The genetic determinants of common human obesity



The genetic determinants of common human obesity have been elusive until recently, when work from several groups led to the identification of 16 loci that reproducibly associate with common human obesity. These loci reveal that the genetic architecture of common human obesity likely involves rare high penetrant loci, common low penetrant loci, and likely intermediate loci that are yet to be discovered. These loci implicate central nervous system processes in the pathophysiology of common human obesity, are not limited to effects in the central nervous system, and confirm a genetic susceptibility to obesity that may be harder for some individuals to overcome compared with others.

References and Recommended Reading

  1. 1.
    Ogden CL, Carroll MD, McDowell MA, Flegal KM: Obesity among adults in the United States-no statistically significant chance since 2003–2004. NCHS Data Brief 2007, 1:1–8.PubMedGoogle Scholar
  2. 2.
    Kopelman PG: Obesity as a medical problem. Nature 2000, 404:635–643.PubMedGoogle Scholar
  3. 3.
    Stunkard AJ, Foch TT, Hrubec Z: A twin study of human obesity. JAMA 1986, 256:51–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Allison DB, Kaprio J, Korkeila M, et al.: The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord 1996, 20:501–506.PubMedGoogle Scholar
  5. 5.
    Schousboe K, Willemsen G, Kyvik KO, et al.: Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries. Twin Res 2003, 6:409–421.CrossRefPubMedGoogle Scholar
  6. 6.
    Rose KM, Newman B, Mayer-Davis EJ, Selby JV: Genetic and behavioral determinants of waist-hip ratio and waist circumference in women twins. Obes Res 1998, 6:383–392.PubMedGoogle Scholar
  7. 7.
    Montague CT, Farooqi IS, Whitehead JP, et al.: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997, 387:903–908.CrossRefPubMedGoogle Scholar
  8. 8.
    Clement K, Vaisse C, Lahlou N, et al.: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998, 392:398–401.CrossRefPubMedGoogle Scholar
  9. 9.
    Farooqi IS, Keogh JM, Yeo GS, et al.: Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003, 348:1085–1095.CrossRefPubMedGoogle Scholar
  10. 10.
    O’Rahilly S, Farooqi IS: Genetics of obesity. Philos Trans R Soc Lond B Biol Sci 2006, 361:1095–1105.CrossRefPubMedGoogle Scholar
  11. 11.
    Han JC, Liu QR, Jones M, et al.: Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008, 359:918–927.CrossRefPubMedGoogle Scholar
  12. 12.
    Altshuler D, Pollara VJ, Cowles CR, et al.: An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 2000, 407:513–516.CrossRefPubMedGoogle Scholar
  13. 13.
    Frazer KA, Ballinger DG, Cox DR, et al.: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007, 449:851–861.CrossRefPubMedGoogle Scholar
  14. 14.
    Frayling TM, Timpson NJ, Weedon MN, et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316:889–894.CrossRefPubMedGoogle Scholar
  15. 15.
    Scuteri A, Sanna S, Chen WM, et al.: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007, 3:e115.CrossRefPubMedGoogle Scholar
  16. 16.
    Loos RJ, Lindgren CM, Li S, et al.: Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008, 40:768–775.CrossRefPubMedGoogle Scholar
  17. 17.
    Willer CJ, Speliotes EK, Loos RJ, et al.: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009, 41:25–34.CrossRefPubMedGoogle Scholar
  18. 18.
    Thorleifsson G, Walters GB, Gudbjartsson DF, et al.: Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009, 41:18–24.CrossRefPubMedGoogle Scholar
  19. 19.
    Lindgren CM, Heid IM, Randall JC, et al.: Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet 2009, 5:e1000508.CrossRefPubMedGoogle Scholar
  20. 20.
    Heard-Costa NL, Zillikens MC, Monda KL, et al.: NRXN3 is a novel locus for waist circumference: a genomewide association study from the CHARGE Consortium. PLoS Genet 2009, 5:e1000539.CrossRefPubMedGoogle Scholar
  21. 21.
    Ren D, Li M, Duan C, Rui L: Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2005, 2:95–104.CrossRefPubMedGoogle Scholar
  22. 22.
    Huszar D, Lynch CA, Fairchild-Huntress V, et al.: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88:131–141.CrossRefPubMedGoogle Scholar
  23. 23.
    Barsh GS, Schwartz MW: Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 2002, 3:589–600.CrossRefPubMedGoogle Scholar
  24. 24.
    Lyons WE, Mamounas LA, Ricaurte GA, et al.: Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 1999, 96:15239–15244.CrossRefPubMedGoogle Scholar
  25. 25.
    Kernie SG, Liebl DJ, Parada LF: BDNF regulates eating behavior and locomotor activity in mice. EMBO J 2000, 19:1290–1300.CrossRefPubMedGoogle Scholar
  26. 26.
    Rios M, Fan G, Fekete C, et al.: Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 2001, 15:1748–1757.CrossRefPubMedGoogle Scholar
  27. 27.
    Ribases M, Gratacos M, Fernandez-Aranda F, et al.: Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004, 13:1205–1212.CrossRefPubMedGoogle Scholar
  28. 28.
    Marg A, Spaltmann F, Plagge A, et al.: Neurotractin, a novel neurite outgrowth-promoting Ig-like protein that interacts with CEPU-1 and LAMP. J Cell Biol 1999, 145:865–876.CrossRefPubMedGoogle Scholar
  29. 29.
    Schafer M, Brauer AU, Savaskan NE, et al.: Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion. Mol Cell Neurosci 2005, 29:580–590.CrossRefPubMedGoogle Scholar
  30. 30.
    Kelai S, Maussion G, Noble F, et al.: Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction. Neuroreport 2008, 19:751–755.CrossRefPubMedGoogle Scholar
  31. 31.
    Anselme I, Laclef C, Lanaud M, et al.: Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes. Dev Biol 2007, 304:208–220.CrossRefPubMedGoogle Scholar
  32. 32.
    Gerken T, Girard CA, Tung YC, et al.: The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007, 318:1469–1472.CrossRefPubMedGoogle Scholar
  33. 33.
    Shu X, Fry AM, Tulloch B, et al.: RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin. Hum Mol Genet 2005, 14:1183–1197.CrossRefPubMedGoogle Scholar
  34. 34.
    Delous M, Baala L, Salomon R, et al.: The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007, 39:875–881.CrossRefPubMedGoogle Scholar
  35. 35.
    Arts HH, Doherty D, van Beersum SE, et al.: Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 2007, 39:882–888.CrossRefPubMedGoogle Scholar
  36. 36.
    Wolf MT, Saunier S, O’Toole JF, et al.: Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis. Kidney Int 2007, 72:1520–1526.CrossRefPubMedGoogle Scholar
  37. 37.
    Vierkotten J, Dildrop R, Peters T, et al.: Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 2007, 134:2569–2577.CrossRefPubMedGoogle Scholar
  38. 38.
    Stratigopoulos G, Padilla SL, LeDuc CA, et al.: Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 2008, 294:R1185–1196.PubMedGoogle Scholar
  39. 39.
    Enoch MA, Schwartz L, Albaugh B, et al.: Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:599–607.CrossRefPubMedGoogle Scholar
  40. 40.
    Grinberg M, Schwarz M, Zaltsman Y, et al.: Mitochondrial carrier homolog 2 is a target of tBID in cells signaled to die by tumor necrosis factor alpha. Mol Cell Biol 2005, 25:4579–4590.CrossRefPubMedGoogle Scholar
  41. 41.
    Somia NV, Schmitt MJ, Vetter DE, et al.: LFG: an antiapoptotic gene that provides protection from Fas-mediated cell death. Proc Nat Acad Sci USA 1999, 96:12667–12672.CrossRefPubMedGoogle Scholar
  42. 42.
    Moser M, Pscherer A, Roth C, et al.: Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2B. Genes Dev 1997, 11:1938–1948.CrossRefPubMedGoogle Scholar
  43. 43.
    Tsukada S, Tanaka Y, Maegawa H, et al.: Intronic polymorphisms within TFAP2B regulate transcriptional activity and affect adipocytokine gene expression in differentiated adipocytes. Mol Endocrinol 2006, 20:1104–1111.CrossRefPubMedGoogle Scholar
  44. 44.
    Steinberg GR, Kemp BE, Watt MJ: Adipocyte triglyceride lipase expression in human obesity. Am J Physiol Endocrinol Metab 2007, 293:E958–964.CrossRefPubMedGoogle Scholar
  45. 45.
    Schlesser HN, Simon L, Hofmann MC, et al.: Effects of ETV5 (ETS variant gene 5) on testis and body growth, time course of spermatogonial stem cell loss, and fertility in mice. Biol Reprod 2008, 78:483–489.CrossRefPubMedGoogle Scholar
  46. 46.
    Supek F, Madden DT, Hamamoto S, et al.: Sec16p potentiates the action of COPII proteins to bud transport vesicles. J Cell Biol 2002, 158:1029–1038.CrossRefPubMedGoogle Scholar
  47. 47.
    Moskovitz J, Bar-Noy S, Williams WM, et al.: Methionine sulfoxide reductase (MsrA) is a regulator of antioxidant defense and lifespan in mammals. Proc Nat Acad Sci USA 2001, 98:12920–12925.CrossRefPubMedGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Gastrointestinal Unit, Department of MedicineMassachusetts General HospitalBostonUSA

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