Abstract
Objective:
Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with adiposity in European-derived study populations. Limited study of these loci has been reported in African Americans. Here we examined the effects of these previously identified adiposity loci in African Americans.
Methods:
A total of 46 representative single-nucleotide polymorphisms (SNPs) in 19 loci that were previously reported in GWAS in Europeans (including FTO and MC4R) were genotyped in 4992 subjects from six African-American cohorts. These SNPs were tested for association with body mass index (BMI) after adjustment for age, gender, disease status and population structure in each cohort. Meta-analysis was conducted to combine the results.
Results:
Meta-analysis of 4992 subjects revealed seven SNPs near four loci, including NEGR1, TMEM18, SH2B1 /ATP2A1 and MC4R, showing significant association at 0.005<P<0.05, and had effect sizes between 0.04 and 0.06 s.d. units (or 0.30 to 0.44 kg m−2) of BMI for each copy of the BMI-increasing allele. The most significantly associated SNPs (rs9424977, rs3101336 and rs2568958) are located in the NEGR1 gene (P=0.005, 0.020 and 0.019, respectively).
Conclusion:
We replicated the association of variants at four loci in six African-American cohorts that demonstrated a consistent direction of association with previous studies of adiposity in Europeans. These loci are all highly expressed in the brain, consistent with an important role for central nervous system processes in weight regulation. However, further comprehensive examination of these regions may be necessary to fine map and elucidate for possible genetic differences between these two populations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH . The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 2009; 9: 88.
Flegal KM, Carroll MD, Ogden CL, Johnson CL . Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–1727.
Flegal KM, Carroll MD, Ogden CL, Curtin LR . Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010; 303: 235–241.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM . Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006; 295: 1549–1555.
Loos RJ, Bouchard C . Obesity—is it a genetic disorder? J Intern Med 2003; 254: 401–425.
Nelson TL, Brandon DT, Wiggins SA, Whitfield KE . Genetic and environmental influences on body-fat measures among African-American twins. Obes Res 2002; 10: 733–739.
Duncan AE, Agrawal A, Grant JD, Bucholz KK, Madden PA, Heath AC . Genetic and environmental contributions to BMI in adolescent and young adult women. Obesity (Silver Spring) 2009; 17: 1040–1043.
Sale MM, Freedman BI, Hicks PJ, Williams AH, Langefeld CD, Gallagher CJ et al. Loci contributing to adult height and body mass index in African American families ascertained for type 2 diabetes. Ann Hum Genet 2005; 69: 517–527.
Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.
Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD 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.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM 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.
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3: e115.
Benzinou M, Creemers JW, Choquet H, Lobbens S, Dina C, Durand E et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 2008; 40: 943–945.
Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P et al. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008; 40: 716–718.
Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 2008; 40: 768–775.
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009; 41: 25–34.
Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 2009; 41: 18–24.
Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S 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.
Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L et al. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 2009; 5: e1000508.
Heard-Costa NL, Zillikens MC, Monda KL, Johansson A, Harris TB, Fu M et al. NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet 2009; 5: e1000539.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 2010; 42: 949–960.
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ 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.
Tan JT, Dorajoo R, Seielstad M, Sim XL, Ong RT, Chia KS et al. FTO variants are associated with obesity in the Chinese and Malay populations in Singapore. Diabetes 2008; 57: 2851–2857.
Hotta K, Nakamura M, Nakamura T, Matsuo T, Nakata Y, Kamohara S et al. Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. J Hum Genet 2009; 54: 727–731.
Ng MC, Tam CH, So WY, Ho JS, Chan AW, Lee HM et al. Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese. J Clin Endocrinol Metab 2010; 95: 2418–2425.
Grant SF, Bradfield JP, Zhang H, Wang K, Kim CE, Annaiah K et al. Investigation of the locus near MC4R with childhood obesity in Americans of European and African ancestry. Obesity (Silver Spring) 2009; 17: 1461–1465.
Kang SJ, Chiang CW, Palmer CD, Tayo BO, Lettre G, Butler JL et al. Genome-wide association of anthropometric traits in African- and African-derived populations. Hum Mol Genet 2010; 19: 2725–2738.
Bollepalli S, Dolan LM, Deka R, Martin LJ . Association of FTO gene variants with adiposity in African-American adolescents. Obesity (Silver Spring) 2010; 18: 1959–1963.
Grant SF, Li M, Bradfield JP, Kim CE, Annaiah K, Santa E et al. Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS One 2008; 3: e1746.
Wing MR, Ziegler J, Langefeld CD, Ng MC, Haffner SM, Norris JM et al. Analysis of FTO gene variants with measures of obesity and glucose homeostasis in the IRAS Family Study. Hum Genet 2009; 125: 615–626.
Hassanein MT, Lyon HN, Nguyen TT, Akylbekova EL, Waters K, Lettre G et al. Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet 2010; 19: 2907–2916.
Freedman BI, Hicks PJ, Bostrom MA, Comeau ME, Divers J, Bleyer AJ et al. Non-muscle myosin heavy chain 9 gene MYH9 associations in African Americans with clinically diagnosed type 2 diabetes mellitus-associated ESRD. Nephrol Dial Transplant 2009; 24: 3366–3371.
Divers J, Wagenknecht LE, Bowden DW, Carr JJ, Hightower RC, Ding J et al. Regional adipose tissue associations with calcified atherosclerotic plaque: African American-diabetes heart study. Obesity (Silver Spring) 2010; 18: 2004–2009.
Bowden DW, Rudock M, Ziegler J, Lehtinen AB, Xu J, Wagenknecht LE et al. Coincident linkage of type 2 diabetes, metabolic syndrome, and measures of cardiovascular disease in a genome scan of the diabetes heart study. Diabetes 2006; 55: 1985–1994.
Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD et al. Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol 2003; 13: 211–217.
Wagenknecht LE, Mayer EJ, Rewers M, Haffner S, Selby J, Borok GM et al. The insulin resistance atherosclerosis study (IRAS) objectives, design, and recruitment results. Ann Epidemiol 1995; 5: 464–472.
O’Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Keene KL, Mychaleckyj JC, Leak TS, Smith SG, Perlegas PS, Divers J et al. Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease. Hum Genet 2008; 124: 147–154.
Purcell S, Cherny SS, Sham PC . Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.
Marg A, Sirim P, Spaltmann F, Plagge A, Kauselmann G, Buck F 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.
Schafer M, Brauer AU, Savaskan NE, Rathjen FG, Brummendorf T . Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion. Mol Cell Neurosci 2005; 29: 580–590.
Jurvansuu J, Zhao Y, Leung DS, Boulaire J, Yu YH, Ahmed S et al. Transmembrane protein 18 enhances the tropism of neural stem cells for glioma cells. Cancer Res 2008; 68: 4614–4622.
Jamshidi Y, Snieder H, Ge D, Spector TD, O’Dell SD . The SH2B gene is associated with serum leptin and body fat in normal female twins. Obesity (Silver Spring) 2007; 15: 5–9.
Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S . Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348: 1085–1095.
Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005; 123: 493–505.
Palmer ND, Hester JM, An SS, Adeyemo A, Rotimi C, Langefeld CD et al. Resequencing and analysis of variation in the TCF7L2 gene in African Americans suggests that SNP rs7903146 is the causal diabetes susceptibility variant. Diabetes 2011; 60: 662–668.
Cooper RS, Tayo B, Zhu X . Genome-wide association studies: implications for multiethnic samples. Hum Mol Genet 2008; 17: R151–R155.
Cossrow N, Falkner B . Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab 2004; 89: 2590–2594.
Bacha F, Saad R, Gungor N, Janosky J, Arslanian SA . Obesity, regional fat distribution, and syndrome X in obese black versus white adolescents: race differential in diabetogenic and atherogenic risk factors. J Clin Endocrinol Metab 2003; 88: 2534–2540.
Acknowledgements
We thank the study subjects for their participation. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. This work was supported by NIH Grants R01 DK087914 (MCYN), R01 DK066358 (DWB), R01 DK053591 (DWB), R01 HL56266 (BIF), R01 DK070941 (BIF), R01 HL060944 (LW), R01 HL061210 (MB), K99 DK081350 (NDP) and by the Wake Forest University School of Medicine Grant M01 RR07122 and Venture Fund (MCYN).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on International Journal of Obesity website
Supplementary information
Rights and permissions
About this article
Cite this article
Hester, J., Wing, M., Li, J. et al. Implication of European-derived adiposity loci in African Americans. Int J Obes 36, 465–473 (2012). https://doi.org/10.1038/ijo.2011.131
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2011.131
Keywords
This article is cited by
-
The rs1421085 variant within FTO promotes brown fat thermogenesis
Nature Metabolism (2023)
-
The Impact of Variants in Four Genes: MC4R, FTO, PPARG and PPARGC1A in Overweight and Obesity in a Large Sample of the Brazilian Population
Biochemical Genetics (2021)
-
Gene-nutrient interactions and susceptibility to human obesity
Genes & Nutrition (2017)
-
Association of gene coding variation and resting metabolic rate in a multi-ethnic sample of children and adults
BMC Obesity (2017)
-
Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Obesity-Related Traits
Current Diabetes Reports (2015)