Integrated analyses of growth differentiation Factor-15 concentration and cardiometabolic diseases in humans

  1. Susanna Lemmelä  Is a corresponding author
  2. Eleanor May Wigmore  Is a corresponding author
  3. Christian Benner
  4. Aki S Havulinna
  5. Rachel MY Ong
  6. Tibor Kempf
  7. Kai C Wollert
  8. Stefan Blankenberg
  9. Tanja Zeller
  10. James Edward Peters
  11. Veikko Salomaa
  12. Maria Fritsch
  13. Ruth March
  14. Aarno Palotie
  15. Mark Daly
  16. Adam Butterworth
  17. Mervi Kinnunen
  18. Dirk S Paul
  19. Athena Matakidou
  1. University of Helsinki, Finland
  2. AstraZeneca, United Kingdom
  3. University of Cambridge, United Kingdom
  4. Hannover Medical School, Germany
  5. University Medical Center Hamburg-Eppendorf, Germany
  6. Imperial College London, United Kingdom
  7. National Institute of Health and Family Welfare, Finland
  8. AstraZeneca, Sweden

Abstract

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 6,610 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 3 different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant rs1058587 in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine-mapping identified 4 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 do not support a role for elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.

Data availability

Participant-level genotype and phenotype data from UK Biobank are available by application: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.Participant-level genotype and phenotype data (as part of the FinnGen consortium) are available by application: https://www.finngen.fi/en/access_results.INTERVAL-SomaScan participant-level genotype and protein data, and full summary association results from the genetic analysis are available through the European Genotype Archive (accession number EGA00001002555). Summary association results are also publically available at http://www.phpc.cam.ac.uk/ceu/proteins/, through PhenoScanner (http://www.phenoscanner.medschl.cam.ac.uk) and from the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics).INTERVAL-Olink summary association results are publically available at http://www.phpc.cam.ac.uk/ceu/proteins/.

The following previously published data sets were used

Article and author information

Author details

  1. Susanna Lemmelä

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    For correspondence
    susanna.lemmela@helsinki.fi
    Competing interests
    No competing interests declared.
  2. Eleanor May Wigmore

    Centre for Genomics Research, AstraZeneca, Cambridge, United Kingdom
    For correspondence
    eleanor.wigmore@astrazeneca.com
    Competing interests
    Eleanor May Wigmore, is an employee of AstraZeneca.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0864-9990
  3. Christian Benner

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  4. Aki S Havulinna

    Institute of Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4787-8959
  5. Rachel MY Ong

    British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    Rachel MY Ong, is currently an employee of GlaxoSmithKline (although was not when this work was carried out).
  6. Tibor Kempf

    Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  7. Kai C Wollert

    Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  8. Stefan Blankenberg

    Clinic for General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    No competing interests declared.
  9. Tanja Zeller

    Clinic for General and Interventional Cardiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    No competing interests declared.
  10. James Edward Peters

    Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9415-3440
  11. Veikko Salomaa

    National Institute of Health and Family Welfare, Helsinki, Finland
    Competing interests
    No competing interests declared.
  12. Maria Fritsch

    esearch and Early Development Cardiovascular, Renal and Metabolism, AstraZeneca, Gothenburg, Sweden
    Competing interests
    Maria Fritsch, MF is an employee of AstraZeneca.
  13. Ruth March

    Precision Medicine, AstraZeneca, Cambridge, United Kingdom
    Competing interests
    Ruth March, RM is an employee of AstraZeneca.
  14. Aarno Palotie

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  15. Mark Daly

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  16. Adam Butterworth

    British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  17. Mervi Kinnunen

    Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
    Competing interests
    No competing interests declared.
  18. Dirk S Paul

    Centre for Genomics Research, AstraZeneca, Cambridge, United Kingdom
    Competing interests
    Dirk S Paul, is an employee of AstraZeneca.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8230-0116
  19. Athena Matakidou

    Centre for Genomics Research, AstraZeneca, Cambridge, United Kingdom
    Competing interests
    Athena Matakidou, is an employee of AstraZeneca.

Funding

NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)

  • Rachel MY Ong

Sydäntutkimussäätiö

  • Veikko Salomaa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: FINRISK study was approved by the Ethics Committee of Helsinki and Uusimaa Hospital District.Informed consent was obtained from all participants and the INTERVAL study was approved by the National Research Ethics Service (11/EE/0538).All study participants provided informed consent and the UK Biobank has approval from the North-West Multi-centre Research Ethics Committee (MREC; 11/NW/0382).

Reviewing Editor

  1. Edward D Janus, University of Melbourne, Australia

Publication history

  1. Received: December 10, 2021
  2. Accepted: August 1, 2022
  3. Accepted Manuscript published: August 2, 2022 (version 1)

Copyright

© 2022, Lemmelä et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Susanna Lemmelä
  2. Eleanor May Wigmore
  3. Christian Benner
  4. Aki S Havulinna
  5. Rachel MY Ong
  6. Tibor Kempf
  7. Kai C Wollert
  8. Stefan Blankenberg
  9. Tanja Zeller
  10. James Edward Peters
  11. Veikko Salomaa
  12. Maria Fritsch
  13. Ruth March
  14. Aarno Palotie
  15. Mark Daly
  16. Adam Butterworth
  17. Mervi Kinnunen
  18. Dirk S Paul
  19. Athena Matakidou
(2022)
Integrated analyses of growth differentiation Factor-15 concentration and cardiometabolic diseases in humans
eLife 11:e76272.
https://doi.org/10.7554/eLife.76272

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