The genetics of obesity

Current Diabetes Reports

Volumn 10, Issue 6, 2010, Pages 498-505

  Herrera, Blanca M ^a   Lindgren, Cecilia M ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

BMI; Common obesity; Genetics; GWA; Susceptibility; WHR

Indexed keywords

UNTRANSLATED RNA;

ADIPOCYTE; BODY MASS; COPY NUMBER VARIATION; DISEASE SEVERITY; EPIGENETICS; FOOD INTAKE; GENE IDENTIFICATION; GENE LOCATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HERITABILITY; HUMAN; METABOLIC DISORDER; NONHUMAN; OBESITY; PATHOGENESIS; PHENOTYPE; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

ANIMALS; BODY MASS INDEX; EATING; GENETIC PREDISPOSITION TO DISEASE; HUMANS; OBESITY;

EID: 77958488285     PISSN: 15344827     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11892-010-0153-z     Document Type: Review

References (72)

1. S O'Rahilly 2009 Human genetics illuminates the paths to metabolic disease Nature 462 307 314 10.1038/nature08532 19924209
2. KM Flegal BI Graubard DF Williamson MH Gail 2007 Cause-specific excess deaths associated with underweight, overweight, and obesity JAMA 298 2028 2037 1:CAS:528:DC%2BD2sXht1yjsLjF 10.1001/jama.298.17.2028 17986696 (Pubitemid 350074800)
3. T Pischon H Boeing K Hoffmann, et al. 2008 General and abdominal adiposity and risk of death in Europe N Engl J Med 359 2105 2120 1:CAS:528:DC%2BD1cXhtlOrsrnJ 10.1056/NEJMoa0801891 19005195
4. KR Fontaine DT Redden C Wang, et al. 2003 Years of life lost due to obesity JAMA 289 187 193 10.1001/jama.289.2.187 12517229 (Pubitemid 36068706)
5. Teucher B, Rohrmann S, Kaaks R: Obesity: focus on all-cause mortality and cancer. Maturitas 65:112-116.
6. 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.
7. CL Ogden SZ Yanovski MD Carroll KM Flegal 2007 The epidemiology of obesity Gastroenterology 132 2087 2102 10.1053/j.gastro.2007.03.052 17498505 (Pubitemid 46693751)
8. The Health and Social Care Information Centre: Statistics on obesity, physical activity and diet, England 2006. Available at http://www.ic.nhs.uk/ statistics-and-data-collections/health-and-lifestyles/obesity/ statistics-on-obesity-physical-activity-and-diet-england-2006. Accessed September 2010.
9. A Berghofer T Pischon T Reinhold, et al. 2008 Obesity prevalence from a European perspective: a systematic review BMC Public Health 8 200 10.1186/1471-2458-8-200 18533989 (Pubitemid 351907992)
10. A Cuevas V Alvarez C Olivos 2009 The emerging obesity problem in Latin America Expert Rev Cardiovasc Ther 7 281 288 10.1586/14779072.7.3.281 19296766
11. WP Jia C Wang S Jiang JM Pan 2010 Characteristics of obesity and its related disorders in China Biomed Environ Sci 23 4 11 1:CAS:528: DC%2BC3cXlt1OlsbY%3D 10.1016/S0895-3988(10)60025-6 20486430
12. AD Sniderman R Bhopal D Prabhakaran, et al. 2007 Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis Int J Epidemiol 36 220 225 10.1093/ije/dyl245 17510078 (Pubitemid 47061601)
13. AP Coll IS Farooqi BG Challis, et al. 2004 Proopiomelanocortin and energy balance: insights from human and murine genetics J Clin Endocrinol Metab 89 2557 2562 1:CAS:528:DC%2BD2cXmtlGqt7g%3D 10.1210/jc.2004-0428 15181023 (Pubitemid 38766331)
14. NA Shapira MC Lessig AG He, et al. 2005 Satiety dysfunction in Prader-Willi syndrome demonstrated by fMRI J Neurol Neurosurg Psychiatry 76 260 262 1:STN:280:DC%2BD2M%2FislSrug%3D%3D 10.1136/jnnp.2004.039024 15654046 (Pubitemid 40143720)
15. T Rankinen A Zuberi YC Chagnon, et al. 2006 The human obesity gene map: the 2005 update Obesity (Silver Spring) 14 529 644 10.1038/oby.2006.71
16. P Wiklund F Toss L Weinehall, et al. 2008 Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women J Clin Endocrinol Metab 93 4360 4366 1:CAS:528:DC%2BD1cXhtlyqs7bK 10.1210/jc.2008-0804 18728169 (Pubitemid 352789532)
17. CM Lindgren IM Heid JC Randall, et al. 2009 Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution PLoS Genet 5 e1000508 10.1371/journal.pgen.1000508 19557161 This is a large collaborative meta-analysis that identified the first robustly WHR-associated locus, which shows a strong sex-specific association in women
18. P Poulsen A Vaag K Kyvik H Beck-Nielsen 2001 Genetic versus environmental aetiology of the metabolic syndrome among male and female twins Diabetologia 44 537 543 1:CAS:528:DC%2BD3MXivVSisrk%3D 10.1007/s001250051659 11380071 (Pubitemid 32411269)
19. AJ Stunkard TT Foch Z Hrubec 1986 A twin study of human obesity JAMA 256 51 54 1:STN:280:DyaL283isl2lsg%3D%3D 10.1001/jama.256.1.51 3712713 (Pubitemid 16093199)
20. M Turula J Kaprio A Rissanen M Koskenvuo 1990 Body weight in the Finnish Twin Cohort Diabetes Res Clin Pract 10 Suppl 1 S33 S36 10.1016/0168-8227(90) 90137-I 2286148 (Pubitemid 20315095)
21. J Wardle S Carnell CM Haworth R Plomin 2008 Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment Am J Clin Nutr 87 398 404 1:CAS:528:DC%2BD1cXitFajtr4%3D 18258631
22. AJ Stunkard TI Sorensen C Hanis, et al. 1986 An adoption study of human obesity N Engl J Med 314 193 198 1:STN:280:DyaL28%2Fpt1Whuw%3D%3D 10.1056/NEJM198601233140401 3941707
23. PP Moll TL Burns RM Lauer 1991 The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study Am J Hum Genet 49 1243 1255 1:STN:280:DyaK38%2FotFOksg%3D%3D 1746554
24. PK Magnusson F Rasmussen 2002 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 26 1225 1231 1:STN:280:DC%2BD38vjtVejtA%3D%3D 10.1038/sj.ijo.0802041 12187400
25. JV Selby B Newman CP Quesenberry Jr, et al. 1989 Evidence of genetic influence on central body fat in middle-aged twins Hum Biol 61 179 194 1:STN:280:DyaL1Mzlsl2gtQ%3D%3D 2767669
26. KM Rose B Newman EJ Mayer-Davis JV Selby 1998 Genetic and behavioral determinants of waist-hip ratio and waist circumference in women twins Obes Res 6 383 392 1:STN:280:DyaK1M%2FlvFelsg%3D%3D 9845227
27. SB Eaton M Konner M Shostak 1988 Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective Am J Med 84 739 749 1:STN:280:DyaL1c3pt1eitg%3D%3D 10.1016/0002-9343(88)90113-1 3135745
28. CL Saunders BD Chiodini P Sham, et al. 2007 Meta-analysis of genome-wide linkage studies in BMI and obesity Obesity (Silver Spring) 15 2263 2275 10.1038/oby.2007.269 (Pubitemid 350004094)
29. TM Frayling NJ Timpson MN Weedon, et al. 2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity Science 316 889 894 1:CAS:528:DC%2BD2sXltVentL0%3D 10.1126/science. 1141634 17434869 This is the first genome-wide search for type 2 diabetes susceptibility genes that identified an unequivocal BMI association to a common variant in the FTO gene (Pubitemid 46764279)
30. A Scuteri S Sanna WM Chen, et al. 2007 Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits PLoS Genet 3 e115 10.1371/journal.pgen.0030115 17658951 (Pubitemid 47203970)
31. International HapMap Consortium 2005 A haplotype map of the human genome Nature 437 1299 1320 10.1038/nature04226 (Pubitemid 41568671)
32. National Center for Biotechnology Information, National Library of Medicine: Database of Single Nucleotide Polymorphisms-dbSNP Build ID: 131. Available at http://www.ncbi.nlm.nih.gov/SNP/. Accessed September 2010.
33. JC Barrett LR Cardon 2006 Evaluating coverage of genome-wide association studies Nat Genet 38 659 662 1:CAS:528:DC%2BD28XltVOhur8%3D 10.1038/ng1801 16715099 (Pubitemid 43927307)
34. I Pe'er PI de Bakker J Maller, et al. 2006 Evaluating and improving power in whole-genome association studies using fixed marker sets Nat Genet 38 663 667 10.1038/ng1816 16715096 (Pubitemid 43927308)
35. JC Chambers P Elliott D Zabaneh, et al. 2008 Common genetic variation near MC4R is associated with waist circumference and insulin resistance Nat Genet 40 716 718 1:CAS:528:DC%2BD1cXmsVejtrw%3D 10.1038/ng.156 18454146 This is the first large-scale screen in non-European (Indian Asians) samples for obesity genes that identifies and/or replicates both FTO and MC4R to be associated with measures of obesity and insulin resistance (Pubitemid 351748872)
36. CJ Willer EK Speliotes RJ Loos, et al. 2009 Six new loci associated with body mass index highlight a neuronal influence on body weight regulation Nat Genet 41 25 34 1:CAS:528:DC%2BD1cXhsV2hsrnK 10.1038/ng.287 19079261 This is a large-scale search for genes associated with common obesity as measured by BMI that yielded six novel, robust obesity susceptibility loci. A number of the genes in the associated loci are expressed in and/or are known to act in the hypothalamus
37. G Thorleifsson GB Walters DF Gudbjartsson, et al. 2009 Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity Nat Genet 41 18 24 1:CAS:528:DC%2BD1cXhsV2hsrjO 10.1038/ng.274 19079260 This was a search for common variants that affect two measures of obesity-weight and BMI-in European and African samples that identified seven novel, significantly associated obesity loci
38. D Meyre J Delplanque JC Chevre, et al. 2009 Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations Nat Genet 41 157 159 1:CAS:528:DC%2BD1MXntFGktg%3D%3D 10.1038/ng.301 19151714 This was the first large-scale GWAS for extreme forms of obesity (early-onset and morbid adult obesity) that identifies three novel obesity loci showing little overlap with the GWAS for quantitative measures of obesity
39. A Scherag C Dina A Hinney, et al. 2010 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 6 e1000916 10.1371/journal.pgen.1000916 20421936
40. RJ Loos CM Lindgren S Li, et al. 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity Nat Genet 40 768 775 1:CAS:528:DC%2BD1cXmsVejsLo%3D 10.1038/ng.140 18454148 After combining GWA data from 16,876 individuals, a locus about 188-kb downstream of the MC4R gene was associated with BMI. MC4R mutations are the leading cause of monogenic severe childhood-onset obesity (Pubitemid 351748863)
41. T Gerken CA Girard YC Tung, et al. 2007 The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase Science 318 1469 1472 1:CAS:528:DC%2BD2sXhtlGmtLbI 10.1126/science.1151710 17991826 This is a functional study in which both bioinformatics work and animal models point to FTO having DNA methylation activity, with expression regulated by energy intake patterns (Pubitemid 350208961)
42. R Fredriksson M Hagglund PK Olszewski, et al. 2008 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 149 2062 2071 1:CAS:528:DC%2BD1cXht1GmsLvN 10.1210/en.2007-1457 18218688 (Pubitemid 351574484)
43. J Wardle C Llewellyn S Sanderson R Plomin 2009 The FTO gene and measured food intake in children Int J Obes (Lond) 33 42 45 1:CAS:528: DC%2BD1MXkslyrtA%3D%3D 10.1038/ijo.2008.174
44. S O'Rahilly IS Farooqi 2008 Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions Diabetes 57 2905 2910 10.2337/db08-0210 18971438
45. D Huszar CA Lynch V Fairchild-Huntress, et al. 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice Cell 88 131 141 1:CAS:528:DyaK2sXltF2nsg%3D%3D 10.1016/S0092-8674(00)81865-6 9019399
46. Z Li Y Zhou C Carter-Su, et al. 2007 SH2B1 enhances leptin signaling by both Janus kinase 2 Tyr813 phosphorylation-dependent and -independent mechanisms Mol Endocrinol 21 2270 2281 1:CAS:528:DC%2BD2sXhtVSqtb%2FF 10.1210/me.2007-0111 17565041 (Pubitemid 47347387)
47. M Gratacos JR Gonzalez JM Mercader, et al. 2007 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 61 911 922 1:CAS:528: DC%2BD2sXjtFGlurk%3D 10.1016/j.biopsych.2006.08.025 17217930 (Pubitemid 46420580)
48. NL Heard-Costa MC Zillikens KL Monda, et al. 2009 NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium PLoS Genet 5 e1000539 10.1371/journal.pgen.1000539 19557197
49. J Jurvansuu Y Zhao DS Leung, et al. 2008 Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells Cancer Res 68 4614 4622 1:CAS:528:DC%2BD1cXnt1aqtLs%3D 10.1158/0008-5472.CAN-07-5291 18559506
50. S Virtue A Vidal-Puig 2008 It's not how fat you are, it's what you do with it that counts PLoS Biol 6 e237 10.1371/journal.pbio.0060237 18816166
51. MC Zillikens M Yazdanpanah LM Pardo, et al. 2008 Sex-specific genetic effects influence variation in body composition Diabetologia 51 2233 2241 1:CAS:528:DC%2BD1cXhtlCjs7%2FN 10.1007/s00125-008-1163-0 18839131 This study provides evidence for sex-specific genetic effects that may underlie sex differences for several body composition and fat distribution traits
52. Y Jamshidi H Snieder D Ge, et al. 2007 The SH2B gene is associated with serum leptin and body fat in normal female twins Obesity (Silver Spring) 15 5 9 1:CAS:528:DC%2BD2sXosVeisr4%3D 10.1038/oby.2007.637
53. YS Cho MJ Go YJ Kim, et al. 2009 A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits Nat Genet 41 527 534 1:CAS:528:DC%2BD1MXltValt7k%3D 10.1038/ng.357 19396169 This is the first Korean GWAS that identifies a WHR association on chromosome 12q24, to a variant that is not in HapMap and thus has not been evaluated in European populations yet
54. F Stutzmann V Vatin S Cauchi, et al. 2007 Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene Hum Mol Genet 16 1837 1844 1:CAS:528:DC%2BD2sXosFKltbw%3D 10.1093/hmg/ddm132 17519222 (Pubitemid 47244532)
55. M Benzinou JW Creemers H Choquet, et al. 2008 Common nonsynonymous variants in PCSK1 confer risk of obesity Nat Genet 40 943 945 1:CAS:528:DC%2BD1cXptVKku78%3D 10.1038/ng.177 18604207
56. YY Shugart L Chen IN Day, et al. 2009 Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI Eur J Hum Genet 17 1050 1055 1:CAS:528:DC%2BD1MXptVaqtrY%3D 10.1038/ejhg.2008.272 19209189
57. DF Conrad D Pinto R Redon, et al. 2010 Origins and functional impact of copy number variation in the human genome Nature 464 704 712 1:CAS:528:DC%2BD1MXht1CisLrL 10.1038/nature08516 19812545
58. TA Manolio FS Collins NJ Cox, et al. 2009 Finding the missing heritability of complex diseases Nature 461 747 753 1:CAS:528:DC%2BD1MXht1CisbrF 10.1038/nature08494 19812666
59. SA McCarroll FG Kuruvilla JM Korn, et al. 2008 Integrated detection and population-genetic analysis of SNPs and copy number variation Nat Genet 40 1166 1174 1:CAS:528:DC%2BD1cXhtFKht7%2FN 10.1038/ng.238 18776908
60. RG Walters S Jacquemont A Valsesia, et al. 2010 A new highly penetrant form of obesity due to deletions on chromosome 16p11.2 Nature 463 671 675 1:CAS:528:DC%2BC3cXhsVyns7k%3D 10.1038/nature08727 20130649 This group identified deletions on chromosome 16p11.2 to be associated with morbid, adult forms of obesity
61. EG Bochukova N Huang J Keogh, et al. 2010 Large, rare chromosomal deletions associated with severe early-onset obesity Nature 463 666 670 1:CAS:528:DC%2BD1MXhsFWksbrL 10.1038/nature08689 19966786 Here large, rare deletions on chromosome 16p11.2 are shown to be associated with severe early-onset obesity. The deletion overlaps with a locus that is associated with BMI and contains several genes including SH2B1
62. IS Farooqi T Wangensteen S Collins, et al. 2007 Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor N Engl J Med 356 237 247 1:CAS:528:DC%2BD2sXnslSrsg%3D%3D 10.1056/NEJMoa063988 17229951 (Pubitemid 46143227)
63. DL Morris KW Cho Y Zhou L Rui 2009 SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins Diabetes 58 2039 2047 1:CAS:528:DC%2BD1MXhtFChsbnF 10.2337/db08-1388 19542202
64. J Krutzfeldt M Stoffel 2006 MicroRNAs: a new class of regulatory genes affecting metabolism Cell Metab 4 9 12 1:CAS:528:DC%2BD28XmvFyiu7s%3D 10.1016/j.cmet.2006.05.009 16814728 (Pubitemid 43942256)
65. H Xie L Sun HF Lodish 2009 Targeting microRNAs in obesity Expert Opin Ther Targets 13 1227 1238 1:CAS:528:DC%2BD1MXhtFWks77F 10.1517/14728220903190707 19650761
66. A Bird 2007 Perceptions of epigenetics Nature 447 396 398 1:CAS:528:DC%2BD2sXlsFOgsrk%3D 10.1038/nature05913 17522671 (Pubitemid 46816744)
67. R Stoger 2008 Epigenetics and obesity Pharmacogenomics 9 1851 1860 1:CAS:528:DC%2BD1cXhsFWjtbrP 10.2217/14622416.9.12.1851 19072643
68. RA Waterland RL Jirtle 2004 Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases Nutrition 20 63 68 1:CAS:528:DC%2BD3sXpvF2qtLY%3D 10.1016/j.nut.2003. 09.011 14698016 (Pubitemid 38091581)
69. M Bluher 2010 The distinction of metabolically 'healthy' from 'unhealthy' obese individuals Curr Opin Lipidol 21 38 43 10.1097/MOL.0b013e3283346ccc 19915462
70. RM Freathy NJ Timpson DA Lawlor, et al. 2008 Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI Diabetes 57 1419 1426 1:CAS:528:DC%2BD1cXlvVKjur0%3D 10.2337/db07-1466 18346983
71. C Cotsapas EK Speliotes IJ Hatoum, et al. 2009 Common body mass index-associated variants confer risk of extreme obesity Hum Mol Genet 18 3502 3507 1:CAS:528:DC%2BD1MXhtVehurnJ 10.1093/hmg/ddp292 19553259
72. A Hinney TT Nguyen A Scherag, et al. 2007 Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants PLoS One 2 e1361 10.1371/journal.pone.0001361 18159244 (Pubitemid 351753322)