Which of the following best describes research findings on the genetics of obesity?

1. Hirschhorn JN. Genome wide association studies -- Illuminating biologic pathways. N. Engl. J. Med. 2009;360(17):1699–1701. [PubMed] [Google Scholar]

2. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, Balkau B, Potoczna N, Horber F, O'Rahilly S, Farooqi IS, Froguel P, Meyre D. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes. 2008;57(9):2511–2518. [PMC free article] [PubMed] [Google Scholar]

3. Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S, Siffert W, Platzer M, Hess C, Gudermann T, Biebermann H, Wichmann HE, Schafer H, Hinney A, Hebebrand J. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am. J. Hum. Genet. 2004;74(3):572–581. [PMC free article] [PubMed] [Google Scholar]

4. Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, Tounian P, Levy-Marchal C, Buzzetti R, Pinelli L, Balkau B, Horber F, Bougneres P, Froguel P, Meyre D. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum. Mol. Genet. 2007;16(15 ):1837–1844. [PubMed] [Google Scholar]

5. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R, Meyre D, Munroe PB, Morris AD, Ness AR, Neville MJ, Nica AC, Ong KK, O'Rahilly S, Owen KR, Palmer CN, Papadakis K, Potter S, Pouta A, Qi L, Randall JC, Rayner NW, Ring SM, Sandhu MS, Scherag A, Sims MA, Song K, Soranzo N, Speliotes EK, Syddall HE, Teichmann SA, Timpson NJ, Tobias JH, Uda M, Vogel CI, Wallace C, Waterworth DM, Weedon MN, Willer CJ, Wraight; Yuan X, Zeggini E, Hirschhorn JN, Strachan DP, Ouwehand WH, Caulfield MJ, Samani NJ, Frayling TM, Vollenweider P, Waeber G, Mooser V, Deloukas P, McCarthy MI, Wareham NJ, Barroso I, Jacobs KB, Chanock SJ, Hayes RB, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Kraft P, Hankinson SE, Hunter DJ, Hu FB, Lyon HN, Voight BF, Ridderstrale M, Groop L, Scheet P, Sanna S, Abecasis GR, Albai G, Nagaraja R, Schlessinger D, Jackson AU, Tuomilehto J, Collins FS, Boehnke M, Mohlke KL. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 2008;40(6):768–775. [PMC free article] [PubMed] [Google Scholar]

6. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8(1):e1000294. [PMC free article] [PubMed] [Google Scholar]

7. Scherag A, Jarick I, Grothe J, Biebermann H, Scherag S, Volckmar AL, Vogel CI, Greene B, Hebebrand J, Hinney A. Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PLoS One. 2010;5(11):e13967. [PMC free article] [PubMed] [Google Scholar]

8. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 2009;41(1):18–24. [PubMed] [Google Scholar]

9. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2009;463(7281):666–670. [PMC free article] [PubMed] [Google Scholar]

10. Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, Bader PI, Hamati A, Reitnauer PJ, Smith R, Stockton DW, Muhle H, Helbig I, Eichler EE, Ballif BC, Rosenfeld J, Tsuchiya KD. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet. Med. 2010;12(10):641–647. [PubMed] [Google Scholar]

11. Ren D, Zhou Y, Morris D, Li M, Li Z, Rui L. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J. Clin. Invest. 2007;117(2):397–406. [PMC free article] [PubMed] [Google Scholar]

12. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Magi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segre AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpelainen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proenca C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grassler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jorgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, Konig IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaloy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimaki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O'Donnell CJ, O'Rahilly S, Ong KK, Oostra B, Pare G, Parker AN, Perola M, Pichler I, Pietilainen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstrale M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tonjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kahonen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Gronberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, Loos RJ. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 2010;42(11):937–948. [PMC free article] [PubMed] [Google Scholar]

13. Church C, Lee S, Bagg EA, McTaggart JS, Deacon R, Gerken T, Lee A, Moir L, Mecinovic J, Quwailid MM, Schofield CJ, Ashcroft FM, Cox RD. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet. 2009;5(8):e1000599. [PMC free article] [PubMed] [Google Scholar]

14. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, Wells S, Bruning JC, Nolan PM, Ashcroft FM, Cox RD. Overexpression of Fto leads to increased food intake and results in obesity. Nat. Genet. 2010;42(12 ):1086–1092. [PMC free article] [PubMed] [Google Scholar]

15. Meyre D, Proulx K, Kawagoe-Takaki H, Vatin V, Gutierrez-Aguilar R, Lyon D, Ma M, Choquet H, Horber F, Van Hul W, Van Gaal L, Balkau B, Visvikis-Siest S, Pattou F, Farooqi IS, Saudek V, O'Rahilly S, Froguel P, Sedgwick B, Yeo GS. Prevalence of loss of function FTO mutations in lean and obese individuals. Diabetes. 2010;59(1):311–318. [PMC free article] [PubMed] [Google Scholar]

16. O'Rahilly S, Farooqi IS. Human obesity as a heritable disorder of the central control of energy balance. Int. J. Obes. (Lond) 2008;32(Suppl 7):S55–61. [PubMed] [Google Scholar]

17. Walley AJ, Asher JE, Froguel P. The genetic contribution to non-syndromic human obesity. Nat. Rev. Genet. 2009;10(7):431–442. [PubMed] [Google Scholar]

18. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–894. [PMC free article] [PubMed] [Google Scholar]

19. Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougneres P, Kovacs P, Marre M, Balkau B, Cauchi S, Chevre JC, Froguel P. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 2007;39(6):724–726. [PubMed] [Google Scholar]

20. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN. An obesity-associated FTO gene variant and increased energy intake in children. N. Engl. J. Med. 2008;359(24):2558–2566. [PubMed] [Google Scholar]

21. Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, Davey Smith G. The fat mass- and obesity-associated locus and dietary intake in children. Am. J. Clin. Nutr. 2008;88(4):971–978. [PMC free article] [PubMed] [Google Scholar]

22. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring) 2008;16(8):1961–1965. [PubMed] [Google Scholar]

23. Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety. J. Clin. Endocrinol. Metab. 2008;93(9):3640–3643. [PubMed] [Google Scholar]

24. den Hoed M, Westerterp-Plantenga MS, Bouwman FG, Mariman EC, Westerterp KR. Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO. Am. J. Clin. Nutr. 2009;90(5):1426–1432. [PubMed] [Google Scholar]

25. Stutzmann F, Cauchi S, Durand E, Calvacanti-Proenca C, Pigeyre M, Hartikainen AL, Sovio U, Tichet J, Marre M, Weill J, Balkau B, Potoczna N, Laitinen J, Elliott P, Jarvelin MR, Horber F, Meyre D, Froguel P. Common genetic variation near MC4R is associated with eating behaviour patterns in European populations. Int. J. Obes. (Lond) 2009;33(3):373–378. [PubMed] [Google Scholar]

26. Valladares M, Dominguez-Vasquez P, Obregon AM, Weisstaub G, Burrows R, Maiz A, Santos JL. Melanocortin-4 receptor gene variants in Chilean families: association with childhood obesity and eating behavior. Nutr. Neurosci. 2010;13(2):71–78. [PubMed] [Google Scholar]

27. Qi L, Kraft P, Hunter DJ, Hu FB. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum. Mol. Genet. 2008;17(22):3502–3508. [PMC free article] [PubMed] [Google Scholar]

28. Bauer F, Elbers CC, Adan RA, Loos RJ, Onland-Moret NC, Grobbee DE, van Vliet-Ostaptchouk JV, Wijmenga C, van der Schouw YT. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am. J. Clin. Nutr. 2009;90(4):951–959. [PubMed] [Google Scholar]

29. Wardle J, Carnell S. Appetite is a heritable phenotype associated with adiposity. Ann. Behav. Med. 2009 (Epub ahed of print) [PubMed] [Google Scholar]

30. Fricker J, Fumeron F, Clair D, Apfelbaum M. A positive correlation between energy intake and body mass index in a population of 1312 overweight subjects. Int. J. Obes. 1989;13(5):673–681. [PubMed] [Google Scholar]

31. Peters T, Ausmeier K, Ruther U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm. Genome. 1999;10(10):983–986. [PubMed] [Google Scholar]

32. Wing MR, Ziegler J, Langefeld CD, Ng MC, Haffner SM, Norris JM, Goodarzi MO, Bowden DW. Analysis of FTO gene variants with measures of obesity and glucose homeostasis in the IRAS Family Study. Hum. Genet. 2009;125(5-6):615–626. [PMC free article] [PubMed] [Google Scholar]

33. Hotta K, Nakata Y, Matsuo T, Kamohara S, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Masuzaki H, Yoneda M, Nakajima A, Miyazaki S, Tokunaga K, Kawamoto M, Funahashi T, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Nakao K, Sakata T, Matsuzawa Y, Tanaka K, Kamatani N, Nakamura Y. Variations in the FTO gene are associated with severe obesity in the Japanese. J. Hum. Genet. 2008;53(6):546–553. [PMC free article] [PubMed] [Google Scholar]

34. Rees SD, Islam M, Hydrie MZ, Chaudhary B, Bellary S, Hashmi S, O'Hare JP, Kumar S, Sanghera DK, Chaturvedi N, Barnett AH, Shera AS, Weedon MN, Basit A, Frayling TM, Kelly MA, Jafar TH. An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabet. Med. 2011 (Epub ahed of print). [PMC free article] [PubMed] [Google Scholar]

35. Villalobos-Comparan M, Teresa Flores-Dorantes M, Teresa Villarreal-Molina M, Rodriguez-Cruz M, Garcia-Ulloa AC, Robles L, Huertas-Vazquez A, Saucedo-Villarreal N, Lopez-Alarcon M, Sanchez-Munoz F, Dominguez-Lopez A, Gutierrez-Aguilar R, Menjivar M, Coral-Vazquez R, Hernandez-Stengele G, Vital-Reyes VS, Acuna-Alonzo V, Romero-Hidalgo S, Ruiz-Gomez DG, Riano-Barros D, Herrera MF, Gomez-Perez FJ, Froguel P, Garcia-Garcia E, Teresa Tusie-Luna M, Aguilar-Salinas CA, Canizales-Quinteros S. The FTO gene is associated with adulthood obesity in the Mexican population. Obesity (Silver Spring) 2008;16(10):2296–2301. [PubMed] [Google Scholar]

36. Rong R, Hanson RL, Ortiz D, Wiedrich C, Kobes S, Knowler WC, Bogardus C, Baier LJ. Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes. 2009;58(2):478–488. [PMC free article] [PubMed] [Google Scholar]

37. Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS, Meyre D, Golzio C, Molinari F, Kadhom N, Etchevers HC, Saudek V, Farooqi IS, Froguel P, Lindahl T, O'Rahilly S, Munnich A, Colleaux L. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 2009;85(1):106–111. [PMC free article] [PubMed] [Google Scholar]

38. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U. Inactivation of the Fto gene protects from obesity. Nature. 2009;458(7240):894–898. [PubMed] [Google Scholar]

39. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318(5855):1469–1472. [PMC free article] [PubMed] [Google Scholar]

40. Tung YC, Ayuso E, Shan X, Bosch F, O'Rahilly S, Coll AP, Yeo GS. Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. PLoS One. 2010;5(1):e8771. [PMC free article] [PubMed] [Google Scholar]

41. Wang P, Yang FJ, Du H, Guan YF, Xu TY, Xu XW, Su DF, Miao CY. Involvement of leptin receptor (LepRb)-STAT3 signaling pathway in brain FTO downregulation during energy restriction. Mol. Med. 2011 [Epub ahead of print]. [PMC free article] [PubMed] [Google Scholar]

42. Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature. 2010;464(7292):1205–1209. [PubMed] [Google Scholar]

43. Wu Q, Saunders RA, Szkudlarek-Mikho M, Serna Ide L, Chin KV. The obesity-associated Fto gene is a transcriptional coactivator. Biochem. Biophys. Res. Commun. 2010;401(3):390–395. [PMC free article] [PubMed] [Google Scholar]

44. Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, Teschendorff AE, Akan P, Stupka E, Down TA, Prokopenko I, Morison IM, Mill J, Pidsley R, Deloukas P, Frayling TM, Hattersley AT, McCarthy MI, Beck S, Hitman GA. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One. 2010;5(11):e14040. [PMC free article] [PubMed] [Google Scholar]

45. Davey Smith G, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 2003;32(1):1–22. [PubMed] [Google Scholar]

46. Li S, Zhao JH, Luan J, Langenberg C, Luben RN, Khaw KT, Wareham NJ, Loos RJ. Genetic predisposition to obesity leads to increased risk of type 2 diabetes. Diabetologia. 2011;54(4):776–782. [PMC free article] [PubMed] [Google Scholar]

47. Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A, Ebrahim S, Shields B, Zeggini E, Weedon MN, Lindgren CM, Lango H, Melzer D, Ferrucci L, Paolisso G, Neville MJ, Karpe F, Palmer CN, Morris AD, Elliott P, Jarvelin MR, Smith GD, McCarthy MI, Hattersley AT, Frayling TM. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes. 2008;57(5):1419–1426. [PMC free article] [PubMed] [Google Scholar]

48. Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Perusse L, Vohl MC, Engert JC. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes. 2008;57(4):1147–1150. [PubMed] [Google Scholar]

49. Timpson NJ, Harbord R, Davey Smith G, Zacho J, Tybjaerg-Hansen A, Nordestgaard BG. Does greater adiposity increase blood pressure and hypertension risk?: Mendelian randomization using the FTO/MC4R genotype. Hypertension. 2009;54(1):84–90. [PubMed] [Google Scholar]

50. Welsh P, Polisecki E, Robertson M, Jahn S, Buckley BM, de Craen AJ, Ford I, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Hingorani AD, Smith GD, Schaefer E, Sattar N. Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach. J. Clin. Endocrinol. Metab. 2010;95(1):93–99. [PMC free article] [PubMed] [Google Scholar]

51. Timpson NJ, Sayers A, Davey-Smith G, Tobias JH. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J. Bone Miner. Res. 2009;24(3):522–533. [PMC free article] [PubMed] [Google Scholar]

52. Kivimaki M, Smith GD, Timpson NJ, Lawlor DA, Batty GD, Kahonen M, Juonala M, Ronnemaa T, Viikari JS, Lehtimaki T, Raitakari OT. Lifetime body mass index and later atherosclerosis risk in young adults: examining causal links using Mendelian randomization in the Cardiovascular Risk in Young Finns study. Eur. Heart J. 2008;29(20 ):2552–2560. [PMC free article] [PubMed] [Google Scholar]

53. Ahmad T, Chasman DI, Mora S, Pare G, Cook NR, Buring JE, Ridker PM, Lee IM. The fat-mass and obesity-associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am. Heart J. 2010;160(6):1163–1169. [PMC free article] [PubMed] [Google Scholar]

54. Brennan P, McKay J, Moore L, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chow WH, Rothman N, Chabrier A, Gaborieau V, Timpson N, Hung RJ, Smith GD. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. Int. J. Epidemiol. 2009;38(4):971–975. [PMC free article] [PubMed] [Google Scholar]

55. Lurie G, Gaudet MM, Spurdle AB, Carney ME, Wilkens LR, Yang HP, Weiss NS, Webb PM, Thompson PJ, Terada K, Setiawan VW, Rebbeck TR, Prescott J, Orlow I, O'Mara T, Olson SH, Narod SA, Matsuno RK, Lissowska J, Liang X, Levine DA, Le Marchand L, Kolonel LN, Henderson BE, Garcia-Closas M, Doherty JA, De Vivo I, Chen C, Brinton LA, Akbari MR, Goodman MT. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-hispanic white women. PLoS One. 2010;6(2):e16756. [PMC free article] [PubMed] [Google Scholar]

56. Lewis SJ, Murad A, Chen L, Davey Smith G, Donovan J, Palmer T, Hamdy F, Neal D, Lane JA, Davis M, Cox A, Martin RM. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS One. 2010;5(10):e13485. [PMC free article] [PubMed] [Google Scholar]

57. Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, Xie X, Byrne EH, McCarroll SA, Gaudet R, Schaffner SF, Lander ES, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallee C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe'er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Johnson TA, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L'Archeveque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J. Genome-wide detection and characterization of positive selection in human populations. Nature. 2007;449(7164):913–918. [PMC free article] [PubMed] [Google Scholar]

58. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES. Positive natural selection in the human lineage. Science. 2006;312(5780):1614–1620. [PubMed] [Google Scholar]

59. Wells JC. The evolution of human fatness and susceptibility to obesity: an ethological approach. Biol. Rev. Camb. Philos. Soc. 2006;81(2):183–205. [PubMed] [Google Scholar]

60. Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am. J. Hum. Genet. 1962;14:353–362. [PMC free article] [PubMed] [Google Scholar]

61. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Jarvela I. Identification of a variant associated with adult-type hypolactasia. Nat. Genet. 2002;30(2):233–237. [PubMed] [Google Scholar]

62. Rasinpera H, Kuokkanen M, Kolho KL, Lindahl H, Enattah NS, Savilahti E, Orpana A, Jarvela I. Transcriptional downregulation of the lactase (LCT) gene during childhood. Gut. 2005;54(11):1660–1661. [PMC free article] [PubMed] [Google Scholar]

63. Bersaglieri T, Sabeti PC, Patterson N, Vanderploeg T, Schaffner SF, Drake JA, Rhodes M, Reich DE, Hirschhorn JN. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 2004;74(6 ):1111–1120. [PMC free article] [PubMed] [Google Scholar]

64. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L. Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am. J. Hum. Genet. 2008;82(1):57–72. [PMC free article] [PubMed] [Google Scholar]

65. Smith GD, Lawlor DA, Timpson NJ, Baban J, Kiessling M, Day IN, Ebrahim S. Lactase persistence-related genetic variant: population substructure and health outcomes. Eur. J. Hum. Genet. 2009;17(3 ):357–367. [PMC free article] [PubMed] [Google Scholar]

66. Gugatschka M, Dobnig H, Fahrleitner-Pammer A, Pietschmann P, Kudlacek S, Strele A, Obermayer-Pietsch B. Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males. Qjm. 2005;98(12):857–863. [PubMed] [Google Scholar]

67. Kettunen J, Silander K, Saarela O, Amin N, Muller M, Timpson N, Surakka I, Ripatti S, Laitinen J, Hartikainen AL, Pouta A, Lahermo P, Anttila V, Mannisto S, Jula A, Virtamo J, Salomaa V, Lehtimaki T, Raitakari O, Gieger C, Wichmann EH, Van Duijn CM, Smith GD, McCarthy MI, Jarvelin MR, Perola M, Peltonen L. European lactase persistence genotype shows evidence of association with increase in body mass index. Hum. Mol. Genet. 2010;19(6):1129–1136. [PMC free article] [PubMed] [Google Scholar]

68. Park KS, Shin HD, Park BL, Cheong HS, Cho YM, Lee HK, Lee JY, Lee JK, Oh B, Kimm K. Polymorphisms in the leptin receptor (LEPR)--putative association with obesity and T2DM. J. Hum. Genet. 2006;51(2):85–91. [PubMed] [Google Scholar]

69. Kurokawa N, Young EH, Oka Y, Satoh H, Wareham NJ, Sandhu MS, Loos RJ. The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals. Int. J. Obes. (Lond) 2008;32(8 ):1240–1249. [PubMed] [Google Scholar]

70. Grossman SR, Shylakhter I, Karlsson EK, Byrne EH, Morales S, Frieden G, Hostetter E, Angelino E, Garber M, Zuk O, Lander ES, Schaffner SF, Sabeti PC. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science. 2010;327(5967):883–886. [PubMed] [Google Scholar]

71. Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, Macciardi F, Bresolin N, Sironi M. Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am. J. Hum. Genet. 2009;85(1):64–75. [PMC free article] [PubMed] [Google Scholar]

72. Petryshen TL, Sabeti PC, Aldinger KA, Fry B, Fan JB, Schaffner SF, Waggoner SG, Tahl AR, Sklar P. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol. Psychiatry. 2010;15(8):810–815. [PMC free article] [PubMed] [Google Scholar]

73. Southam L, Soranzo N, Montgomery SB, Frayling TM, McCarthy MI, Barroso I, Zeggini E. Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants? Diabetologia. 2009;52(9):1846–1851. [PMC free article] [PubMed] [Google Scholar]

74. Klimentidis YC, Abrams M, Wang J, Fernandez JR, Allison DB. Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions. Hum. Genet. 2011;129(4):407–418. [PMC free article] [PubMed] [Google Scholar]

75. Schioth HB, Lagerstrom MC, Watanobe H, Jonsson L, Vergoni AV, Ringholm A, Skarphedinsson JO, Skuladottir GV, Klovins J, Fredriksson R. Functional role, structure, and evolution of the melanocortin-4 receptor. Ann. N. Y. Acad. Sci. 2003;994:74–83. [PubMed] [Google Scholar]

76. Hughes DA, Hinney A, Brumm H, Wermter AK, Biebermann H, Hebebrand J, Stoneking M. Increased constraints on MC4R during primate and human evolution. Hum. Genet. 2009;124(6):633–647. [PubMed] [Google Scholar]

77. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M, Fontaine KR, Gluckman P, Hanlon EC, Katzmarzyk P, Pietrobelli A, Redden DT, Ruden DM, Wang C, Waterland RA, Wright SM, Allison DB. Ten putative contributors to the obesity epidemic. Crit. Rev. Food Sci. Nutr. 2009;49(10):868–913. [PMC free article] [PubMed] [Google Scholar]

78. Andreasen CH, Stender-Petersen KL, Mogensen MS, Torekov SS, Wegner L, Andersen G, Nielsen AL, Albrechtsen A, Borch-Johnsen K, Rasmussen SS, Clausen JO, Sandbaek A, Lauritzen T, Hansen L, Jorgensen T, Pedersen O, Hansen T. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008;57(1):95–101. [PubMed] [Google Scholar]

79. Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am. J. Clin. Nutr. 2009;90(5 ):1418–1425. [PubMed] [Google Scholar]

80. Sonestedt E, Gullberg B, Ericson U, Wirfalt E, Hedblad B, Orho-Melander M. Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int. J. Obes. (Lond) 2010 [Epub ahead of print]. [PubMed] [Google Scholar]

81. Ahmad T, Lee IM, Pare G, Chasman DI, Rose L, Ridker PM, Mora S. Lifestyle interaction with fat mass and obesity-associated (FTO) genotype and risk of obesity in apparently healthy U.S. women. Diabetes Care. 2011;34(3):675–680. [PMC free article] [PubMed] [Google Scholar]

82. Li S, Zhao JH, Luan J, Ekelund U, Luben RN, Khaw KT, Wareham NJ, Loos RJ. Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study. PLoS Med. 2010;7(8):e1000332. [PMC free article] [PubMed] [Google Scholar]

83. Corella D, Peloso G, Arnett DK, Demissie S, Cupples LA, Tucker K, Lai CQ, Parnell LD, Coltell O, Lee YC, Ordovas JM. APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations. Arch. Intern. Med. 2009;169(20):1897–1906. [PMC free article] [PubMed] [Google Scholar]

84. Corella D, Tai ES, Sorli JV, Chew SK, Coltell O, Sotos-Prieto M, Garcia-Rios A, Estruch R, Ordovas JM. Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene-saturated fat interaction. Int. J. Obes. (Lond) 2010 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

85. Roskam AJ, Kunst AE, Van Oyen H, Demarest S, Klumbiene J, Regidor E, Helmert U, Jusot F, Dzurova D, Mackenbach JP. Comparative appraisal of educational inequalities in overweight and obesity among adults in 19 European countries. Int. J. Epidemiol. 2010;39(2):392–404. [PubMed] [Google Scholar]

86. Corella D, Carrasco P, Sorli JV, Coltell O, Ortega-Azorin C, Guillen M, Gonzalez JI, Saiz C, Estruch R, Ordovas JM. Education modulates the association of the FTO rs9939609 polymorphism with body mass index and obesity risk in the Mediterranean population. Nutr. Metab. Cardiovasc. Dis. 2010 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

87. Hardy R, Wills AK, Wong A, Elks CE, Wareham NJ, Loos RJ, Kuh D, Ong KK. Life course variations in the associations between FTO and MC4R gene variants and body size. Hum. Mol. Genet. 2010;19(3):545–552. [PMC free article] [PubMed] [Google Scholar]

88. Kaakinen M, Laara E, Pouta A, Hartikainen AL, Laitinen J, Tammelin TH, Herzig KH, Sovio U, Bennett AJ, Peltonen L, McCarthy MI, Elliott P, De Stavola B, Jarvelin MR. Life-course analysis of a fat mass and obesity-associated (fto) gene variant and body mass index in the northern finland birth cohort 1966 using structural equation modeling. Am. J. Epidemiol. 2010;172(6):653–655. [PMC free article] [PubMed] [Google Scholar]

89. Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CG, Nilsson PM, Rukh G, Midthjell K, Hveem K, Melander O, Groop L, Lyssenko V, Molven A, Orho-Melander M, Njolstad PR. FTO, Type 2 diabetes, and weight gain throughout adult life: A meta-analysis of 41,504 subjects from the scandinavian HUNT, MDC, and MPP studies. Diabetes. 2011 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

90. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295(13):1549–1555. [PubMed] [Google Scholar]

91. Dempfle A, Hinney A, Heinzel-Gutenbrunner M, Raab M, Geller F, Gudermann T, Schafer H, Hebebrand J. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J. Med. Genet. 2004;41(10):795–800. [PMC free article] [PubMed] [Google Scholar]

92. Stone S, Abkevich V, Russell DL, Riley R, Timms K, Tran T, Trem D, Frank D, Jammulapati S, Neff CD, Iliev D, Gress R, He G, Frech GC, Adams TD, Skolnick MH, Lanchbury JS, Gutin A, Hunt SC, Shattuck D. TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Hum. Mol. Genet. 2006;15(18):2709–2720. [PubMed] [Google Scholar]

93. Meyre D, Farge M, Lecoeur C, Proenca C, Durand E, Allegaert F, Tichet J, Marre M, Balkau B, Weill J, Delplanque J, Froguel P. R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Hum. Mol. Genet. 2008;17(12):1798–1802. [PubMed] [Google Scholar]

94. Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L, Speliotes EK, Thorleifsson G, Willer CJ, Herrera BM, Jackson AU, Lim N, Scheet P, Soranzo N, Amin N, Aulchenko YS, Chambers JC, Drong A, Luan J, Lyon HN, Rivadeneira F, Sanna S, Timpson NJ, Zillikens MC, Zhao JH, Almgren P, Bandinelli S, Bennett AJ, Bergman RN, Bonnycastle LL, Bumpstead SJ, Chanock SJ, Cherkas L, Chines P, Coin L, Cooper C, Crawford G, Doering A, Dominiczak A, Doney AS, Ebrahim S, Elliott P, Erdos MR, Estrada K, Ferrucci L, Fischer G, Forouhi NG, Gieger C, Grallert H, Groves CJ, Grundy S, Guiducci C, Hadley D, Hamsten A, Havulinna AS, Hofman A, Holle R, Holloway JW, Illig T, Isomaa B, Jacobs LC, Jameson K, Jousilahti P, Karpe F, Kuusisto J, Laitinen J, Lathrop GM, Lawlor DA, Mangino M, McArdle WL, Meitinger T, Morken MA, Morris AP, Munroe P, Narisu N, Nordstrom A, Nordstrom P, Oostra BA, Palmer CN, Payne F, Peden JF, Prokopenko I, Renstrom F, Ruokonen A, Salomaa V, Sandhu MS, Scott LJ, Scuteri A, Silander K, Song K, Yuan X, Stringham HM, Swift AJ, Tuomi T, Uda M, Vollenweider P, Waeber G, Wallace C, Walters GB, Weedon MN, Witteman JC, Zhang C, Zhang W, Caulfield MJ, Collins FS, Davey Smith G, Day IN, Franks PW, Hattersley AT, Hu FB, Jarvelin MR, Kong A, Kooner JS, Laakso M, Lakatta E, Mooser V, Morris AD, Peltonen L, Samani NJ, Spector TD, Strachan DP, Tanaka T, Tuomilehto J, Uitterlinden AG, van Duijn CM, Wareham NJ, Hugh W, Waterworth DM, Boehnke M, Deloukas P, Groop L, Hunter DJ, Thorsteinsdottir U, Schlessinger D, Wichmann HE, Frayling TM, Abecasis GR, Hirschhorn JN, Loos RJ, Stefansson K, Mohlke KL, Barroso I, McCarthy MI. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet. 2009;5(6):e1000508. [PMC free article] [PubMed] [Google Scholar]

95. Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, Thorleifsson G, Zillikens MC, Speliotes EK, Magi R, Workalemahu T, White CC, Bouatia-Naji N, Harris TB, Berndt SI, Ingelsson E, Willer CJ, Weedon MN, Luan J, Vedantam S, Esko T, Kilpelainen TO, Kutalik Z, Li S, Monda KL, Dixon AL, Holmes CC, Kaplan LM, Liang L, Min JL, Moffatt MF, Molony C, Nicholson G, Schadt EE, Zondervan KT, Feitosa MF, Ferreira T, Allen HL, Weyant RJ, Wheeler E, Wood AR, Estrada K, Goddard ME, Lettre G, Mangino M, Nyholt DR, Purcell S, Smith AV, Visscher PM, Yang J, McCarroll SA, Nemesh J, Voight BF, Absher D, Amin N, Aspelund T, Coin L, Glazer NL, Hayward C, Heard-Costa NL, Hottenga JJ, Johansson A, Johnson T, Kaakinen M, Kapur K, Ketkar S, Knowles JW, Kraft P, Kraja AT, Lamina C, Leitzmann MF, McKnight B, Morris AP, Ong KK, Perry JR, Peters MJ, Polasek O, Prokopenko I, Rayner NW, Ripatti S, Rivadeneira F, Robertson NR, Sanna S, Sovio U, Surakka I, Teumer A, van Wingerden S, Vitart V, Zhao JH, Cavalcanti-Proenca C, Chines PS, Fisher E, Kulzer JR, Lecoeur C, Narisu N, Sandholt C, Scott LJ, Silander K, Stark K, Tammesoo ML, Teslovich TM, Timpson NJ, Watanabe RM, Welch R, Chasman DI, Cooper MN, Jansson JO, Kettunen J, Lawrence RW, Pellikka N, Perola M, Vandenput L, Alavere H, Almgren P, Atwood LD, Bennett AJ, Biffar R, Bonnycastle LL, Bornstein SR, Buchanan TA, Campbell H, Day IN, Dei M, Dorr M, Elliott P, Erdos MR, Eriksson JG, Freimer NB, Fu M, Gaget S, Geus EJ, Gjesing AP, Grallert H, Grassler J, Groves CJ, Guiducci C, Hartikainen AL, Hassanali N, Havulinna AS, Herzig KH, Hicks AA, Hui J, Igl W, Jousilahti P, Jula A, Kajantie E, Kinnunen L, Kolcic I, Koskinen S, Kovacs P, Kroemer HK, Krzelj V, Kuusisto J, Kvaloy K, Laitinen J, Lantieri O, Lathrop GM, Lokki ML, Luben RN, Ludwig B, McArdle WL, McCarthy A, Morken MA, Nelis M, Neville MJ, Pare G, Parker AN, Peden JF, Pichler I, Pietilainen KH, Platou CG, Pouta A, Ridderstrale M, Samani NJ, Saramies J, Sinisalo J, Smit JH, Strawbridge RJ, Stringham HM, Swift AJ, Teder-Laving M, Thomson B, Usala G, van Meurs JB, van Ommen GJ, Vatin V, Volpato CB, Wallaschofski H, Walters GB, Widen E, Wild SH, Willemsen G, Witte DR, Zgaga L, Zitting P, Beilby JP, James AL, Kahonen M, Lehtimaki T, Nieminen MS, Ohlsson C, Palmer LJ, Raitakari O, Ridker PM, Stumvoll M, Tonjes A, Viikari J, Balkau B, Ben-Shlomo Y, Bergman RN, Boeing H, Smith GD, Ebrahim S, Froguel P, Hansen T, Hengstenberg C, Hveem K, Isomaa B, Jorgensen T, Karpe F, Khaw KT, Laakso M, Lawlor DA, Marre M, Meitinger T, Metspalu A, Midthjell K, Pedersen O, Salomaa V, Schwarz PE, Tuomi T, Tuomilehto J, Valle TT, Wareham NJ, Arnold AM, Beckmann JS, Bergmann S, Boerwinkle E, Boomsma DI, Caulfield MJ, Collins FS, Eiriksdottir G, Gudnason V, Gyllensten U, Hamsten A, Hattersley AT, Hofman A, Hu FB, Illig T, Iribarren C, Jarvelin MR, Kao WH, Kaprio J, Launer LJ, Munroe PB, Oostra B, Penninx BW, Pramstaller PP, Psaty BM, Quertermous T, Rissanen A, Rudan I, Shuldiner AR, Soranzo N, Spector TD, Syvanen AC, Uda M, Uitterlinden A, Volzke H, Vollenweider P, Wilson JF, Witteman JC, Wright AF, Abecasis GR, Boehnke M, Borecki IB, Deloukas P, Frayling TM, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, North KE, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, Hirschhorn JN, Assimes TL, Wichmann HE, Thorsteinsdottir U, van Duijn CM, Stefansson K, Cupples LA, Loos RJ, Barroso I, McCarthy MI, Fox CS, Mohlke KL, Lindgren CM. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat. Genet. 2011;42(11):949–960. [PMC free article] [PubMed] [Google Scholar]

96. Traurig M, Mack J, Hanson RL, Ghoussaini M, Meyre D, Knowler WC, Kobes S, Froguel P, Bogardus C, Baier LJ. Common variation in SIM1 is reproducibly associated with BMI in Pima Indians. Diabetes. 2009;58(7):1682–1689. [PMC free article] [PubMed] [Google Scholar]

97. Ghoussaini M, Stutzmann F, Couturier C, Vatin V, Durand E, Lecoeur C, Degraeve F, Heude B, Tauber M, Hercberg S, Levy-Marchal C, Tounian P, Weill J, Traurig M, Bogardus C, Baier L, Michaud J, Froguel P, Meyre D. Analysis of the SIM1 contribution to polygenic obesity in the French population. Obesity (Silver Spring) 2010;18(8):1670–1675. [PMC free article] [PubMed] [Google Scholar]

98. Pietri-Rouxel F, St John Manning B, Gros J, Strosberg AD. The biochemical effect of the naturally occurring Trp64-->Arg mutation on human beta3-adrenoceptor activity. Eur. J. Biochem. 1997;247(3):1174–1179. [PubMed] [Google Scholar]

99. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Lee JK, Oh B, Kim HL. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat. Genet. 2009;41(5):527–534. [PubMed] [Google Scholar]

100. Santoro N, Perrone L, Cirillo G, Raimondo P, Amato A, Coppola F, Santarpia M, D'Aniello A, Miraglia Del Giudice E. Weight loss in obese children carrying the proopiomelanocortin R236G variant. J. Endocrinol. Invest. 2006;29(3):226–230. [PubMed] [Google Scholar]

101. Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm H, Biebermann H, Hinney A. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. Obesity (Silver Spring) 2009;17(2):382–389. [PubMed] [Google Scholar]

102. Muller TD, Hinney A, Scherag A, Nguyen TT, Schreiner F, Schafer H, Hebebrand J, Roth CL, Reinehr T. 'Fat mass and obesity associated' gene (FTO): no significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents. BMC Med. Genet. 2008;9:85. [PMC free article] [PubMed] [Google Scholar]

103. Grau K, Hansen T, Holst C, Astrup A, Saris WH, Arner P, Rossner S, Macdonald I, Polak J, Oppert JM, Langin D, Martinez JA, Pedersen O, Sorensen TI. Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans. Int. J. Obes. (Lond) 2009;33(11):1227–1234. [PubMed] [Google Scholar]

104. Razquin C, Martinez JA, Martinez-Gonzalez MA, Bes-Rastrollo M, Fernandez-Crehuet J, Marti A. A 3-year intervention with a Mediterranean diet modified the association between the rs9939609 gene variant in FTO and body weight changes. Int. J. Obes. (Lond) 2010;34(2):266–272. [PubMed] [Google Scholar]

105. Mitchell JA, Church TS, Rankinen T, Earnest CP, Sui X, Blair SN. FTO genotype and the weight loss benefits of moderate intensity exercise. Obesity (Silver Spring) 2010;18(3):641–643. [PMC free article] [PubMed] [Google Scholar]

106. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 2002;110(8):1093–1103. [PMC free article] [PubMed] [Google Scholar]

107. Paz-Filho G, Wong ML, Licinio J. Ten years of leptin replacement therapy. Obes. Rev. 2011 [Epub ahead of print] [PubMed] [Google Scholar]

108. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16 ):1568–1575. [PubMed] [Google Scholar]

109. Roubert P, Dubern B, Plas P, Lubrano-Berthelier C, Alihi R, Auger F, Deoliveira DB, Dong JZ, Basdevant A, Thurieau C, Clement K. Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. J. Endocrinol. 2010;207(2 ):177–183. [PubMed] [Google Scholar]

110. Rene P, Le Gouill C, Pogozheva ID, Lee G, Mosberg HI, Farooqi IS, Valenzano KJ, Bouvier M. Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. J. Pharmacol. Exp. Ther. 2010;335(3):520–532. [PubMed] [Google Scholar]

111. Hauner H, Meier M, Jockel KH, Frey UH, Siffert W. Prediction of successful weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit gene (GNB3) C825T polymorphism. Pharmacogenetics. 2003;13(8 ):453–459. [PubMed] [Google Scholar]

112. Hsiao DJ, Wu LS, Huang SY, Lin E. Weight loss and body fat reduction under sibutramine therapy in obesity with the C825T polymorphism in the GNB3 gene. Pharmacogenet. Genomics. 2009;19(9):730–733. [PubMed] [Google Scholar]

113. Grudell AB, Sweetser S, Camilleri M, Eckert DJ, Vazquez-Roque MI, Carlson PJ, Burton DD, Braddock AE, Clark MM, Graszer KM, Kalsy SA, Zinsmeister AR. A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese or overweight adults. Gastroenterology. 2008;135(4):1142–1154. [PMC free article] [PubMed] [Google Scholar]

114. Aslan IR, Ranadive SA, Ersoy BA, Rogers SJ, Lustig RH, Vaisse C. Bariatric surgery in a patient with complete MC4R deficiency. Int. J. Obes. (Lond) 2011;35(3):457–461. [PMC free article] [PubMed] [Google Scholar]

115. Aslan IR, Campos GM, Calton MA, Evans DS, Merriman RB, Vaisse C. Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations. Obes. Surg. 2010 [Epub ahead of print] [PMC free article] [PubMed] [Google Scholar]

116. Sarzynski MA, Jacobson P, Rankinen T, Carlsson B, Sjostrom L, Bouchard C, Carlsson LM. Associations of markers in 11 obesity candidate genes with maximal weight loss and weight regain in the SOS bariatric surgery cases. Int. J. Obes. (Lond) 2010 [Epub ahead of print] [PubMed] [Google Scholar]

117. Still CD, Wood GC, Chu X, Erdman R, Manney CH, Benotti PN, Petrick AT, Strodel WE, Mirshahi UL, Mirshahi T, Carey DJ, Gerhard GS. High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery. Obesity (Silver Spring) 2011 [Epub ahead of print] [PubMed] [Google Scholar]

118. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk of complex disease. Curr. Opin. Genet. Dev. 2008;18(3):257–263. [PubMed] [Google Scholar]

119. Sandholt CH, Sparso T, Grarup N, Albrechtsen A, Almind K, Hansen L, Toft U, Jorgensen T, Hansen T, Pedersen O. Combined analyses of 20 common obesity susceptibility variants. Diabetes. 2010;59(7):1667–1673. [PMC free article] [PubMed] [Google Scholar]

120. Kooperberg C, LeBlanc M, Obenchain V. Risk prediction using genome-wide association studies. Genet. Epidemiol. 2010;34(7):643–652. [PMC free article] [PubMed] [Google Scholar]

121. Wei Z, Wang K, Qu HQ, Zhang H, Bradfield J, Kim C, Frackleton E, Hou C, Glessner JT, Chiavacci R, Stanley C, Monos D, Grant SF, Polychronakos C, Hakonarson H. From disease association to risk assessment: an optimistic view from genome-wide association studies on type 1 diabetes. PLoS Genet. 2009;5(10):e1000678. [PMC free article] [PubMed] [Google Scholar]

122. Melchior C, Kiess W, Dittrich K, Schulz A, Schoneberg T, Korner A. Slim despite a genetic predisposition for obesity--influence of environmental factors as chance? A case report. Dtsch. Med. Wochenschr. 2009;134(20):1047–1050. [PubMed] [Google Scholar]

123. O'Rahilly S, Farooqi IS. Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions. Diabetes. 2008;57(11):2905–2910. [PMC free article] [PubMed] [Google Scholar]

Which of the following best describes research findings on the genetic of obesity?

What causes obesity biologically?

How is obesity measured in research?

What is the biology of obesity?