Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10？7 for BMI, 1.80×10？6 for FM, and 5.29×10？4 for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10？3 to 4.94×10？2). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.
References
[1]
Kopelman PG (2000) Obesity as a medical problem. Nature 404: 635–643.
[2]
Wang Y, Beydoun MA, Liang L, Caballero B, Kumanyika SK (2008) Will all Americans become overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring) 16: 2323–2330.
[3]
Kelly T, Yang W, Chen CS, Reynolds K, He J (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 32: 1431–1437.
[4]
Malis C, Rasmussen EL, Poulsen P, Petersen I, Christensen K, et al. (2005) Total and regional fat distribution is strongly influenced by genetic factors in young and elderly twins. Obes Res 13: 2139–2145.
[5]
Stunkard AJ, Foch TT, Hrubec Z (1986) A twin study of human obesity. JAMA 256: 51–54.
[6]
Allison DB, Saunders SE (2000) Obesity in North America. An overview. Med Clin North Am 84: 305–332, v.
[7]
Prentice AM, Jebb SA (2001) Beyond body mass index. Obes Rev 2: 141–147.
[8]
Comuzzie AG, Allison DB (1998) The search for human obesity genes. Science 280: 1374–1377.
[9]
Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, et al. (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14: 529–644.
[10]
Lu Y, Loos RJ (2013) Obesity genomics: assessing the transferability of susceptibility loci across diverse populations. Genome Med 5: 55.
[11]
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, et al. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42: 937–948.
[12]
Tartaglia LA (1997) The leptin receptor. J Biol Chem 272: 6093–6096.
[13]
Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A, Pories WJ, et al. (1997) Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 99: 2416–2422.
[14]
Lafontan M, Berlan M (1993) Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res 34: 1057–1091.
[15]
Dalgaard LT, Pedersen O (2001) Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Diabetologia 44: 946–965.
[16]
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, et al. (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318: 1469–1472.
[17]
Liu YJ, Liu XG, Wang L, Dina C, Yan H, et al. (2008) Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum Mol Genet 17: 1803–1813.
[18]
Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 19: 61–109.
[19]
Cauley JA, Danielson ME, Boudreau R, Barbour KE, Horwitz MJ, et al. (2011) Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women’s Health Initiative (WHI). J Bone Miner Res 26: 2378–2388.
[20]
Plourde M, Vohl MC, Bellis C, Carless M, Dyer T, et al. (2013) A variant in the LRRFIP1 gene is associated with adiposity and inflammation. Obesity (Silver Spring) 21: 185–192.
[21]
Pei Y-F, Zhang L, Liu Y, Li J, Shen H, et al. (2014) Meta-analysis of Genome-Wide Association Data Identifies Novel Susceptibility Loci for Obesity. Hum Mol Genet 23: 820–30.
[22]
Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34: 816–834.
[23]
Zhang L, Li J, Pei YF, Liu Y, Deng HW (2009) Tests of association for quantitative traits in nuclear families using principal components to correct for population stratification. Ann Hum Genet 73: 601–613.
[24]
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191.
[25]
Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.
[26]
Manning AK, Hivert MF, Scott RA, Grimsby JL, Bouatia-Naji N, et al. (2012) A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet 44: 659–669.
[27]
Jia G, Fu Y, Zhao X, Dai Q, Zheng G, et al. (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7: 885–887.
[28]
Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, et al. (2010) Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 5: e14040.
[29]
Peters U, North KE, Sethupathy P, Buyske S, Haessler J, et al. (2013) A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet 9: e1003171.
[30]
Andreasen CH, Mogensen MS, Borch-Johnsen K, Sandbaek A, Lauritzen T, et al. (2009) Studies of CTNNBL1 and FDFT1 variants and measures of obesity: analyses of quantitative traits and case-control studies in 18,014 Danes. BMC Med Genet 10: 17.
[31]
Vogel CI, Greene B, Scherag A, Muller TD, Friedel S, et al. (2009) Non-replication of an association of CTNNBL1 polymorphisms and obesity in a population of Central European ancestry. BMC Med Genet 10: 14.
[32]
Qian L, Xu K, Xu X, Gu R, Liu X, et al. (2013) UCP2–866G/A, Ala55Val and UCP3–55C/T polymorphisms in association with obesity susceptibility - a meta-analysis study. PLoS One 8: e58939.
[33]
Jalba MS, Rhoads GG, Demissie K (2008) Association of codon 16 and codon 27 beta 2-adrenergic receptor gene polymorphisms with obesity: a meta-analysis. Obesity (Silver Spring) 16: 2096–2106.
[34]
Prakash J, Srivastava N, Awasthi S, Agarwal C, Natu S, et al. (2012) Association of PPAR-gamma gene polymorphisms with obesity and obesity-associated phenotypes in North Indian population. Am J Hum Biol 24: 454–459.
[35]
Murugesan D, Arunachalam T, Ramamurthy V, Subramanian S (2010) Association of polymorphisms in leptin receptor gene with obesity and type 2 diabetes in the local population of Coimbatore. Indian J Hum Genet 16: 72–77.
[36]
Heard-Costa NL, Zillikens MC, Monda KL, Johansson A, Harris TB, et al. (2009) NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet 5: e1000539.
[37]
Song Y, You NC, Hsu YH, Howard BV, Langer RD, et al. (2008) FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women. Obesity (Silver Spring) 16: 2472–2480.
[38]
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, et al. (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3: e115.
[39]
Wing MR, Ziegler JM, Langefeld CD, Roh BH, Palmer ND, et al. (2011) Analysis of FTO gene variants with obesity and glucose homeostasis measures in the multiethnic Insulin Resistance Atherosclerosis Study cohort. Int J Obes (Lond) 35: 1173–1182.
[40]
Adeyemo A, Chen G, Zhou J, Shriner D, Doumatey A, et al. (2010) FTO genetic variation and association with obesity in West Africans and African Americans. Diabetes 59: 1549–1554.
[41]
Dorajoo R, Blakemore AI, Sim X, Ong RT, Ng DP, et al. (2012) Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations. Int J Obes (Lond) 36: 159–163.
[42]
Chang YC, Liu PH, Lee WJ, Chang TJ, Jiang YD, et al. (2008) Common variation in the fat mass and obesity-associated (FTO) gene confers risk of obesity and modulates BMI in the Chinese population. Diabetes 57: 2245–2252.
[43]
Li H, Kilpelainen TO, Liu C, Zhu J, Liu Y, et al. (2012) Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians. Diabetologia 55: 981–995.
[44]
Ng MC, Park KS, Oh B, Tam CH, Cho YM, et al. (2008) Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 57: 2226–2233.
[45]
Hassanein MT, Lyon HN, Nguyen TT, Akylbekova EL, Waters K, et al. (2010) Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet 19: 2907–2916.
[46]
Grant SF, Li M, Bradfield JP, Kim CE, Annaiah K, et al. (2008) Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS One 3: e1746.
[47]
Bollepalli S, Dolan LM, Deka R, Martin LJ (2010) Association of FTO gene variants with adiposity in African-American adolescents. Obesity (Silver Spring) 18: 1959–1963.
[48]
Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, et al. (2008) Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med 168: 1791–1797.
[49]
Zhang G, Karns R, Narancic NS, Sun G, Cheng H, et al. (2010) Common SNPs in FTO gene are associated with obesity related anthropometric traits in an island population from the eastern Adriatic coast of Croatia. PLoS One 5: e10375.
[50]
Galbete C, Contreras R, Martinez JA, Martinez-Gonzalez MA, Guillen-Grima F, et al. (2012) Physical activity and sex modulate obesity risk linked to 3111T/C gene variant of the CLOCK gene in an elderly population: the SUN Project. Chronobiol Int 29: 1397–1404.
[51]
Zillikens MC, Yazdanpanah M, Pardo LM, Rivadeneira F, Aulchenko YS, et al. (2008) Sex-specific genetic effects influence variation in body composition. Diabetologia 51: 2233–2241.
[52]
Schousboe K, Willemsen G, Kyvik KO, Mortensen J, Boomsma DI, et al. (2003) Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries. Twin Res 6: 409–421.
[53]
Jacobsson JA, Danielsson P, Svensson V, Klovins J, Gyllensten U, et al. (2008) Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes. Biochem Biophys Res Commun 368: 476–482.
[54]
Benjamin AM, Suchindran S, Pearce K, Rowell J, Lien LF, et al. (2011) Gene by sex interaction for measures of obesity in the framingham heart study. J Obes 2011: 329038.
[55]
Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, et al. (2012) Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet 44: 302–306.
[56]
Huang W, Sun Y, Sun J (2011) Combined effects of FTO rs9939609 and MC4R rs17782313 on obesity and BMI in Chinese Han populations. Endocrine 39: 69–74.
[57]
Xi B, Cheng H, Shen Y, Chandak GR, Zhao X, et al. (2013) Study of 11 BMI-associated loci identified in GWAS for associations with central obesity in the Chinese children. PLoS One 8: e56472.
[58]
Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, 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.
[59]
Scherag A, Dina C, Hinney A, Vatin V, Scherag S, 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.
[60]
Wang K, Li WD, Zhang CK, Wang Z, Glessner JT, et al. (2011) A genome-wide association study on obesity and obesity-related traits. PLoS One 6: e18939.
[61]
Cotsapas C, Speliotes EK, Hatoum IJ, Greenawalt DM, Dobrin R, et al. (2009) Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet 18: 3502–3507.
[62]
Wan ES, Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, et al. (2011) Genome-wide association analysis of body mass in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 45: 304–310.
[63]
Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, 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.
[64]
Yang J, Loos RJ, Powell JE, Medland SE, Speliotes EK, et al. (2012) FTO genotype is associated with phenotypic variability of body mass index. Nature 490: 267–272.
[65]
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, 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.
