The genetics of obesity

Blanca M Herrera, Cecilia M Lindgren, Blanca M Herrera, Cecilia M Lindgren

Abstract

Obesity is a result of excess body fat accumulation. This excess is associated with adverse health effects such as CVD, type 2 diabetes, and cancer. The development of obesity has an evident environmental contribution, but as shown by heritability estimates of 40% to 70%, a genetic susceptibility component is also needed. Progress in understanding the etiology has been slow, with findings largely restricted to monogenic, severe forms of obesity. However, technological and analytical advances have enabled detection of more than 20 obesity susceptibility loci. These contain genes suggested to be involved in the regulation of food intake through action in the central nervous system as well as in adipocyte function. These results provide plausible biological pathways that may, in the future, be targeted as part of treatment or prevention strategies. Although the proportion of heritability explained by these genes is small, their detection heralds a new phase in understanding the etiology of common obesity.

Figures

Fig. 1
Fig. 1
Genes associated with obesity-related anthropometric measures. BMI body mass index, WC waist circumference, WHR waist to hip ratio. aIndicates type 2 diabetes association. bIndicates association with monogenic obesity

References

    1. O'Rahilly S. Human genetics illuminates the paths to metabolic disease. Nature. 2009;462:307–314. doi: 10.1038/nature08532.
    1. Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298:2028–2037. doi: 10.1001/jama.298.17.2028.
    1. Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359:2105–2120. doi: 10.1056/NEJMoa0801891.
    1. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA. 2003;289:187–193. doi: 10.1001/jama.289.2.187.
    1. Teucher B, Rohrmann S, Kaaks R: Obesity: focus on all-cause mortality and cancer. Maturitas 65:112–116.
    1. World Health Organization . Obesity: preventing and managing the global epidemic: report of a WHO Consultation on Obesity, Geneva, 3–5 June, 1997. Geneva: World Health Organization; 1998.
    1. Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology. 2007;132:2087–2102. doi: 10.1053/j.gastro.2007.03.052.
    1. The Health and Social Care Information Centre: Statistics on obesity, physical activity and diet, England 2006. Available at . Accessed September 2010.
    1. Berghofer A, Pischon T, Reinhold T, et al. Obesity prevalence from a European perspective: a systematic review. BMC Public Health. 2008;8:200. doi: 10.1186/1471-2458-8-200.
    1. Cuevas A, Alvarez V, Olivos C. The emerging obesity problem in Latin America. Expert Rev Cardiovasc Ther. 2009;7:281–288. doi: 10.1586/14779072.7.3.281.
    1. Jia WP, Wang C, Jiang S, Pan JM. Characteristics of obesity and its related disorders in China. Biomed Environ Sci. 2010;23:4–11. doi: 10.1016/S0895-3988(10)60025-6.
    1. Sniderman AD, Bhopal R, Prabhakaran D, et al. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol. 2007;36:220–225. doi: 10.1093/ije/dyl245.
    1. Coll AP, Farooqi IS, Challis BG, et al. Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab. 2004;89:2557–2562. doi: 10.1210/jc.2004-0428.
    1. Shapira NA, Lessig MC, He AG, et al. Satiety dysfunction in Prader-Willi syndrome demonstrated by fMRI. J Neurol Neurosurg Psychiatry. 2005;76:260–262. doi: 10.1136/jnnp.2004.039024.
    1. Rankinen T, Zuberi A, Chagnon YC, et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring) 2006;14:529–644. doi: 10.1038/oby.2006.71.
    1. Wiklund P, Toss F, Weinehall L, et al. Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women. J Clin Endocrinol Metab. 2008;93:4360–4366. doi: 10.1210/jc.2008-0804.
    1. 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. doi: 10.1371/journal.pgen.1000508.
    1. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H. Genetic versus environmental aetiology of the metabolic syndrome among male and female twins. Diabetologia. 2001;44:537–543. doi: 10.1007/s001250051659.
    1. Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. JAMA. 1986;256:51–54. doi: 10.1001/jama.256.1.51.
    1. Turula M, Kaprio J, Rissanen A, Koskenvuo M. Body weight in the Finnish Twin Cohort. Diabetes Res Clin Pract. 1990;10(Suppl 1):S33–S36. doi: 10.1016/0168-8227(90)90137-I.
    1. Wardle J, Carnell S, Haworth CM, Plomin R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr. 2008;87:398–404.
    1. Stunkard AJ, Sorensen TI, Hanis C, et al. An adoption study of human obesity. N Engl J Med. 1986;314:193–198. doi: 10.1056/NEJM198601233140401.
    1. Moll PP, Burns TL, Lauer RM. The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study. Am J Hum Genet. 1991;49:1243–1255.
    1. Magnusson PK, Rasmussen F. Familial resemblance of body mass index and familial risk of high and low body mass index. A study of young men in Sweden. Int J Obes Relat Metab Disord. 2002;26:1225–1231. doi: 10.1038/sj.ijo.0802041.
    1. Selby JV, Newman B, Quesenberry CP, Jr, et al. Evidence of genetic influence on central body fat in middle-aged twins. Hum Biol. 1989;61:179–194.
    1. 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.
    1. Eaton SB, Konner M, Shostak M. Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med. 1988;84:739–749. doi: 10.1016/0002-9343(88)90113-1.
    1. Saunders CL, Chiodini BD, Sham P, et al. Meta-analysis of genome-wide linkage studies in BMI and obesity. Obesity (Silver Spring) 2007;15:2263–2275. doi: 10.1038/oby.2007.269.
    1. 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. doi: 10.1126/science.1141634.
    1. 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. doi: 10.1371/journal.pgen.0030115.
    1. International HapMap Consortium A haplotype map of the human genome. Nature. 2005;437:1299–1320. doi: 10.1038/nature04226.
    1. National Center for Biotechnology Information, National Library of Medicine: Database of Single Nucleotide Polymorphisms—dbSNP Build ID: 131. Available at . Accessed September 2010.
    1. Barrett JC, Cardon LR. Evaluating coverage of genome-wide association studies. Nat Genet. 2006;38:659–662. doi: 10.1038/ng1801.
    1. Pe’er I, de Bakker PI, Maller J, et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat Genet. 2006;38:663–667. doi: 10.1038/ng1816.
    1. Chambers JC, Elliott P, Zabaneh D, et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet. 2008;40:716–718. doi: 10.1038/ng.156.
    1. 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. doi: 10.1038/ng.287.
    1. 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. doi: 10.1038/ng.274.
    1. Meyre D, Delplanque J, Chevre JC, et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet. 2009;41:157–159. doi: 10.1038/ng.301.
    1. Scherag A, Dina C, Hinney A, et al. Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet. 2010;6:e1000916. doi: 10.1371/journal.pgen.1000916.
    1. 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. doi: 10.1038/ng.140.
    1. 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. doi: 10.1126/science.1151710.
    1. Fredriksson R, Hagglund M, Olszewski PK, et al. The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology. 2008;149:2062–2071. doi: 10.1210/en.2007-1457.
    1. Wardle J, Llewellyn C, Sanderson S, Plomin R. The FTO gene and measured food intake in children. Int J Obes (Lond) 2009;33:42–45. doi: 10.1038/ijo.2008.174.
    1. O’Rahilly S, Farooqi IS. Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions. Diabetes. 2008;57:2905–2910. doi: 10.2337/db08-0210.
    1. 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. doi: 10.1016/S0092-8674(00)81865-6.
    1. Li Z, Zhou Y, Carter-Su C, et al. SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanisms. Mol Endocrinol. 2007;21:2270–2281. doi: 10.1210/me.2007-0111.
    1. Gratacos M, Gonzalez JR, Mercader JM, et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61:911–922. doi: 10.1016/j.biopsych.2006.08.025.
    1. Heard-Costa NL, Zillikens MC, Monda KL, et al. NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet. 2009;5:e1000539. doi: 10.1371/journal.pgen.1000539.
    1. Jurvansuu J, Zhao Y, Leung DS, et al. Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res. 2008;68:4614–4622. doi: 10.1158/0008-5472.CAN-07-5291.
    1. Virtue S, Vidal-Puig A. It’s not how fat you are, it’s what you do with it that counts. PLoS Biol. 2008;6:e237. doi: 10.1371/journal.pbio.0060237.
    1. Zillikens MC, Yazdanpanah M, Pardo LM, et al. Sex-specific genetic effects influence variation in body composition. Diabetologia. 2008;51:2233–2241. doi: 10.1007/s00125-008-1163-0.
    1. Jamshidi Y, Snieder H, Ge D, et al. The SH2B gene is associated with serum leptin and body fat in normal female twins. Obesity (Silver Spring) 2007;15:5–9. doi: 10.1038/oby.2007.637.
    1. Cho YS, Go MJ, Kim YJ, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527–534. doi: 10.1038/ng.357.
    1. Stutzmann F, Vatin V, Cauchi S, et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet. 2007;16:1837–1844. doi: 10.1093/hmg/ddm132.
    1. Benzinou M, Creemers JW, Choquet H, et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet. 2008;40:943–945. doi: 10.1038/ng.177.
    1. Shugart YY, Chen L, Day IN, et al. Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI. Eur J Hum Genet. 2009;17:1050–1055. doi: 10.1038/ejhg.2008.272.
    1. Conrad DF, Pinto D, Redon R, et al. Origins and functional impact of copy number variation in the human genome. Nature. 2010;464:704–712. doi: 10.1038/nature08516.
    1. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753. doi: 10.1038/nature08494.
    1. McCarroll SA, Kuruvilla FG, Korn JM, et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008;40:1166–1174. doi: 10.1038/ng.238.
    1. Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010;463:671–675. doi: 10.1038/nature08727.
    1. Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2010;463:666–670. doi: 10.1038/nature08689.
    1. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–247. doi: 10.1056/NEJMoa063988.
    1. Morris DL, Cho KW, Zhou Y, Rui L. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes. 2009;58:2039–2047. doi: 10.2337/db08-1388.
    1. Krutzfeldt J, Stoffel M. MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metab. 2006;4:9–12. doi: 10.1016/j.cmet.2006.05.009.
    1. Xie H, Sun L, Lodish HF. Targeting microRNAs in obesity. Expert Opin Ther Targets. 2009;13:1227–1238. doi: 10.1517/14728220903190707.
    1. Bird A. Perceptions of epigenetics. Nature. 2007;447:396–398. doi: 10.1038/nature05913.
    1. Stoger R. Epigenetics and obesity. Pharmacogenomics. 2008;9:1851–1860. doi: 10.2217/14622416.9.12.1851.
    1. Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition. 2004;20:63–68. doi: 10.1016/j.nut.2003.09.011.
    1. Bluher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol. 2010;21:38–43. doi: 10.1097/MOL.0b013e3283346ccc.
    1. Freathy RM, Timpson NJ, Lawlor DA, et al. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI. Diabetes. 2008;57:1419–1426. doi: 10.2337/db07-1466.
    1. Cotsapas C, Speliotes EK, Hatoum IJ, et al. Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet. 2009;18:3502–3507. doi: 10.1093/hmg/ddp292.
    1. Hinney A, Nguyen TT, Scherag A, et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One. 2007;2:e1361. doi: 10.1371/journal.pone.0001361.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren