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Genetics and Epigenetics

Thanks for opening an overdue discussion on GWAS of BMI: a reply to Prof. Speakman et al.

International Journal of Obesity volume 43, pages 217–218 (2019)Cite this article

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We are grateful to Prof. Speakman et al. [1] for their response to our recent reflections upon the meaningfulness of GWAS of BMI [2]. Making a strong case for the latter, however, the authors refrain from addressing the great need to expand obesity research strategies beyond GWAS. In our view, there are indeed many unresolved some issues worth further discussion.

  1. 1.

    If GWAS are mainly for generating hypotheses [1], then they have done an excellent job—but enough should be enough. The main benefit of ever more GWAS on ever larger samples is an improved chance to detect smaller and smaller effects. In consequence, future GWAS of BMI likely yield signals that end up at the very end of researchers’ work lists (if at all).

  2. 2.

    Since obesity is also (or even predominantly) an environmental condition, GWAS of BMI are at a high risk of confounding by environmental factors, particularly in large and heterogeneous populations. Therefore, the power gain by increasing sample sizes may well be outdone by a concomitant inflation of spurious results.

  3. 3.

    There is yet no consensus framework for body weight homeostasis in humans [3]. Biological control appears likely during caloric restriction and weight loss [4, 5], but is weak or non-existent during overfeeding and weight gain. Therefore, GWAS of BMI may well target the wrong end by looking for potential brakemen, rather than drivers, of the obesity pandemic.

  4. 4.

    Speakman et al. [1] advocate use of the BMI because it allegedly surpasses more sophisticated phenotypes by its ease of measurement and access. However, the arguments put forward against alternative phenotyping are all about cost efficiency, which renders them unacceptably opportunistic in our view. Moreover, even replacing single by multiple measurements of BMI would already represent a conceptual leap forward.

  5. 5.

    Since population-wide obesity is largely due to external drivers this would override the biological control of body weight in response to overfeeding, if it were to exist [6, 7]. Hence, equal attention should be paid in the future to researching actionable root causes of obesity (including education, socio-economic determinants of health) and the need of developing participatory forms changing our social arrangements.

If GWAS are mainly for generating hypotheses [1], then they have done an excellent job—but enough should be enough. The main benefit of ever more GWAS on ever larger samples is an improved chance to detect smaller and smaller effects. In consequence, future GWAS of BMI likely yield signals that end up at the very end of researchers’ work lists (if at all).

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References

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Authors and Affiliations

  1. Institut für Humanernährung und Lebensmittelkunde, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Manfred J. Müller, Corinna Geisler & Anja Bosy-Westphal

  2. Institut für Medizinische Informatik und Statistik, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Michael Krawczak

  3. Pennington Biomedical Research Center, Baton Rouge, LA, USA

    Steven Heymsfield

  4. Institute de Physiology, University of Lausanne, Lausanne, Switzerland

    Yves Schutz

  5. Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland

    Abdul Dulloo

  6. Institute of Psychological Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK

    John Blundell

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  1. Manfred J. Müller
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Correspondence to Manfred J. Müller.

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Müller, M.J., Krawczak, M., Heymsfield, S. et al. Thanks for opening an overdue discussion on GWAS of BMI: a reply to Prof. Speakman et al.. Int J Obes 43, 217–218 (2019). https://doi.org/10.1038/s41366-018-0264-1

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