Correspondence | Published:

Genetics and Epigenetics

GWAS for BMI: a treasure trove of fundamental insights into the genetic basis of obesity

International Journal of Obesityvolume 42pages15241531 (2018) | Download Citation


Muller et al. [1] have provided a strong critique of the Genome-Wide Association Studies (GWAS) of body-mass index (BMI), arguing that the GWAS approach for the study of BMI is flawed, and has provided us with few biological insights. They suggest that what is needed instead is a new start, involving GWAS for more complex energy balance related traits. In this invited counter-point, we highlight the substantial advances that have occurred in the obesity field, directly stimulated by the GWAS of BMI. We agree that GWAS for BMI is not perfect, but consider that the best route forward for additional discoveries will likely be to expand the search for common and rare variants linked to BMI and other easily obtained measures of obesity, rather than attempting to perform new, much smaller GWAS for energy balance traits that are complex and expensive to measure. For GWAS in general, we emphasise that the power from increasing the sample size of a crude but easily measured phenotype outweighs the benefits of better phenotyping.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Müller MJ, Geisler C, Blundell J, Dulloo A, Schutz Y, Krawczak M, et al. The case of GWAS of obesity: Does body weight control play by the rules? Int J Obesity. 2018.

  2. 2.

    Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443:289–95.

  3. 3.

    Barsh GS, Farooqi IS, O’Rahilly S. Genetics of body-weight regulation. Nature. 2000;404:644–51.

  4. 4.

    Zhang YY, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homolog. Nature. 1994;372:425–32.

  5. 5.

    Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse Ob protein—evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–9.

  6. 6.

    Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–70. Epub 1998/10/31

  7. 7.

    Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Ser B-Bio. 1953;140:578–92.

  8. 8.

    Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Morgan PJ, et al. Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J Neuroendocrinol. 1996;8:733–5.

  9. 9.

    Ahima RS, Prabakaran D, Mantzoros C, Qu DQ, Lowell B, MaratosFlier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250–2.

  10. 10.

    Boston BA, Blaydon KM, Varnerin J, Cone RD. Independent and additive effects of central POMC and leptin pathways on murine obesity. Science. 1997;278:1641–4.

  11. 11.

    Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999;23:775–86.

  12. 12.

    Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999;24:155–63.

  13. 13.

    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908–13.

  14. 14.

    Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3-36. New Engl J Med. 2003;349:941–8.

  15. 15.

    Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci USA. 1998;95:741–6.

  16. 16.

    Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661–71.

  17. 17.

    Mercer JG, Speakman JR. Hypothalamic neuropeptide mechanisms for regulating energy balance: from rodent models to human obesity. Neurosci Biobehav R. 2001;25:101–16.

  18. 18.

    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–8.

  19. 19.

    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401. Epub 1998/04/16

  20. 20.

    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New Engl J Med. 1999;341:879–84.

  21. 21.

    Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, et al. Congenital leptin deficiency due to homozygosity for the Delta 133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocr Metab. 2004;89:4821–6.

  22. 22.

    Jackson RS, Creemers JWM, Ohagi S, RaffinSanson ML, Sanders L, Montague CT, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16:303–6.

  23. 23.

    Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155–7.

  24. 24.

    Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20:113–4.

  25. 25.

    Yeo GSH, Farooqi IS, Aminian S, Halsall DJ, Stanhope RC, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20:111–2.

  26. 26.

    Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocr Metab. 1999;84:1483–6.

  27. 27.

    Clement K. Monogenic forms of obesity: from mice to human. Ann Endocrinol-Paris. 2000;61:39–49.

  28. 28.

    Farooqi IS, O’Rahilly S. Monogenic obesity in humans. Annu Rev Med. 2005;56:443.

  29. 29.

    Friedman JM. Obesity in the new millennium. Nature. 2000;404:632–4.

  30. 30.

    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–94.

  31. 31.

    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.

  32. 32.

    Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CNA. An obesity-associated FTO gene variant and increased energy intake in children. New Engl J Med. 2008;359:2558–66.

  33. 33.

    Speakman JR. Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: the ‘drifty gene’ hypothesis. Int J Obes. 2008;32:1611.

  34. 34.

    Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, et al. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr. 2008;88:971–8.

  35. 35.

    Wardle J, Carnell S, Haworth CMA, Farooqi IS, O’Rahilly S, Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocr Metab. 2008;93:3640–3.

  36. 36.

    Gerken T, Girard CA, Tung YCL, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–72.

  37. 37.

    Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458:894–8. Epub 2009/02/24

  38. 38.

    Cheung MK, Gulati P, O’Rahilly S, Yeo GSH. FTO expression is regulated by availability of essential amino acids. Int J Obes. 2013;37:744–7.

  39. 39.

    Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc Natl Acad Sci USA. 2013;110:2557–62. Epub 2013/01/30

  40. 40.

    Gulati P, Yeo GS. The biology of FTO: from nucleic acid demethylase to amino acid sensor. Diabetologia. 2013;56:2113–21. Epub 2013/07/31

  41. 41.

    Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gomez-Marin C, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014;507:371.

  42. 42.

    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–U53.

  43. 43.

    Speakman JR. Functional analysis of seven genes linked to body mass index and adiposity by genome-wide association studies: a review. Hum Hered. 2013;75:57–79.

  44. 44.

    Goodarzi MO. Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. Lancet Diabetes & Endocrinol. 2018;6:223–36.

  45. 45.

    Lee AWS, Hengstler H, Schwald K, Berriel-Diaz M, Loreth D, Kirsch M, et al. Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype. PLoS ONE. 2012;7:e41537.

  46. 46.

    Rathjen T, Yan X, Kononenko NL, Ku MC, Song K, Ferrarese L, et al. Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1. Nat Neurosci. 2017;20:1096.

  47. 47.

    Yan X, Wang Z, Schmidt V, Gauert A, Willnow TE, Heinig M, et al. Cadm2 regulates body weight and energy homeostasis in mice. Mol Metab. 2018;8:180–8. Epub 2017/12/09

  48. 48.

    Grarup N, Moltke I, Andersen MK, Dalby M, Vitting-Seerup K, Kern T, et al. Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nat Genet. 2018;50:172–4. Epub 2018/01/10

  49. 49.

    Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, et al. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat Genet. 2018;50:175–9. Epub 2018/01/10

  50. 50.

    Siljee JE, Wang Y, Bernard AA, Ersoy BA, Zhang SM, Marley A, et al. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat Genet. 2018;50:180.

  51. 51.

    Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Felix R, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–U401.

  52. 52.

    Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, et al. Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. Nat Genet. 2017;49:1458.

  53. 53.

    Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet. 2017;101:5–22.

  54. 54.

    Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet. 2012;90:7–24.

  55. 55.

    Gibson G. Rare and common variants: twenty arguments. Nat Rev Genet. 2012;13:135–45.

  56. 56.

    Yang J, Zeng J, Goddard ME, Wray NR, Visscher PM. Concepts, estimation and interpretation of SNP-based heritability. Nat Genet. 2017;49:1304–U243.

  57. 57.

    Panagiotou OA, Willer CJ, Hirschhorn JN, Ioannidis JP. The power of meta-analysis in genome-wide association studies. Annu Rev Genom Hum Genet. 2013;14:441–65. Epub 2013/06/04

  58. 58.

    Allison DB, Heshka S, Neale MC, Tishler PV, Heymsfield SB. Genetic, environmental, and phenotypic links between body mass index and blood pressure among women. Am J Med Genet. 1995;55:335–41. Epub 1995/01/30

  59. 59.

    Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC, Hayakawa K. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes. 1996;20:501–6.

  60. 60.

    Dhurandhar EJ, Vazquez AI, Argyropoulos GA, Allison DB. Even modest prediction accuracy of genomic models can have large clinical utility. Front Genet. 2014;5:417.

  61. 61.

    Willer CJ, Speliotes EK, Loos RJF, Li SX, Lindgren CM, Heid IM, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41:25–34.

  62. 62.

    Romero-Corral A, Somers VK, Sierra-Johnson J, Thomas RJ, Collazo-Clavell ML, Korinek J, et al. Accuracy of body mass index in diagnosing obesity in the adult general population. Int J Obes. 2008;32:959–66.

  63. 63.

    Kilpelainen TO, Zillikens MC, Stancakova A, Finucane FM, Ried JS, Langenberg C, et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nat Genet. 2011;43:753–U58.

  64. 64.

    Chu AY, Deng X, Fisher VA, Drong A, Zhang Y, Feitosa MF, et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat Genet. 2017;49:125–30.

  65. 65.

    Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR. Energy balance and its components: implications for body weight regulation. Am J Clin Nutr. 2012;95:989–94.

  66. 66.

    Lin XC, Eaton CB, Manson JE, Liu SM. The genetics of physical activity. Curr Cardiol Rep. 2017;19:119.

  67. 67.

    Benjamin DJ, Cesarini D, van der Loos MJHM, Dawes CT, Koellinger PD, PKE Magnusson, et al. The genetic architecture of economic and political preferences. Proc Natl Acad Sci USA. 2012;109:8026–31.

  68. 68.

    Koenig LB, McGue M, Krueger RF, Bouchard TJ Jr.. Genetic and environmental influences on religiousness: findings for retrospective and current religiousness ratings. J Personal. 2005;73:471–88. Epub 2005/03/05

  69. 69.

    Bouchard C, Tremblay A, Despres 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.

  70. 70.

    Stunkard AJ, Harris JR, Pedersen NL, Mcclearn GE. The body-mass index of twins who have been reared apart. New Engl J Med. 1990;322:1483–7.

  71. 71.

    Elks CE, den Hoed M, Zhao JH, Sharp SJ, Wareham NJ, Loos RJ, et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol. 2012;3:29. Epub 2012/05/31

  72. 72.

    Silventoinen K, Jelenkovic A, Sund R, Yokoyama Y, Hur YM, Cozen W, et al. Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts. Am J Clin Nutr. 2017;106:457–66.

  73. 73.

    Turcot V, Lu YC, Highland HM, Schurmann C, Justice AE, Fine RS, et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2018;50:26.

  74. 74.

    Wang G, Speakman John R. Analysis of positive selection at single nucleotide polymorphisms associated with body mass index does not support the 'thrifty gene' hypothesis. Cell Metab. 2016;24:531–41. Epub 2016/09/27

  75. 75.

    Minster RL, Hawley NL, Su CT, Sun G, Kershaw EE, Cheng H, et al. A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet. 2016;48:1049.

Download references


The authors declare no conflicts of interest. JRS is supported by a Wolfson merit professorship from the UK Royal Society and a grant from the National Science Foundation of China microevolution program (NSFC 91731303). RJFL is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, and R01DK107786). DBA is supported by NIH Grants R25DK099080 and R25HL124208. The opinions are those of the authors and not necessarily the NIH or any other organization.

Author information


  1. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    • J. R. Speakman
  2. Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, Scotland, UK

    • J. R. Speakman
  3. The Charles Bronfman Insititute for Personalized Medicine at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • R. J. F. Loos
  4. Wellcome Trust-MRC Institute of Metabolic Science,Addenbrookes Treatment, Centre University of Cambridge, Cambridge, CB2 OQQ, UK

    • S. O’Rahilly
  5. Division of Endocrinology and Center for Basic and Translational Research, Boston Children’s Hospital, Boston, MA, USA

    • J. N. Hirschhorn
  6. Broad institute, Cambridge, MA, USA

    • J. N. Hirschhorn
  7. School of Public Health, University of Indiana Bloomington, Bloomington, IN, USA

    • D. B. Allison


  1. Search for J. R. Speakman in:

  2. Search for R. J. F. Loos in:

  3. Search for S. O’Rahilly in:

  4. Search for J. N. Hirschhorn in:

  5. Search for D. B. Allison in:

Corresponding author

Correspondence to J. R. Speakman.

About this article

Publication history