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

  1. Susanna Lemmelä
  2. Eleanor M 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 E Peters
  11. Veikko Salomaa
  12. Maria Fritsch
  13. Ruth March
  14. Aarno Palotie
  15. Mark Daly
  16. Adam S Butterworth
  17. Mervi Kinnunen
  18. Dirk S Paul
  19. Athena Matakidou

  • Curated by eLife

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    Evaluation Summary:

    This integrated observational and genetic analysis using data from large biobanks comprehensively investigated the role of Growth Differentiation Factor-15 in a wide range of human diseases and will be of interest to cardiometabolic disorder researchers. The study showed that elevated blood GDF15 level in humans is not a causal factor in human cardiometabolic disease but a biomarker of metabolic stress, and BMI is a causal factor for GDF15 blood levels.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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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 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 p FDR = 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.

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  1. Version published to 10.7554/elife.76272 on eLife
  2. eLife

    Evaluation Summary:

    This integrated observational and genetic analysis using data from large biobanks comprehensively investigated the role of Growth Differentiation Factor-15 in a wide range of human diseases and will be of interest to cardiometabolic disorder researchers. The study showed that elevated blood GDF15 level in humans is not a causal factor in human cardiometabolic disease but a biomarker of metabolic stress, and BMI is a causal factor for GDF15 blood levels.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    The authors have used a multipronged approach to elucidate the role of Growth Differentiation Factor- 15 ( GDF-15) in cardiometabolic disease.

    Strengths of methods and results:

    1. The use of well-defined cohorts FINRISK and INTERVAL with high-quality data

    2. The use of different methods to elucidate causation - (1) observational analysis for associations of GDF15 levels with disease outcomes and quantitative biomarkers, (2) GWAS in independent cohorts and (3) mendelian randomisation, reverse mendelian randomization and effect of protein truncating variants on cardiometabolic traits.

    Weaknesses of methods and results:

    1. There are limitations in the plasma GDF15 assays with heterogeneity across different methods at least partly due to epitope binding artefacts due to a common missense variant. The authors performed additional analyses to deal with this.

    2. The truncated variants had no significant effects but given the subjects also had a normal allele this presumably compensated for the truncated allele. A homozygote or compound heterozygote for a non functioning allele could be highly informative but will probably be rare and hard to find. This could be further discussed.

    The authors largely achieved their aims and the results support their conclusions.
    The work is very thorough and comprehensive and is very clearly presented so that after each heading its very clear what has been found and the authors then elaborate on this.
    They show that plasma GDF15 levels are a non specific general marker for risk of multiple cardiometabolic and other diseases, probably an indicator of metabolic stress, analogous to CRP, and not a causative factor.

    Likely impact of the work on the field, and the utility of the methods and data to the community. The well conducted and multi pronged approach is an excellent example of how research into questions of this type can be addressed. The findings provide a good basis for further research into GDF 15.

    Additional significance of the work: This highlights again the critical role of the assay determining the analyte under investigation. If the assay has significant limitations the whole study has inherent limitations. The authors note this and address this as best they can.

  4. eLife

    Reviewer #2 (Public Review):

    The authors attempt to explore the role of growth differentiation factor 15 (GDF-15) in cardio metabolic traits using different designs (i.e. observational analyses, genetic analyses, and Mendelian randomisation). Although the authors found that GDF-15 associated with multiple traits in a cohort design, the authors did not find evidence in favour of causation using Mendelian randomisation. Whilst the use of genetics to verify observational results should be commended and the conclusion is largely supported by the analyses presented, there remains some limitations in this study.

    Strengths:

    The use of both observational analyses and genetic analyses is a powerful approach to ascertain the causal role of GDF-15 in cardio-metabolic traits.

    The use of different cohorts to obtain genetic predictors of GDF-15, and hence improve the statistical power of the Mendelian randomisation design. Based on genetic analyses, intervening on GDF-15 would not impact on cardio-metabolic traits although there was evidence of reverse causation for some traits such as body mass index.

    Limitations:

    Whilst the use of Mendelian randomisation design may circumvent issues with confounding in observational studies, there was a lack of certain analyses which may improve robustness of findings, as well as concerns over the instruments which appeared to be correlated.

    Nevertheless, the use of different approaches presented in this paper would be a good example of using triangulation of evidence to assess the causal role of potential markers in cardio metabolic traits, which has implications for targets of interventions.

  5. eLife

    Reviewer #3 (Public Review):

    GDF15 has been shown to be upregulated in response to cellular stress and cancer. Elevation of Gdf15 is observed in animal models of obesity and genetic overexpression of Gdf15 showed beneficial effects against obesity. Higher GDF15 levels have also been associated with all-cause mortality in humans. This study conducted a systematic and extensive phenotypic and genotypic analysis of GDF15 with cardiometabolic traits and diseases, and to ascertain the causal relationship between GDF15 levels and cardiometabolic traits using Mendelian randomization and protein-truncating variant analysis.

    The strength of this study is the utilization of three large biobanks to dissect the causality of upregulated GDF15 and its association with cardiometabolic diseases, the relationship of GDF15 levels with commonly analyzed blood biomarkers, and GWAS variants with GDF15 levels. The other strength is that the authors performed rigor analysis by taking into consideration the different methods of measuring GDF15 levels in different cohorts and utilizing protein truncation variants as a valid approach to determine the function of GDF15. The presentation of their findings is very good, for example, the forest plots of Cox proportional hazard for independent predictors of targeted outcomes gave readers a clear picture for the GDF15 contributions.

    The authors' conclusion is justified based on the comprehensive analysis performed. This is the first study that utilizes the largest sample size of data and the comprehensive genetic, GDF15 levels and potential causality evaluation.

  6. Version published to 10.1101/2021.12.15.21267719v1 on medRxiv