Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

Autoři: Michael Wainberg aff001;  Anubha Mahajan aff002;  Anshul Kundaje aff001;  Mark I. McCarthy aff002;  Erik Ingelsson aff006;  Nasa Sinnott-Armstrong aff004;  Manuel A. Rivas aff010
Působiště autorů: Department of Computer Science, Stanford University, Stanford, California, United States of America aff001;  Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom aff002;  Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom aff003;  Department of Genetics, Stanford University, Stanford, California, United States of America aff004;  NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom aff005;  Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden aff006;  Science for Life Laboratory, Uppsala University, Uppsala, Sweden aff007;  Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff008;  Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America aff009;  Department of Biomedical Data Science, Stanford University, Stanford, California, United States of America aff010
Vyšlo v časopise: Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study. PLoS Med 16(12): e32767. doi:10.1371/journal.pmed.1002982
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002982



Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk.

Methods and findings

We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12–1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13–1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual’s entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life.


In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.

Klíčová slova:

Body Mass Index – Genome-wide association studies – Medical risk factors – Obesity – Public and occupational health – Weight loss


1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068–83. doi: 10.1016/S0140-6736(13)62154-6 24315620

2. Ahmad LA, Crandall JP. Type 2 diabetes prevention: a review. Clin Diabetes. 2010;28:53–9.

3. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med. 2010;363:2339–50. doi: 10.1056/NEJMra0906948 21142536

4. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782–7. doi: 10.1038/414782a 11742409

5. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403. doi: 10.1056/NEJMoa012512 11832527

6. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50. doi: 10.1056/NEJM200105033441801 11333990

7. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537–44. doi: 10.2337/diacare.20.4.537 9096977

8. Can B, Can B. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med. 2018;378:2537.

9. Jackson SL, Long Q, Rhee MK, Olson DE, Tomolo AM, Cunningham SA, et al. Weight loss and incidence of diabetes with the Veterans Health Administration MOVE! lifestyle change programme: an observational study. Lancet Diabetes Endocrinol. 2015;3:173–80. doi: 10.1016/S2213-8587(14)70267-0 25652129

10. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27. doi: 10.1056/NEJMoa1614362 28604169

11. Ma Q, Lu AYH. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63:437–59. doi: 10.1124/pr.110.003533 21436344

12. Zhou K, Yee SW, Seiser EL, van Leeuwen N, Tavendale R, Bennett AJ, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet. 2016;48:1055–9. doi: 10.1038/ng.3632 27500523

13. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375:2349–58. doi: 10.1056/NEJMoa1605086 27959714

14. Scott RA, Scott LJ, Mägi R, Marullo L, Gaulton KJ, Kaakinen M, et al. An expanded genome-wide association study of type 2 diabetes in Europeans. Diabetes. 2017;66:2888–902. doi: 10.2337/db16-1253 28566273

15. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779. doi: 10.1371/journal.pmed.1001779 25826379

16. Eastwood SV, Mathur R, Atkinson M, Brophy S, Sudlow C, Flaig R, et al. Algorithms for the capture and adjudication of prevalent and incident diabetes in UK Biobank. PLoS ONE. 2016;11:e0162388. doi: 10.1371/journal.pone.0162388 27631769

17. American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes–2018. Diabetes Care. 2018;41:S13–27. doi: 10.2337/dc18-S002 29222373

18. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. Genome-wide genetic data on ~500,000 UK Biobank participants. bioRxiv. 2017 Jul 20. doi: 10.1101/166298

19. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9. doi: 10.1038/ng1847 16862161

20. Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50:1505–13. doi: 10.1038/s41588-018-0241-6 30297969

21. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53. doi: 10.1038/nature08494 19812666

22. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–25. doi: 10.1093/ije/dyv080 26050253

23. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA. 2017;318:1925–6. doi: 10.1001/jama.2017.17219 29164242

24. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. doi: 10.1086/519795 17701901

25. Burgess S, Davies NM, Thompson SG. Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol. 2016;40:597–608. doi: 10.1002/gepi.21998 27625185

26. 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. doi: 10.1038/nature14177 25673413

27. Tyrrell J, Jones SE, Beaumont R, Astley CM, Lovell R, Yaghootkar H, et al. Height, body mass index, and socioeconomic status: Mendelian randomisation study in UK Biobank. BMJ. 2016;352:i582. doi: 10.1136/bmj.i582 26956984

28. Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum Mol Genet. 2018;27:3641–9. doi: 10.1093/hmg/ddy271 30124842

29. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case-control association studies. Nat Protoc. 2010;5:1564–73. doi: 10.1038/nprot.2010.116 21085122

30. Canela-Xandri O, Rawlik K, Tenesa A. An atlas of genetic associations in UK Biobank. bioRxiv. 2017 Aug 18. doi: 10.1101/176834

31. Staley JR, Burgess S. Semiparametric methods for estimation of a nonlinear exposure-outcome relationship using instrumental variables with application to Mendelian randomization. Genet Epidemiol. 2017;41:341–52. doi: 10.1002/gepi.22041 28317167

32. Cole SR, Platt RW, Schisterman EF, Chu H, Westreich D, Richardson D, et al. Illustrating bias due to conditioning on a collider. Int J Epidemiol. 2010;39:417–20. doi: 10.1093/ije/dyp334 19926667

33. Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc. 1979;74:829–36.

34. Gatineau M, Hancock C, Holman N, Outhwaite H, Oldridge L, Christie A, et al. Adult obesity and type 2 diabetes. London: Public Health England; 2014 [cited 2019 Nov 1]. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/338934/Adult_obesity_and_type_2_diabetes_.pdf.

35. InterAct Consortium, Scott RA, Langenberg C, Sharp SJ, Franks PW, Rolandsson O, et al. The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study. Diabetologia. 2013;56:60–9. doi: 10.1007/s00125-012-2715-x 23052052

36. Basto-Abreu A, Barrientos-Gutiérrez T, Zepeda-Tello R, Camacho V, Gimeno Ruiz de Porras D, Hernández-Ávila M. The relationship of socioeconomic status with body mass index depends on the socioeconomic measure used. Obesity. 2018;26:176–84. doi: 10.1002/oby.22042 29152913

37. Rabi DM, Edwards AL, Southern DA, Svenson LW, Sargious PM, Norton P, et al. Association of socio-economic status with diabetes prevalence and utilization of diabetes care services. BMC Health Serv Res. 2006;6:124. doi: 10.1186/1472-6963-6-124 17018153

38. Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol. 2006;163:397–403. doi: 10.1093/aje/kwj062 16410347

39. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet. 2012;380:572–80. doi: 10.1016/S0140-6736(12)60312-2 22607825

40. Emdin CA, Khera AV, Natarajan P, Klarin D, Zekavat SM, Hsiao AJ, et al. Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA. 2017;317:626–34. doi: 10.1001/jama.2016.21042 28196256

41. Lyall DM, Celis-Morales C, Ward J, Iliodromiti S, Anderson JJ, Gill JMR, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. 2017;2:882–9. doi: 10.1001/jamacardio.2016.5804 28678979

42. Carreras-Torres R, Johansson M, Haycock PC, Relton CL, Davey Smith G, Brennan P, et al. Role of obesity in smoking behaviour: Mendelian randomisation study in UK Biobank. BMJ. 2018;361:k1767. doi: 10.1136/bmj.k1767 29769355

43. Mountjoy E, Davies NM, Plotnikov D, Smith GD, Rodriguez S, Williams CE, et al. Education and myopia: assessing the direction of causality by Mendelian randomisation. BMJ. 2018;361:k2022. doi: 10.1136/bmj.k2022 29875094

44. Corbin LJ, Richmond RC, Wade KH, Burgess S, Bowden J, Smith GD, et al. BMI as a modifiable risk factor for type 2 diabetes: refining and understanding causal estimates using Mendelian randomization. Diabetes. 2016;65:3002–7. doi: 10.2337/db16-0418 27402723

45. Zhu Z, Zheng Z, Zhang F, Wu Y, Trzaskowski M, Maier R, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat Commun. 2018;9:224. doi: 10.1038/s41467-017-02317-2 29335400

46. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:1690–1. doi: 10.1001/jama.280.19.1690 9832001

47. Lemstra M, Bird Y, Nwankwo C, Rogers M, Moraros J. Weight loss intervention adherence and factors promoting adherence: a meta-analysis. Patient Prefer Adherence. 2016;10:1547–59. doi: 10.2147/PPA.S103649 27574404

48. 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.

49. InterAct Consortium, Langenberg C, Sharp SJ, Schulze MB, Rolandsson O, Overvad K, et al. Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study. PLoS Med. 2012;9:e1001230. doi: 10.1371/journal.pmed.1001230 22679397

50. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33:30–42. doi: 10.1093/ije/dyh132 15075143

51. Gkatzionis A, Burgess S. Contextualizing selection bias in Mendelian randomization: how bad is it likely to be? arXiv: 1803.03987v1. 2018 Mar 11.

52. Swanson SA, Tiemeier H, Ikram MA, Hernán MA. Nature as a trialist?: deconstructing the analogy between Mendelian randomization and randomized trials. Epidemiology. 2017;28:653–9. doi: 10.1097/EDE.0000000000000699 28590373

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