Review Article | Published:


The case of GWAS of obesity: does body weight control play by the rules?

International Journal of Obesityvolume 42pages13951405 (2018) | Download Citation


As yet, genome-wide association studies (GWAS) have not added much to our understanding of the mechanisms of body weight control and of the etiology of obesity. This shortcoming is widely attributed to the complexity of the issues. The appeal of this explanation notwithstanding, we surmise that (i) an oversimplification of the phenotype (namely by the use of crude anthropometric traits) and (ii) a lack of sound concepts of body weight control and, thus, a lack of a clear research focus have impeded better insights most. The idea of searching for polygenetic mechanisms underlying common forms of obesity was born out of the impressive findings made for monogenetic forms of extreme obesity. In the case of common obesity, however, observational studies on normal weight and overweight subjects never provided any strong evidence for a tight internal control of body weight. In addition, empirical studies of weight changes in normal weight and overweight subjects revealed an intra-individual variance that was similar to inter-individual variance suggesting the absence of tight control of body weight. Not least, this lack of coerciveness is reflected by the present obesity epidemic. Finally, data on detailed body composition highlight that body weight is too heterogeneous a phenotype to be controlled as a single entity. In summary GWAS of obesity using crude anthropometric traits have likely been misled by popular heritability estimates that may have been inflated in the first place. To facilitate more robust and useful insights into the mechanisms of internal control of human body weight and, consequently, the genetic basis of obesity, we argue in favor of a broad discussion between scientists from the areas of integrative physiologic and of genomics. This discussion should aim at better conceived studies employing biologically more meaningful phenotypes based on in depth body composition analysis. To advance the scientific community—including the editors of our top journals—needs a re-launch of future GWAS of obesity.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.

  2. 2.

    Papandonatos GD, Pan Q, Pajewski NM, Delahanty LM, Peter I, Erar B, et al. Diabetes Prevention Program and the Look AHEAD Research Groups. Genetic Predisposition to Weight Loss and Regain with Lifestyle Intervention: Analyses from the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials. Diabetes. 2015;64:4312–21.

  3. 3.

    Blundell J, Dulloo AG, Salvador J. Frühbeck G on behalf of the EASO SAB Working Group on BMI. Beyond BMI-phenotyping the obesities. Obes facts. 2014;7:322–8.

  4. 4.

    Müller MJ, Braun W, Enderle J, Bosy-Westphal A. Beyond BMI: conceptual issues related to overweight and obese patients. Obes facts. 2016;9:193–205.

  5. 5.

    Gonzales MC, Correira MITD, Heymsfield SB. A requiem for BMI in the clinical setting. Curr Op Clin Nutr Metab. 2017,

  6. 6.

    Ried JS, Jeff MJ, Chu AY, Bragg-Gresham JL, van Dongen J, Huffman JE. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat Commun. 2016;7:13357.

  7. 7.

    Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S, et al. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 2015;11:e1005378.

  8. 8.

    Winkler TW, Justice AE, Graff M, Barata L, Feitosa MF, Chu S. Correction: The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 2016;12:e1006166.

  9. 9.

    Lu Y, Day FR, Gustafsson S, Buchkovich ML, Na J, Bataille V, Cousminer DJ, et al. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nat Commun. 2016;7:10495.

  10. 10.

    Sung YJ, Pérusse L, Sarzynski MA, Fornage M, Sidney S, Sternfeld B, et al. Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat. Int J Obes. 2016;40:662–74.

  11. 11.

    Fox CS, Liu Y, White CC, Feitosa M, Smith AV, Heard-Costa N, et al. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet. 2012;8:e1002695.

  12. 12.

    Zillikens MC, Demissie S, Hsu YH, Yerges-Armstrong LM, Chou WC, Stolk L, et al. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nat Commun. 2017;8:80

  13. 13.

    Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42:937–48.

  14. 14.

    Livshits G, Malkan L, Moayyeri A, Spector TD, Hammond CI. Association of FTO gene variants with body composition in UK twins. Ann Hum Genet. 2012;76:333–41.

  15. 15.

    Speakman JR. The ‘Fat mass and obesity related’ (FTO) gene: mechanisms of impact on obesity and energy balance. Curr Obes Rep. 2015;4:73–91.

  16. 16.

    C Bouchard, GA Bray (editors), Regulation of body weight, biological and behavioral mechanisms. Dahlem Workshop Reports, Life Sciences Research Report No 57, John Wiley & Sons, Chichester, UK, 1996.

  17. 17.

    Müller MJ, Langemann D, Gehrke I, Later W, Heller M, Glüer CC, et al. Effect of constitution on mass of individual organs and their association with metabolic rate in humans--a detailed view on allometric scaling. PLoS ONE. 2011;6:e22732.

  18. 18.

    Schuna JM Jr, Peterson CM, Thomas DM, Heo M, Hong S, Choi W, Heymsfield SB. Scaling of adult regional body mass and body composition as a whole to height: relevance to body shape and body mass index. Am J Hum Biol. 2015;27:372–9.

  19. 19.

    Bergman RN. A better index of body adiposity. Obesity. 2012;20:1135.

  20. 20.

    Krakauer NY, Krakauer JC. A new body shape index predicts mortality hazard independently of body mass index. PLoS ONE. 2012;7:e39504.

  21. 21.

    Thomas DM, Bredlau K, Bosy-Westphal A, Müller MJ, Shen W, et al. Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model. Obesity. 2013;21:2264–71.

  22. 22.

    Katzmarzyk PT, Bouchard C. Where is the beef? Waist circumference is more highly correlated with BMI and total body fat than with abdominal visceral fat in children. Int J Obes. 2014;38:753–4.

  23. 23.

    Bouchard C. BMI, fat mass, abdominal adiposity and visceral fat: where is the ‘beef’? Int J Obes. 2007;31:1552–3.

  24. 24.

    Bosy-Westphal A, Danielzik S, Geisler C, Onur S, Korth O, Selberg O, et al. Use of height3: waist circumference3 as an index for metabolic risk assessment? Br J Nutr. 2006;95:1212–20.

  25. 25.

    Soileau L, Bautista D, Johnson C, Gao C, Zhang K, Li X, et al. Automated anthropometric phenotyping with novel Kinect-based three-dimensional imaging method: comparison with a reference laser imaging system. Eur J Clin Nutr. 2016;70:475–81.

  26. 26.

    He W, Li Q, Yang M, Jiao J, Ma X, Zhou Y, et al. Lower BMI cutoffs to define overweight and obesity in China. Obesity. 2015;23:684–91.

  27. 27.

    Katzmarzyk PT, Bray GA, Greenway FL, Johnson WD, Newton RL Jr, Ravussin E, et al. Ethnic-specific BMI and waist circumference thresholds. Obesity. 2011;19:1272–8.

  28. 28.

    Schutz Y. Balance. In: Caballero B, Allen L, Prentice A, editors. Encyclopedia of human nutrition, 2nd edn. 2005; Vol. 2, pp. 115–25.

  29. 29.

    Leibel R. Molecular physiology of weight regulation in mice and humans. Int J Obes. 2008;32(Suppl 7):S98–S108.

  30. 30.

    Müller MJ, Enderle J, Bosy-Westphal A. Changes in energy expenditure with weight gain and weight loss in humans. Curr Obes Rep. 2016;5:413–23.

  31. 31.

    Pourhassan M, Bosy-Westphal A, Schautz B, Braun W, Glüer CC, Müller MJ. Impact of body composition during weight change on resting energy expenditure and homeostasis model assessment index in overweight nonsmoking adults. Am J Clin Nutr. 2014;99:779–91.

  32. 32.

    Keys A, Brozek J, Henschel A, Mickelsen O, Taylor HL. The Biology of Human Starvation. Minneapolis: The University of Minnesota Press; 1950.

  33. 33.

    Dulloo AG, Jaquet J. The control of partitioning between protein and fat during human starvation: its internal determinants and biological significance. Br J Nutr. 1999;82:339–56.

  34. 34.

    Hall KD. Modeling metabolic adaptations and energy regulation in ⎕humans. Annu Rev Nutr. 2012;32:35–54.

  35. 35.

    Hopkins M, Blundell JE. Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity. Clin Sci. 2016;130:1615–28.

  36. 36.

    Müller MJ. From BMI to functional body composition. Eur J Clin Nutr. 2013;67:1119–21.

  37. 37.

    Müller MJ, Braun W, Pourhassan M, Geisler C, Bosy-Westphal A. Application of standards and models in body composition analysis. Proc Nutr Soc. 2016;75:181–7.

  38. 38.

    Speakman JR. If body fatness is under physiological regulation, then how come we have an obesity epidemic. Physiology. 2014;29:88–98.

  39. 39.

    Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev. 2017;16:603–34.

  40. 40.

    Hill JO. Can a small-changes approach help to address the obesity epidemic? A report of the joint task force of the American Society of Nutrition, Institute of Food Technologies and International Food Information Council. Am J Clin Nutr. 2009; 477–84.

  41. 41.

    Speakman JR, Levitsky DA, Allison DB, Bray MS, de Castro JM, Clegg DJ, et al. Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity. Dis Model Mech. 2011;4:733–45.

  42. 42.

    Edholm OG, Fletcher JG, Widdowson EM, McChance RA. The energy expenditure and food intake of individual men. Br J Nutr. 1955;9:286–300.

  43. 43.

    Dulloo AG, Jacquet J, Girardier L. Autoregulation of body composition during weight recovery in human: the Minnesota Experiment revisited. Int J Obes. 1996;20:393–405.

  44. 44.

    Dulloo AG, Jacquet J, Girardier L. Poststarvation hyperphagia and body fat over-shooting in humans: a role for feedback signals from lean and fat tissues. Am J Clin Nutr. 1997;65:717–23.

  45. 45.

    Dulloo AG, Jaquet J, Miles-Chan JL, Schutz Y. Passive and active roles of fat-free mass in the control of energy intake and body composition regulation. Eur J Clin Nutr. 2016;71:353–7.

  46. 46.

    Lissner L, Habicht JP, Strupp BJ, Haas JD, Roe DA. Body composition and energy intake: Do overweight women overeat or underreport? Am J Clin Nutr. 1989;49:320–5.

  47. 47.

    Blundell JE, Finlayson G, Gibbons C, Caudwell P, Hopkins M. The biology of appetite control: Do resting metabolic rate and fat-free mass drive energy intake? Physiol Behav. 2015;152(Pt B):473–8.

  48. 48.

    Heymsfield SB, Gonzalez MC, Shen W, Redman L, Thomas D. Weight loss is one-fourth fat free mass: A critical review and critique of this widely cited rule. Obes Rev. 2014;15:310–21.

  49. 49.

    Hall KD, Sacks G, Chandramohan D, Chow CC, Wang YC, Gortmaker SL, Swinburn BA. Quantification of the effect of energy imbalance on body weight. Lancet. 2011;378:826–37.

  50. 50.

    Bosy-Westphal A, Schautz B, Lagerpusch M, Pourhassan M, Braun W, Goele K, et al. Effect of weight loss and regain on adipose tissue distribution, composition of lean mass and resting energy expenditure in young overweight and obese patients. Int J Obes. 2013;37:1371–7.

  51. 51.

    Bouchard C (editor), The genetics of obesity. Boca Raton, USA: CRC Press; 1994.

  52. 52.

    Segal NL, Allison DB. Twins and virtual twins: bases of relative body weight revisited. Int J Obes. 2001;26:437–41.

  53. 53.

    Segal NL, Feng R, McGuire SA, Allison DB, Miller S. Genetic and environmental contributions to body mass index: comparative analysis of monozygotic twins, dizygotic twins and same-age unrelated siblings. Int J Obes. 2009;33:37–41.

  54. 54.

    Bouchard C. Defining the genetic architecture of the predis-position to obesity: a challenging but insurmountable task. Am J Clin Nutr. 2010;91:5–6.

  55. 55.

    Poehlman ET, Depres JP, Marcotte M, Tremblay A, Theriault G, Bouchard C. Genotype-dependency of adaptation of adipose tissue metabolism after short-term overfeeding. Am J Physiol. 1986;250:E480–5.

  56. 56.

    Bouchard C, Tremblay A, Depres JP, Nadeau A, Lupien PJ, Theriault G, et al. The response to long-term overfeeding in identical twins. New Engl J Med. 1990;322:1477–82.

  57. 57.

    Bouchard C, Tremblay A, Depres JP, Theriault G, Nadeau A, Lupien PJ, Moorjani S. The response to exercise with constant energy intake in identical twins. Obes Res. 1994;2:400–10.

  58. 58.

    Poehlman ET, Tremblay A, Marcotte M, Perusse L, Theriault G, Bouchard C. Heredity and changes in body composition and adipose tissue metabolism after short-term exercise-training. Eur J Appl Physiol. 1987;56:398–402.

  59. 59.

    Müller MJ, Enderle J, Pourhassan M, Braun W, Eggeling B, Lagerpusch M, et al. Metabolic adaptation to caloric restriction and subsequent refeeding: the Minnesota Starvation Experiment revisited. Am J Clin Nutr. 2015;102:807–19.

  60. 60.

    Mistry SK, Puthussery S. Risk factors of overweight and obesity in childhood and adolescence in South Asian countries: a systematic review of evidence. Public Health. 2015;129:200–9.

  61. 61.

    Plachta-Danielzik S, Landsberg B, Johannsen M, Lange D, Müller MJ. Determinants of the prevalence and incidence of overweight in children and adolescence. Public Health Nutr. 2010;13:1870–81.

  62. 62.

    Müller MJ, Bosy-Westphal A, Heymsfield SB. Is there evidence for a set point that regulates human body weight? F1000 Med Rep. 2010;2:59

  63. 63.

    Swinburn BA, Jolley D, Kremer PJ, Salbe AD, Ravussin E. Estimating the effects of energy imbalance on changes in body weight in children. Am J Clin Nutr. 2006;83:859–63.

  64. 64.

    Müller MJ, Geisler C. From the past to future: From energy expenditure to energy intake to energy expenditure. Eur J Clin Nutr. 2016;71:678

  65. 65.

    Bray MS, Loos RJ, McCaffery JM, Ling C, Franks PW, Weinstock GM, et al. Conference Working Group. NIH working group report-using genomic information to guide weight management: From universal to precision treatment. Obesity. 2016;24:14–22.

  66. 66.

    Ronn T, Volkov P, Davegardth, Dayeh T, Hall E, Olsson AH, Nilsson E, Tornberg A, Dekker Nitert M, Eriksson KF, Jones HA, Groop L, Ling C. A six months exercise intervention influences genome-wide DNA-methylation pattern in human adipose tissue. PLoS Genet. 2013;9:e1003572.

  67. 67.

    Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541:81–86.

  68. 68.

    Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with complications of obesity. Proc Nat Acad Sci. 2009;106:15430–5.

  69. 69.

    Haufe S, Engeli S, Budziarek P, Utz W, Schulz-Menger J, Hermsdorf M, et al. Cardiorespiratory fitness and insulin sensitivity in overweight or obese subjects may be linked through intrahepatic lipid content. Diabetes. 2010;59:1640–7.

  70. 70.

    Haufe S, Engeli S, Kast P, Böhnke J, Utz W, Haas V, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53:1504–14.

  71. 71.

    Bosy-Westphal A, Geisler C, Onur S, Korth O, Selberg O, Schrezenmeir J, Müller MJ. Value of body fat assessment vs anthropometric obesity indices in the assessment of metablic risk factors. Int J Obes. 2006;30:475–83.

  72. 72.

    Sokal A. Beyond the Hoax. Science, philosophy and culture.. Oxford, UK: Oxford University Press; 2008.

  73. 73.

    Foresight. Tackling Obesities: Future Choices—Obesity System Atlas. In: Vandenbroeck P, Goossens J, Marshall C, editors. UK: Government Office for Science; 2007.

Download references


The study was funded by a grant of the German Ministry of Education and Research (BMBF 0315681), BMBF Competence Network Obesity (CNO), and the German Research Foundation (DFG Bo 3296/1-1 and DFG Mü 714/ 8-3).

Author information


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

    • Manfred J. Müller
    • , Corinna Geisler
    • , Anja Bosy-Westphal
    •  & Janna Enderle
  2. Institute of Psychological Sciences, Faculty of Medicine and Health, University of Leeds, Leeds, UK

    • John Blundell
  3. Department of Medicine, Division of Physiology, University of Fribourg, Fribourg, Switzerland

    • Abdul Dulloo
  4. Institute de Physiology, University Lausanne, Lausanne, Switzerland

    • Yves Schutz
  5. Institut für Medizinische Informatik und Statistik, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    • Michael Krawczak
  6. Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Germany

    • Steven B. Heymsfield


  1. Search for Manfred J. Müller in:

  2. Search for Corinna Geisler in:

  3. Search for John Blundell in:

  4. Search for Abdul Dulloo in:

  5. Search for Yves Schutz in:

  6. Search for Michael Krawczak in:

  7. Search for Anja Bosy-Westphal in:

  8. Search for Janna Enderle in:

  9. Search for Steven B. Heymsfield in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Manfred J. Müller.

About this article

Publication history





Issue Date


Further reading