Mapping the aetiological foundations of the heart failure spectrum using human genetics

Heart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, including IGFBP7 as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment. ### Competing Interest Statement A.Henry and R.T.L. received funding from Pfizer. J.S.W. have acted as a consultant for MyoKardia, Pfizer, Foresite Labs, and Health Lumen, and received institutional support from Bristol-Myers Squibb and Pfizer. S.d.D. was supported through grants from AstraZeneca, Roche Molecular Science/DalCor. J.R.K. declares stock ownership in AbbVie, Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck, Pfizer. N.A.M. received speaking honoraria from Amgen and is involved in clinical trials with Ionis, Amgen, Pfizer, and Novartis. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. C.T.R. received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, and received institutional research grants from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. M.S.S. received significant research grant support from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Roche Diagnostics, and Takeda; and has received consulting fees from Alnylam, AstraZeneca, Bristol-Myers Squibb, CVS, Amgen. A.A.V. received consultancy fees and/or research support from AnaCardia, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Corteria, Cytokinetics, EliLilly, Moderna, Novartis, NovoNordisk, Roche Diagnostics. M-P.D. declares holding equity in Dalcor Pharmaceuticals, unrelated to this work. Members of the TIMI Study Group (ENGAGE, FOURIER, PEGASUS, SAVOR, SOLID) have received institutional research grant support through Brigham and Womens Hospital from: Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Zora Biosciences, Caremark, Dyrnamix, Esperon, IFM Pharmaceuticals, MyoKardia. The authors who are affiliated with deCODE genetics/Amgen Inc. and the authors affiliated with Pfizer Inc. declare competing financial interests as employees. The remaining authors declare no competing interests. ### Funding Statement A.Henry was supported by the BHF Cardiovascular Biomedicine PhD studentship (FS/18/65/34186). R.T.L. and A.Henry are partly supported by a Pfizer Innovative Targets Exploration Network Grant. The project was additionally supported by BigData@Heart Consortium funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074, the UCL British Heart Foundation Accelerator (AA/18/6/34223), National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR203328), and Health Data Research UK (MR/S003754/1). Analyses using the UK Biobank resource presented in this work were conducted under Application Numbers 9922, 15422, 12113, and 47602.  The authors thank all research participants included in the presented work. The views expressed in this work are those of the authors and not necessarily those of the funders. Additional study-level acknowledgements are provided in Supplementary Table 18. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of University College London gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes