, EC1M 68Q, UK.
²⁹ Department of Biomedical Informatics, Emory University School of Medicine, 1639 Pierce Dr NE, Atlanta, GA, 30332, USA.
³⁰ Cardiology Section, VA Providence Healthcare System, 830 Chalkstone Avenue, Providence, RI, 02908, USA. jacob.joseph@va.gov.
³¹ Department of Medicine, Warren Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI, 02903, USA. jacob.joseph@va.gov.

^# Contributed equally.

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.

Publication types

Meta-Analysis
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genome-Wide Association Study*
Heart Failure* / drug therapy
Heart Failure* / genetics
Humans
Mendelian Randomization Analysis
Proteomics

Abstract

Publication types

MeSH terms

Grants and funding