Genetic Variation and Obesity Prior to the Era of Genome-Wide Association Studies

  • Shana E. McCormack


The purpose of this chapter is to present a comprehensive review of the evidence for how genetic variation contributes to common obesity (which we have chosen to define as affecting >1 % of obese individuals, likely non-syndromic in etiology, and related to diet and inactivity) in the general population prior to the era of genome wide association studies (GWAS). Twin and adoption studies demonstrate that the tendency to be obese is highly heritable, and also suggest that the cumulative effect of gene–environment interactions on body mass index (BMI) seems to increase with age. Before GWAS, one common approach to dissecting the role of genetic variability in common obesity was to investigate candidate genes. Some of the genes implicated in monogenic or syndromic obesity by traditional linkage analysis, for example, MC4R, have milder variants that appear to be important in common obesity as well. By 2004, over 600 candidate genes or chromosomal regions had been implicated in the pathogenesis of obesity, and 18 of these had multiple lines of supporting evidence. Despite this, much of the heritability in obesity remained to be explained. Next-generation sequencing technology should produce additional insights that extended these seminal investigations but despite this, much of the so-called missing heritability identified prior to the era of GWAS persists.


Genome Wide Association Study Hypogonadotropic Hypogonadism Adoption Study PCSK1 Gene Biedl Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    James WP (2008) WHO recognition of the global obesity epidemic. Int J Obes (Lond) 32(Suppl 7):S120–S126, Epub 2009/01/16Google Scholar
  2. 2.
    Austin GL, Ogden LG, Hill JO (2011) Trends in carbohydrate, fat, and protein intakes and association with energy intake in normal-weight, overweight, and obese individuals: 1971–2006. Am J Clin Nutr 93(4):836–843, Epub 2011/02/12PubMedGoogle Scholar
  3. 3.
    Ogden CL, Carroll MD, Kit BK, Flegal KM (2012) Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 307(5):483–490, Epub 2012/01/19PubMedGoogle Scholar
  4. 4.
    Wells JC (2012) The evolution of human adiposity and obesity: where did it all go wrong? Dis Model Mech 5(5):595–607, Epub 2012/08/24PubMedGoogle Scholar
  5. 5.
    Perusse L, Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G et al (2005) The human obesity gene map: the 2004 update. Obes Res 13(3):381–490, Epub 2005/04/19PubMedGoogle Scholar
  6. 6.
    Friedman JM (2004) Modern science versus the stigma of obesity. Nat Med 10(6):563–569, Epub 2004/06/01PubMedGoogle Scholar
  7. 7.
    Lyon HN, Hirschhorn JN (2005) Genetics of common forms of obesity: a brief overview. Am J Clin Nutr 82(1 Suppl):215S–217S, Epub 2005/07/09PubMedGoogle Scholar
  8. 8.
    Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14:353–362, Epub 1962/12/01PubMedGoogle Scholar
  9. 9.
    Baig U, Belsare P, Watve M, Jog M (2011) Can thrifty gene(s) or predictive fetal programming for thriftiness lead to obesity? J Obes 2011:861049, Epub 2011/07/21PubMedGoogle Scholar
  10. 10.
    Tenesa A, Haley CS (2013) The heritability of human disease: estimation, uses and abuses. Nat Rev Genet 14(2):139–149, Epub 2013/01/19PubMedGoogle Scholar
  11. 11.
    Hebebrand J, Friedel S, Schauble N, Geller F, Hinney A (2003) Perspectives: molecular genetic research in human obesity. Obes Rev 4(3):139–146, Epub 2003/08/15PubMedGoogle Scholar
  12. 12.
    Farooqi IS, O’Rahilly S (2005) New advances in the genetics of early onset obesity. Int J Obes (Lond) 29(10):1149–1152, Epub 2005/09/13Google Scholar
  13. 13.
    Bell CG, Walley AJ, Froguel P (2005) The genetics of human obesity. Nat Rev Genet 6(3):221–234, Epub 2005/02/11PubMedGoogle Scholar
  14. 14.
    Stunkard AJ, Foch TT, Hrubec Z (1986) A twin study of human obesity. JAMA 256(1):51–54, Epub 1986/07/04PubMedGoogle Scholar
  15. 15.
    Dubois L, Ohm Kyvik K, Girard M, Tatone-Tokuda F, Perusse D, Hjelmborg J et al (2012) Genetic and environmental contributions to weight, height, and BMI from birth to 19 years of age: an international study of over 12,000 twin pairs. PLoS One 7(2):e30153, Epub 2012/02/22PubMedGoogle Scholar
  16. 16.
    Wardle J, Carnell S, Haworth CM, Plomin R (2008) Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 87(2):398–404, Epub 2008/02/09PubMedGoogle Scholar
  17. 17.
    Stunkard AJ, Sorensen TI, Hanis C, Teasdale TW, Chakraborty R, Schull WJ et al (1986) An adoption study of human obesity. N Engl J Med 314(4):193–198, Epub 1986/01/23PubMedGoogle Scholar
  18. 18.
    Stunkard AJ, Harris JR, Pedersen NL, McClearn GE (1990) The body-mass index of twins who have been reared apart. N Engl J Med 322(21):1483–1487, Epub 1990/05/24PubMedGoogle Scholar
  19. 19.
    Knowler WC, Pettitt DJ, Saad MF, Bennett PH (1990) Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab Rev 6(1):1–27, Epub 1990/02/01PubMedGoogle Scholar
  20. 20.
    Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307(5):491–497, Epub 2012/01/19PubMedGoogle Scholar
  21. 21.
    Golden SH, Brown A, Cauley JA, Chin MH, Gary-Webb TL, Kim C et al (2012) Health disparities in endocrine disorders: biological, clinical, and nonclinical factors—an Endocrine Society scientific statement. J Clin Endocrinol Metab 97(9):E1579–E1639, Epub 2012/06/26PubMedGoogle Scholar
  22. 22.
    Kimm SY, Glynn NW, Aston CE, Damcott CM, Poehlman ET, Daniels SR et al (2002) Racial differences in the relation between uncoupling protein genes and resting energy expenditure. Am J Clin Nutr 75(4):714–719, Epub 2002/03/28PubMedGoogle Scholar
  23. 23.
    Yanovski JA, Diament AL, Sovik KN, Nguyen TT, Li H, Sebring NG et al (2000) Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children. Am J Clin Nutr 71(6):1405–1420, Epub 2000/06/06PubMedGoogle Scholar
  24. 24.
    Saxena R, de Bakker PI, Singer K, Mootha V, Burtt N, Hirschhorn JN et al (2006) Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. Am J Hum Genet 79(1):54–61, Epub 2006/06/15PubMedGoogle Scholar
  25. 25.
    Wallace DC (2011) Bioenergetic origins of complexity and disease. Cold Spring Harb Symp Quant Biol 76:1–16, Epub 2011/12/24PubMedGoogle Scholar
  26. 26.
    Kondo I, Hamabe J, Yamamoto K, Niikawa N (1990) Exclusion mapping of the Cohen syndrome gene from the Prader-Willi syndrome locus. Clin Genet 38(6):422–426PubMedGoogle Scholar
  27. 27.
    Beales PL, Warner AM, Hitman GA, Thakker R, Flinter FA (1997) Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J Med Genet 34(2):92–98PubMedGoogle Scholar
  28. 28.
    Bruford EA, Riise R, Teague PW, Porter K, Thomson KL, Moore AT et al (1997) Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21. Genomics 41(1):93–99PubMedGoogle Scholar
  29. 29.
    Young TL, Penney L, Woods MO, Parfrey PS, Green JS, Hefferton D et al (1999) A fifth locus for Bardet-Biedl syndrome maps to chromosome 2q31. Am J Hum Genet 64(3):900–904PubMedGoogle Scholar
  30. 30.
    Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DS, Taylor JF (1998) Alstrom syndrome. Report of 22 cases and literature review. Ophthalmology 105(7):1274–1280PubMedGoogle Scholar
  31. 31.
    Farooqi IS, O’Rahilly S (2000) Recent advances in the genetics of severe childhood obesity. Arch Dis Child 83(1):31–34PubMedGoogle Scholar
  32. 32.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432, Epub 1994/12/01PubMedGoogle Scholar
  33. 33.
    Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41(12):317–318PubMedGoogle Scholar
  34. 34.
    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223):543–546PubMedGoogle Scholar
  35. 35.
    Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269(5223):546–549PubMedGoogle Scholar
  36. 36.
    Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T et al (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269(5223):540–543PubMedGoogle Scholar
  37. 37.
    Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI et al (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379(6566):632–635, Epub 1996/02/15PubMedGoogle Scholar
  38. 38.
    Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L et al (1996) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271(5251):994–996PubMedGoogle Scholar
  39. 39.
    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295PubMedGoogle Scholar
  40. 40.
    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387(6636):903–908, Epub 1997/06/26PubMedGoogle Scholar
  41. 41.
    Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392(6674):398–401, Epub 1998/04/16PubMedGoogle Scholar
  42. 42.
    Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356(3):237–247, Epub 2007/01/19PubMedGoogle Scholar
  43. 43.
    Lucantoni R, Ponti E, Berselli ME, Savia G, Minocci A, Calo G et al (2000) The A19G polymorphism in the 5' untranslated region of the human obese gene does not affect leptin levels in severely obese patients. J Clin Endocrinol Metab 85(10):3589–3591, Epub 2000/11/04PubMedGoogle Scholar
  44. 44.
    Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F (2000) Association of the G-2548A polymorphism in the 5' region of the LEP gene with overweight. Ann Hum Genet 64(Pt 5):391–394, Epub 2001/04/03PubMedGoogle Scholar
  45. 45.
    Jiang Y, Wilk JB, Borecki I, Williamson S, DeStefano AL, Xu G et al (2004) Common variants in the 5' region of the leptin gene are associated with body mass index in men from the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 75(2):220–230, Epub 2004/06/16PubMedGoogle Scholar
  46. 46.
    Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS (2001) The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 86(9):4434–4439, Epub 2001/09/11PubMedGoogle Scholar
  47. 47.
    Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell K et al (2000) Hypertension in obesity and the leptin receptor gene locus. J Clin Endocrinol Metab 85(9):3126–3131, Epub 2000/09/22PubMedGoogle Scholar
  48. 48.
    Wauters M, Mertens I, Rankinen T, Chagnon M, Bouchard C, Van Gaal L (2001) Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance. J Clin Endocrinol Metab 86(7):3227–3232, Epub 2001/07/10PubMedGoogle Scholar
  49. 49.
    Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1):131–141, Epub 1997/01/10PubMedGoogle Scholar
  50. 50.
    Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20(2):111–112, Epub 1998/10/15PubMedGoogle Scholar
  51. 51.
    Vaisse C, Clement K, Guy-Grand B, Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20(2):113–114, Epub 1998/10/15PubMedGoogle Scholar
  52. 52.
    Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J et al (1999) Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 48(3):635–639, Epub 1999/03/17PubMedGoogle Scholar
  53. 53.
    Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A et al (1999) Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 84(4):1483–1486, Epub 1999/04/13PubMedGoogle Scholar
  54. 54.
    Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348(12):1085–1095, Epub 2003/03/21PubMedGoogle Scholar
  55. 55.
    Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C et al (2008) Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes 57(12):3267–3272, Epub 2008/10/07PubMedGoogle Scholar
  56. 56.
    Seidah NG, Benjannet S, Hamelin J, Mamarbachi AM, Basak A, Marcinkiewicz J et al (1999) The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann N Y Acad Sci 885:57–74PubMedGoogle Scholar
  57. 57.
    Cheung CC, Clifton DK, Steiner RA (1997) Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138(10):4489–4492PubMedGoogle Scholar
  58. 58.
    Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19(2):155–157, Epub 1998/06/10PubMedGoogle Scholar
  59. 59.
    Chen Y, Snieder H, Wang X, Kaviya B, McCaffrey C, Spector TD et al (2005) Proopiomelanocortin gene variants are associated with serum leptin and body fat in a normal female population. Eur J Hum Genet 13(6):772–780, Epub 2005/04/07PubMedGoogle Scholar
  60. 60.
    Sutton BS, Langefeld CD, Williams AH, Norris JM, Saad MF, Haffner SM et al (2005) Association of proopiomelanocortin gene polymorphisms with obesity in the IRAS family study. Obes Res 13(9):1491–1498, Epub 2005/10/14PubMedGoogle Scholar
  61. 61.
    Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT et al (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16(3):303–306, Epub 1997/07/01PubMedGoogle Scholar
  62. 62.
    Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E et al (2007) Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab 92(9):3369–3373, Epub 2007/06/28PubMedGoogle Scholar
  63. 63.
    Benzinou M, Creemers JW, Choquet H, Lobbens S, Dina C, Durand E et al (2008) Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 40(8):943–945, Epub 2008/07/08PubMedGoogle Scholar
  64. 64.
    Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385(6612):165–168, Epub 1997/01/09PubMedGoogle Scholar
  65. 65.
    Argyropoulos G, Rankinen T, Neufeld DR, Rice T, Province MA, Leon AS et al (2002) A polymorphism in the human agouti-related protein is associated with late-onset obesity. J Clin Endocrinol Metab 87(9):4198–4202, Epub 2002/09/06PubMedGoogle Scholar
  66. 66.
    Marks DL, Boucher N, Lanouette CM, Perusse L, Brookhart G, Comuzzie AG et al (2004) Ala67Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans. Am J Med Genet A 126A(3):267–271, Epub 2004/04/01PubMedGoogle Scholar
  67. 67.
    Reizes O, Lincecum J, Wang Z, Goldberger O, Huang L, Kaksonen M et al (2001) Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106(1):105–116, Epub 2001/07/20PubMedGoogle Scholar
  68. 68.
    Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR et al (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6(7):736–742, Epub 2003/06/11PubMedGoogle Scholar
  69. 69.
    Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R et al (2001) Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 15(10):1748–1757, Epub 2001/10/02PubMedGoogle Scholar
  70. 70.
    Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM et al (2006) Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55(12):3366–3371, Epub 2006/11/30PubMedGoogle Scholar
  71. 71.
    Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS et al (2008) Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 359(9):918–927, Epub 2008/08/30PubMedGoogle Scholar
  72. 72.
    Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S et al (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7(11):1187–1189, Epub 2004/10/21PubMedGoogle Scholar
  73. 73.
    Ribases M, Gratacos M, Fernandez-Aranda F, Bellodi L, Boni C, Anderluh M et al (2004) Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 13(12):1205–1212, Epub 2004/04/30PubMedGoogle Scholar
  74. 74.
    Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Levy E et al (2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 10(14):1465–1473, Epub 2001/07/13PubMedGoogle Scholar
  75. 75.
    Holder JL Jr, Butte NF, Zinn AR (2000) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9(1):101–108, Epub 1999/12/10PubMedGoogle Scholar
  76. 76.
    Hung CC, Luan J, Sims M, Keogh JM, Hall C, Wareham NJ et al (2007) Studies of the SIM1 gene in relation to human obesity and obesity-related traits. Int J Obes (Lond) 31(3):429–434, Epub 2006/08/23Google Scholar
  77. 77.
    Traurig M, Mack J, Hanson RL, Ghoussaini M, Meyre D, Knowler WC et al (2009) Common variation in SIM1 is reproducibly associated with BMI in Pima Indians. Diabetes 58(7):1682–1689, Epub 2009/04/30PubMedGoogle Scholar
  78. 78.
    Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS et al (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393(6680):72–76, Epub 1998/05/20PubMedGoogle Scholar
  79. 79.
    del Giudice EM, Santoro N, Cirillo G, D’Urso L, Di Toro R, Perrone L (2001) Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family. Diabetes 50(9):2157–2160, Epub 2001/08/28PubMedGoogle Scholar
  80. 80.
    Challis BG, Yeo GS, Farooqi IS, Luan J, Aminian S, Halsall DJ et al (2000) The CART gene and human obesity: mutational analysis and population genetics. Diabetes 49(5):872–875, Epub 2000/07/25PubMedGoogle Scholar
  81. 81.
    Yamada K, Yuan X, Otabe S, Koyanagi A, Koyama W, Makita Z (2002) Sequencing of the putative promoter region of the cocaine- and amphetamine-regulated-transcript gene and identification of polymorphic sites associated with obesity. Int J Obes Relat Metab Disord 26(1):132–136, Epub 2002/01/16PubMedGoogle Scholar
  82. 82.
    Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407(6806):908–913, Epub 2000/11/01PubMedGoogle Scholar
  83. 83.
    Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP et al (2002) Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 346(21):1623–1630, Epub 2002/05/25PubMedGoogle Scholar
  84. 84.
    Ukkola O, Ravussin E, Jacobson P, Snyder EE, Chagnon M, Sjostrom L et al (2001) Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. J Clin Endocrinol Metab 86(8):3996–3999, Epub 2001/08/15PubMedGoogle Scholar
  85. 85.
    Hinney A, Hoch A, Geller F, Schafer H, Siegfried W, Goldschmidt H et al (2002) Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students. J Clin Endocrinol Metab 87(6):2716, Epub 2002/06/07PubMedGoogle Scholar
  86. 86.
    Baessler A, Hasinoff MJ, Fischer M, Reinhard W, Sonnenberg GE, Olivier M et al (2005) Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity. Diabetes 54(1):259–267, Epub 2004/12/24PubMedGoogle Scholar
  87. 87.
    Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR (1985) Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89(5):1070–1077, Epub 1985/11/01PubMedGoogle Scholar
  88. 88.
    Leiter AB, Toder A, Wolfe HJ, Taylor IL, Cooperman S, Mandel G et al (1987) Peptide YY. Structure of the precursor and expression in exocrine pancreas. J Biol Chem 262(27):12984–12988, Epub 1987/09/25PubMedGoogle Scholar
  89. 89.
    Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Collier JM, Hebert S et al (2006) A PYY Q62P variant linked to human obesity. Hum Mol Genet 15(3):387–391, Epub 2005/12/22PubMedGoogle Scholar
  90. 90.
    Shih PA, Wang L, Chiron S, Wen G, Nievergelt C, Mahata M et al (2009) Peptide YY (PYY) gene polymorphisms in the 3'-untranslated and proximal promoter regions regulate cellular gene expression and PYY secretion and metabolic syndrome traits in vivo. J Clin Endocrinol Metab 94(11):4557–4566, Epub 2009/10/13PubMedGoogle Scholar
  91. 91.
    Friedlander Y, Li G, Fornage M, Williams OD, Lewis CE, Schreiner P et al (2010) Candidate molecular pathway genes related to appetite regulatory neural network, adipocyte homeostasis and obesity: results from the CARDIA Study. Ann Hum Genet 74(5):387–398, Epub 2010/07/21PubMedGoogle Scholar
  92. 92.
    Schupp M, Lazar MA (2010) Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem 285(52):40409–40415, Epub 2010/10/20PubMedGoogle Scholar
  93. 93.
    Sewter C, Blows F, Considine R, Vidal-Puig A, O’Rahilly S (2002) Differential effects of adiposity on peroxisomal proliferator-activated receptor gamma1 and gamma2 messenger ribonucleic acid expression in human adipocytes. J Clin Endocrinol Metab 87(9):4203–4207, Epub 2002/09/06PubMedGoogle Scholar
  94. 94.
    Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ et al (1998) Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes 47(11):1806–1808, Epub 1998/10/29PubMedGoogle Scholar
  95. 95.
    Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J et al (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20(3):284–287, Epub 1998/11/07PubMedGoogle Scholar
  96. 96.
    Andersen G, Wegner L, Yangisawa K, Rose CS, Lin J, Glumer C et al (2005) Evidence of an association between genetic variation of the coactivator PGC-1beta and obesity. J Med Genet 42(5):402–7PubMedGoogle Scholar
  97. 97.
    Seol W, Choi HS, Moore DD (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272(5266):1336–1339, Epub 1996/05/31PubMedGoogle Scholar
  98. 98.
    Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K et al (2001) Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci U S A 98(2):575–580, Epub 2001/01/03PubMedGoogle Scholar
  99. 99.
    Echwald SM, Andersen KL, Sorensen TI, Larsen LH, Andersen T, Tonooka N et al (2004) Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G > A (p.G93D) variant with reduced functional activity. Hum Mutat 24(5):381–387PubMedGoogle Scholar
  100. 100.
    Abate N, Carulli L, Cabo-Chan A Jr, Chandalia M, Snell PG, Grundy SM (2003) Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. J Clin Endocrinol Metab 88(12):5927–5934, Epub 2003/12/13PubMedGoogle Scholar
  101. 101.
    Dlamini N, Splitt M, Durkan A, Siddiqui A, Padayachee S, Hobbins S et al (2009) Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications. Am J Med Genet A 149A(3):456–460, Epub 2009/02/12PubMedGoogle Scholar
  102. 102.
    Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM (2010) Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet 86(2):267–272, Epub 2010/02/09PubMedGoogle Scholar
  103. 103.
    Yang-Feng TL, Xue FY, Zhong WW, Cotecchia S, Frielle T, Caron MG et al (1990) Chromosomal organization of adrenergic receptor genes. Proc Natl Acad Sci U S A 87(4):1516–1520, Epub 1990/02/01PubMedGoogle Scholar
  104. 104.
    Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L et al (1997) Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest 100(12):3005–3013, Epub 1998/01/31PubMedGoogle Scholar
  105. 105.
    Ellsworth DL, Coady SA, Chen W, Srinivasan SR, Elkasabany A, Gustat J et al (2002) Influence of the beta2-adrenergic receptor Arg16Gly polymorphism on longitudinal changes in obesity from childhood through young adulthood in a biracial cohort: the Bogalusa Heart Study. Int J Obes Relat Metab Disord 26(7):928–937, Epub 2002/06/25PubMedGoogle Scholar
  106. 106.
    Lonnqvist F, Wahrenberg H, Hellstrom L, Reynisdottir S, Arner P (1992) Lipolytic catecholamine resistance due to decreased beta 2-adrenoceptor expression in fat cells. J Clin Invest 90(6):2175–2186, Epub 1992/12/01PubMedGoogle Scholar
  107. 107.
    Blakemore AI, Froguel P (2008) Is obesity our genetic legacy? J Clin Endocrinol Metab 93(11 Suppl 1):S51–S56, Epub 2008/12/04PubMedGoogle Scholar
  108. 108.
    Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T et al (2006) A common genetic variant is associated with adult and childhood obesity. Science 312(5771):279–283, Epub 2006/04/15PubMedGoogle Scholar
  109. 109.
    Heid IM, Huth C, Loos RJ, Kronenberg F, Adamkova V, Anand SS et al (2009) Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design? PLoS Genet 5(10):e1000694, Epub 2009/10/24PubMedGoogle Scholar
  110. 110.
    Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P et al (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39(6):724–726, Epub 2007/05/15PubMedGoogle Scholar
  111. 111.
    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316(5826):889–894, Epub 2007/04/17PubMedGoogle Scholar
  112. 112.
    Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS et al (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318(5855):1469–1472, Epub 2007/11/10PubMedGoogle Scholar
  113. 113.
    Baker M, Gaukrodger N, Mayosi BM, Imrie H, Farrall M, Watkins H et al (2005) Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study. Diabetes 54(8):2492–2496, Epub 2005/07/28PubMedGoogle Scholar
  114. 114.
    Nicholls RD, Knoll JH, Butler MG, Karam S, Lalande M (1989) Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature 342(6247):281–285, Epub 1989/11/16PubMedGoogle Scholar
  115. 115.
    Chen Y, Liu YJ, Pei YF, Yang TL, Deng FY, Liu XG et al (2011) Copy number variations at the Prader-Willi syndrome region on chromosome 15 and associations with obesity in whites. Obesity (Silver Spring) 19(6):1229–1234, Epub 2011/01/15Google Scholar
  116. 116.
    Oeffner F, Korn T, Roth H, Ziegler A, Hinney A, Goldschmidt H et al (2001) Systematic screening for mutations in the human necdin gene (NDN): identification of two naturally occurring polymorphisms and association analysis in body weight regulation. Int J Obes Relat Metab Disord 25(6):767–769, Epub 2001/07/06PubMedGoogle Scholar
  117. 117.
    Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP et al (2010) The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141(7):1208–1219, Epub 2010/07/07PubMedGoogle Scholar
  118. 118.
    Rahmouni K, Fath MA, Seo S, Thedens DR, Berry CJ, Weiss R et al (2008) Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 118(4):1458–1467, Epub 2008/03/05PubMedGoogle Scholar
  119. 119.
    Benzinou M, Walley A, Lobbens S, Charles MA, Jouret B, Fumeron F et al (2006) Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians. Diabetes 55(10):2876–2882, Epub 2006/09/28PubMedGoogle Scholar
  120. 120.
    Andersen KL, Echwald SM, Larsen LH, Hamid YH, Glumer C, Jorgensen T et al (2005) Variation of the McKuisck-Kaufman gene and studies of relationships with common forms of obesity. J Clin Endo Metab 90(1):225–30, Epub 2004/10/13Google Scholar
  121. 121.
    Sorensen TI, Boutin P, Taylor MA, Larsen LH, Verdich C, Petersen L et al (2006) Genetic polymorphisms and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets. PLoS Clin Trials 1(2):e12, Epub 2006/07/28PubMedGoogle Scholar
  122. 122.
    Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P et al (2002) Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31(1):74–78, Epub 2002/04/10PubMedGoogle Scholar
  123. 123.
    Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S et al (2002) Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 31(1):79–83, Epub 2002/04/10PubMedGoogle Scholar
  124. 124.
    Li G, Vega R, Nelms K, Gekakis N, Goodnow C, McNamara P et al (2007) A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet 3(1):e8, Epub 2007/01/09PubMedGoogle Scholar
  125. 125.
    Patel S, Minton JA, Weedon MN, Frayling TM, Ricketts C, Hitman GA et al (2006) Common variations in the ALMS1 gene do not contribute to susceptibility to type 2 diabetes in a large white UK population. Diabetologia 49(6):1209–1213, Epub 2006/04/08PubMedGoogle Scholar
  126. 126.
    Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I et al (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278(5335):135–138, Epub 1997/10/06PubMedGoogle Scholar
  127. 127.
    Katsuki A, Sumida Y, Gabazza EC, Murashima S, Tanaka T, Furuta M et al (2001) Plasma levels of agouti-related protein are increased in obese men. J Clin Endocrinol Metab 86(5):1921–1924, Epub 2001/05/10PubMedGoogle Scholar
  128. 128.
    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294(5548):1945–1948, Epub 2001/12/01PubMedGoogle Scholar
  129. 129.
    Strader AD, Reizes O, Woods SC, Benoit SC, Seeley RJ (2004) Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. J Clin Invest 114(9):1354–1360, Epub 2004/11/03PubMedGoogle Scholar
  130. 130.
    Ha E, Kim MJ, Choi BK, Rho JJ, Oh DJ, Rho TH et al (2006) Positive association of obesity with single nucleotide polymorphisms of syndecan 3 in the Korean population. J Clin Endocrinol Metab 91(12):5095–5099, Epub 2006/10/05PubMedGoogle Scholar
  131. 131.
    Cassard AM, Bouillaud F, Mattei MG, Hentz E, Raimbault S, Thomas M et al (1990) Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4. J Cell Biochem 43(3):255–264, Epub 1990/07/01PubMedGoogle Scholar
  132. 132.
    Clement K, Ruiz J, Cassard-Doulcier AM, Bouillaud F, Ricquier D, Basdevant A et al (1996) Additive effect of A → G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta 3-adrenergic receptor gene on weight gain in morbid obesity. Int J Obes Relat Metab Disord 20(12):1062–1066, Epub 1996/12/01PubMedGoogle Scholar
  133. 133.
    Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier AM, Ricquier D et al (1994) DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. Int J Obes Relat Metab Disord 18(8):526–531, Epub 1994/08/01PubMedGoogle Scholar
  134. 134.
    Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K et al (2001) A role for ghrelin in the central regulation of feeding. Nature 409(6817):194–198, Epub 2001/02/24PubMedGoogle Scholar
  135. 135.
    Buckley MF, Loveland KA, McKinstry WJ, Garson OM, Goding JW (1990) Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location. J Biol Chem 265(29):17506–17511PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Endocrinology and DiabetesChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations