Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-23T23:09:09.712Z Has data issue: false hasContentIssue false
  • English
  • Français

Genetics of human obesity

Published online by Cambridge University Press:  07 March 2007

Karine Clément
Karine Clément*
Affiliation:
Inserm ‘Avenir’, Paris, EA3502 and Paris 6 University, Nutrition Department, Hôtel-Dieu Hospital, AP/HP, Place du Parvis Notre-Dame, 75004, Paris, France
*
Corresponding author: Dr Karine Clément, fax +33 1 40 51 00 57, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The rapid development of new concepts and tools has led to a change in the way in which researchers carry out nutrition-related research. Obesity is determined by the interaction between predisposing genetic and environmental aspects, but at present the gene–gene and gene–environment interactions contributing to the development of this complex disease cannot be analysed in detail. The purpose of the present paper is to provide some examples of the knowledge that is available in the field of obesity genetics, and also the new strategies being developed that are aimed at studying the relative contribution of numerous genes to obesity and their responses to environmental changes. In the rare cases of monogenic obesities in which a major gene is the cause the molecular approach has proved extremely powerful in the identification of the genes responsible and in defining new syndromes. However, in the common forms of obesity (polygenic obesity) most studies have analysed genotype–phenotype associations without sometimes taking into account the influence of environmental factors (diet, sedentary lifestyle). Among the aspects limiting this integrated approach to obesity are the difficulty of having large enough samples and the expansion of biocomputing tools developed for accessing the question of multiple interactions with no a priori hypotheses. This picture is rapidly changing. Large databases of clinical data and DNA and biological sample banks with more precise environmental information and patient phenotypes are being compiled. The capacity for studying multiple genes simultaneously at the DNA or RNA levels is also possible. Finally, the tremendous progress in biocomputing will allow the integration of these different types of data (relating to environment, phenotype, genotype, gene expression) and will improve the ability to deal with this complex disease.

Keywords

Obesity geneticsMonogenic obesityPolygenic obesityCandidate genesEnvironmental factors
Type
Symposium on ‘Genes, behaviour and environment’
Information
Proceedings of the Nutrition Society , Volume 64 , Issue 2 , May 2005 , pp. 133 - 142
Copyright
Copyright © The Nutrition Society 2005

References

Allison, DB & Heo, M (1998) Meta-analysis of linkage data under worst-case conditions: a demonstration using the human OB region. Genetics 148, 859–865.CrossRefGoogle ScholarPubMed
Altshuler, D, Hirschhorn, JN, Klannemark, M, Lindgren, CM, Vohl, MC & Nemesh, J et al. . (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genetics 26, 76–80.CrossRefGoogle ScholarPubMed
Ardlie, KG, Lunetta, KL & Seielstad, M (2002) Testing for population subdivision and association in four case-control studies. American Journal of Human Genetics 71, 304–311.CrossRefGoogle ScholarPubMed
Arya, R, Duggirala, R, Jenkinson, CP, Almasy, L, Blangero, J, O'Connell, P & Stern, MP (2004) Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in Mexican Americans. American Journal of Human Genetics 74, 272–282.CrossRefGoogle ScholarPubMed
Barsh, GS, Farooqi, IS, O'Rahilly, S (2000) Genetics of body-weight regulation. Nature 404, 644–651.CrossRefGoogle ScholarPubMed
Becker, KG (2004) The common variants/multiple disease hypothesis of common complex genetic disorders. Medical Hypotheses 62, 309–317.CrossRefGoogle ScholarPubMed
Bell, CG, Benzinou, M, Siddiq, A, Lecoeur, C, Dina, C & Lemainque, A et al. . (2004) Genome-wide linkage analysis for severe obesity in French Caucasians finds significant susceptibility locus on chromosome 19q. Diabetes 53, 1857–1865.CrossRefGoogle ScholarPubMed
Bennermo, M, Held, C, Stemme, S, Ericsson, CG, Silveira, A, Green, F & Tornvall, P (2004) Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases. Clinical Chemistry 50, 2136–2140.CrossRefGoogle ScholarPubMed
Bouchard, C (1991) Current understanding of the etiology of obesity: genetic and nongenetic factors. American Journal of Clinical Nutrition 53, Suppl., 1561S–1565S.CrossRefGoogle ScholarPubMed
Boutin, P, Dina, C, Vasseur, F, Dubois, S, Corset, L, Seron, K et al. . (2003) GAD2 on chromosome 10p12 is a candidate gene for human obesity. PLoS Biology 1 E68.CrossRefGoogle ScholarPubMed
Branson, R, Potoczna, N, Kral, JG, Lentes, KU, Hoehe, MR & Horber, FF (2003) Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. New England Journal of Medicine 348, 1096–1103.CrossRefGoogle Scholar
Carmelli, D, Cardon, LR & Fabsitz, R (1994) Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments. American Journal of Human Genetics 55, 566–573.Google ScholarPubMed
Clement, K & Ferre, P (2003) Genetics and the pathophysiology of obesity. Pediatric Research 53, 721–725.CrossRefGoogle ScholarPubMed
Clement, K, Ruiz, J, Cassard-Doulcier, AM, Bouillaud, F, Ricquier, D, Basdevant, A, Guy-Grand, B & Froguel, P (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. International Journal of Obesity and Related Metabolic Disorders 20, 1062–1066.Google ScholarPubMed
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, 398–401.CrossRefGoogle ScholarPubMed
Cone, RD (2000) The melanocortin-4 receptor.In The Melanocortin Receptors 405–448 NJ, Totowa: Humana Press.CrossRefGoogle Scholar
Dempfle, A, Hinney, A, Heinzel-Gutenbrunner, M, Raab, M, Geller, F, Gudermann, T, Schafer, H & Hebebrand, J (2004) Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index (letter). Journal of Medical Genetics 41, 795–800.CrossRefGoogle Scholar
Dong, C, WD, Li, Li, D & Price, RA (2005) Interaction between obesity-susceptibility loci in chromosome regions 2p25-p24 and 13 q13-q21. European Journal of Human Genetics 13, 102–108.CrossRefGoogle Scholar
Dubern, B, Clement, K, Pelloux, V, Froguel, P, Girardet, JP, Guy-Grand, B & Tounian, P (2001) Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. Journal of Pediatrics 139, 204–209.CrossRefGoogle ScholarPubMed
Fan, Y, Esmail, MA, Ansley, SJ, Blacque, OE, Boroevich, K, Ross, AJ et al. . (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nature Genetics 36, 989–993.CrossRefGoogle Scholar
Farooqi, IS, Keogh, JM, Kamath, S, Jones, S, Gibson, WT, Trussell, R, Jebb, SA, Lip, GY, O'Rahilly, S (2001) Partial leptin deficiency and human adiposity. Nature 414, 34–35.CrossRefGoogle ScholarPubMed
Farooqi, IS, Keogh, JM, Yeo, GS, Lank, EJ, Cheetham, T, O'Rahilly, S (2003a) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New England Journal of Medicine 348, 1085–1095.CrossRefGoogle ScholarPubMed
Farooqi, IS, Matarese, G, Lord, GM, Keogh, JM, Lawrence, E, Agwu, C et al. . (2002) Beneficial effects of leptin on obesity T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation 110, 1093–1103.CrossRefGoogle ScholarPubMed
Farooqi, IS, O'Rahilly, S (2004) Monogenic human obesity syndromes. Recent Progress in Hormone Research 59, 409–424.CrossRefGoogle ScholarPubMed
Farooqi, IS, Yeo, GS, Keogh, JM, Aminian, S, Jebb, SA, Butler, G, Cheetham, T, O'Rahilly, S (2000) Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. Journal of Clinical Investigation 106, 271–279.CrossRefGoogle ScholarPubMed
Farooqi, IS, Yeo, GS, O'Rahilly, S (2003b) Binge eating as a phenotype of melanocortin 4 receptor gene mutations. New England Journal of Medicine 349, 606–609.Google ScholarPubMed
Feitosa, MF, Borecki, IB, Rich, SS, Arnett, DK, Sholinsky, P, Myers, RH, Leppert, M & Province, MA (2002) Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart Lung, and Blood Institute Family Heart Study. American Journal of Human Genetics 70, 72–82.CrossRefGoogle ScholarPubMed
Flodmark, CE, Lissau, I, Moreno, LA, Pietrobelli, A & Widhalm, K (2004) New insights into the field of children and adolescents' obesity: the European perspective. International Journal of Obesity and Related Metabolic Disorders 28, 1189–1196.CrossRefGoogle ScholarPubMed
Gotoda, T (2003) Binge eating as a phenotype of melanocortin 4 receptor gene mutations. New England Journal of Medicine 349, 606–609.Google ScholarPubMed
Hager, J, Dina, C, Francke, S, Dubois, S, Houari, M, Vatin, V et al. . (1998) A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nature Genetics 20, 304–308.CrossRefGoogle Scholar
Hebebrand, J, Friedel, S, Schauble, N, Geller, F & Hinney, A (2003) Perspectives: molecular genetic research in human obesity. Obesity Reviews 4, 139–146.CrossRefGoogle ScholarPubMed
Hebebrand, J, Geller, F, Dempfle, A, Heinzel-Gutenbrunner, M, Raab, M, Gerber, G et al. . (2004) Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations. Molecular Psychiatry 9, 796–800.CrossRefGoogle Scholar
Heijmans, BT, Beem, AL, Willemsen, G, Posthuma, D, Slagboom, PE & Boomsma, D (2004) Further evidence for a QTL influencing body mass index on chromosome 7p from a genome-wide scan in Dutch families. Twin Research 7, 192–196.CrossRefGoogle ScholarPubMed
Herpertz, S, Siffert, W & Hebebrand, J (2003) Binge eating as a phenotype of melanocortin 4 receptor gene mutations. New England Journal of Medicine 349, 606–609.Google ScholarPubMed
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. Journal of Clinical Endocrinology and Metabolism 84, 1483–1486.CrossRefGoogle Scholar
Hoh, J & Ott, J (2004) Genetic dissection of diseases: design and methods. Current Opinion in Genetics and Development 14, 229–232.CrossRefGoogle ScholarPubMed
Holder, JL, Butte, NF, Zinn, AR, Holder, JL Jr (2000) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Human Molecular Genetics 9, 101–108.Google ScholarPubMed
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, 131–141.CrossRefGoogle ScholarPubMed
Jackson, RS, Creemers, JW, Farooqi, IS, Raffin-Sanson, ML, Varro, A, Dockray, GJ et al. . (2003) Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. Journal of Clinical Investigation 112, 1550–1560.CrossRefGoogle ScholarPubMed
Jackson, RS, Creemers, JW, Ohagi, S, Raffin-Sanson, ML, Sanders, L, Montague, CT, Hutton, JC, O'Rahilly, S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genetics 16, 303–306.CrossRefGoogle ScholarPubMed
Jacobson, P, Ukkola, O, Rankinen, T, Snyder, EE, Leon, AS, Rao, DC et al. . (2002) Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort. Journal of Clinical Endocrinology and Metabolism 87, 4442–4446.CrossRefGoogle Scholar
Jiang, Y, Wilk, JB, Borecki, I, Williamson, S, DeStefano, AL, Xu, G, Liu, J, Ellison, RC, Province, M & Myers, RH (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. American Journal of Human Genetics 75, 220–230.CrossRefGoogle ScholarPubMed
Katsanis, N, Ansley, SJ, Badano, JL, Eichers, ER, Lewis, RA, Hoskins, BE, Scambler, PJ, Davidson, WS, Beales, PL & Lupski, JR (2001a) Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293, 2256–2259.CrossRefGoogle ScholarPubMed
Katsanis, N, Lupski, JR & Beales, PL (2001b) Exploring the molecular basis of Bardet-Biedl syndrome. Human Molecular Genetics 10, 2293–2299.CrossRefGoogle ScholarPubMed
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. Nature Genetics 19, 155–157.CrossRefGoogle ScholarPubMed
Lander, ES (1996) The new genomics: global views of biology. Science 274, 536–539.CrossRefGoogle ScholarPubMed
Larsen, LH, Echwald, SM, Sorensen, TI, Andersen, T, Wulff, BS & Pedersen, O (2005) Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. Journal of Clinical Endocrinology and Metabolism 90, 219–224.CrossRefGoogle ScholarPubMed
Le Stunff, C, Fallin, D, Schork, NJ & Bougneres, P (2000) The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nature Genetics 26, 444–446.CrossRefGoogle ScholarPubMed
Lubrano-Berthelier, C, Durand, E, Dubern, B, Shapiro, A, Dazin, P, Weill, J, Ferron, C, Froguel, P & Vaisse, C (2003) Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Human Molecular Genetics 12, 145–153.CrossRefGoogle ScholarPubMed
Lubrano-Berthelier, C, Le Stunff, C, Bougneres, P & Vaisse, C (2004) A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. Journal of Clinical Endocrinology and Metabolism 89, 2028–2032.CrossRefGoogle ScholarPubMed
Miraglia, Del, Giudice, E, Cirillo, G, Nigro, V, Santoro, N, D'Urso, L, Raimondo, P, Cozzolino, D, Scafato, D & Perrone, L (2002) Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity. International Journal of Obesity and Related Metabolic Disorders 26, 647–651.CrossRefGoogle Scholar
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, 903–908.CrossRefGoogle ScholarPubMed
Mykytyn, K, Nishimura, DY, Searby, CC, Shastri, M, Yen, HJ, Beck, JS et al. . (2002) Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nature Genetics 31, 435–438.CrossRefGoogle ScholarPubMed
Nijenhuis, WA, Oosterom, J & Adan, RA (2001) AgRP(83–132) acts as an inverse agonist on the human-melanocortin-4 receptor. Molecular Endocrinology 15, 164–171.Google ScholarPubMed
Perusse, L & Bouchard, C (2000) Gene–diet interactions in obesity. American Journal of Clinical Nutrition 72, Suppl., 285S–290S.CrossRefGoogle ScholarPubMed
Perusse, L & Bouchard, C (2003) Genetique de l‘obésité et des complications métaboliques dans l’obésité (Genetics of obesity and metabolic complications in the Quebec Family Study). Médecine Sciences 19, 937–942.Google Scholar
Pritchard, JK (2001) Are rare variants responsible for susceptibility to complex diseases. American Journal of Human Genetics 69, 124–137.CrossRefGoogle ScholarPubMed
Saar, K, Geller, F, Ruschendorf, F, Reis, A, Friedel, S, Schauble, N et al. . (2003) Genome scan for childhood and adolescent obesity in German families. Pediatrics 111, 321–327.CrossRefGoogle ScholarPubMed
Slavotinek, AM, Searby, C, Al-Gazali, L, Hennekam, RC, Schrander-Stumpel, C, Orcana-Losa, M et al. . (2002) Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients. Human Genetics 110, 561–567.CrossRefGoogle ScholarPubMed
Snyder, EE, Walts, B, Perusse, L, Chagnon, YC, Weisnagel, SJ, Rankinen, T & Bouchard, C (2004) The human obesity gene map: the 2003 update. Obesity Research 12, 369–439.CrossRefGoogle ScholarPubMed
Srinivasan, S, Lubrano-Berthelier, C, Govaerts, C, Picard, F, Santiago, P, Conklin, BR & Vaisse, C (2004) Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. Journal of Clinical Investigation 114, 1158–1164.CrossRefGoogle Scholar
Stefan, M & Nicholls, RD (2004) What have rare genetic syndromes taught us about the pathophysiology of the common forms of obesity. Current Diabetes Reports 4, 143–150.CrossRefGoogle ScholarPubMed
Stunkard, AJ, Harris, JR, Pedersen, NL & McClearn, GE (1990) The body-mass index of twins who have been reared apart. New England Journal of Medicine 322, 1483–1487.CrossRefGoogle ScholarPubMed
Suviolahti, E, Oksanen, LJ, Ohman, M, Cantor, RM, Ridderstrale, M, Tuomi, T et al. . (2003) The SLC6A14 gene shows evidence of association with obesity. Journal of Clinical Investigation 112, 1762–1772.CrossRefGoogle ScholarPubMed
Troiano, RP & Flegal, KM (1998) Overweight children and adolescents: description, epidemiology, and demographics. Pediatrics 101, 497–504.CrossRefGoogle ScholarPubMed
Vaisse, C, Clement, K, Durand, E, Hercberg, S, Guy-Grand, B & Froguel, P (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. Journal of Clinical Investigation 106, 253–262.CrossRefGoogle ScholarPubMed
Vaisse, C, Clement, K, Guy-Grand, B & Froguel, P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genetics 20, 113–114.CrossRefGoogle ScholarPubMed
Verdich, C, Clement, K, Sørensen, TIA (2004) Nutrient–gene interactions in the control of obesity.In Functional Foods; Aging and Degenerative Disease, 219–259 [Remacle, CReusen, B, editors]. Cambridge: Woodhead Publishing Ltd.Google Scholar
Wernstedt, I, Eriksson, AL, Berndtsson, A, Hoffstedt, J, Skrtic, S, Hedner, T, Hulten, LM, Wiklund, O, Ohlsson, C & Jansson, JO (2004) A common polymorphism in the interleukin-6 gene promoter is associated with overweight. International Journal of Obesity and Related Metabolic Disorders 28, 1272–1279.CrossRefGoogle ScholarPubMed
Wolford, JK, Colligan, PB, Gruber, JD & Bogardus, C (2003) Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians. Molecular Genetics and Metabolism 80, 338–343.CrossRefGoogle ScholarPubMed
Xu, B, Goulding, EH, Zang, K, Cepoi, D, Cone, RD, Jones, KR, Tecott, LH & Reichardt, LF (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nature Neuroscience 6, 736–742.CrossRefGoogle ScholarPubMed
Yeo, GS, Connie, Hung, CC, Rochford, J, Keogh, J, Gray, J, Sivaramakrishnan, O'Rahilly, S, Farooqi, IS (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nature Neuroscience 7, 1187–1189.CrossRefGoogle Scholar