Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Finnish Institute for Health and Welfare, Helsinki, Finland
Rachel MY Ong
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Tibor Kempf
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
Kai C Wollert
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
Stefan Blankenberg
Clinic of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Population Health Research Department, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Luebeck, Hamburg, Germany
Tanja Zeller
Clinic of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Luebeck, Hamburg, Germany; University Center of Cardiovascular Science, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Department of Immunology and Inflammation, Imperial College London, London, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
Veikko Salomaa
Finnish Institute for Health and Welfare, Helsinki, Finland
Maria Fritsch
Bioscience Renal, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
Ruth March
Precision Medicine, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
Aarno Palotie
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, United States; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
Mark Daly
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, United States; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
Adam S Butterworth
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
Mervi Kinnunen
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Centre for Genomics Research, AstraZeneca, Cambridge, United Kingdom; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
Athena Matakidou
Centre for Genomics Research, AstraZeneca, Cambridge, United Kingdom
Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.