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Theme: Obesity – Review

The genetic underpinnings of body fat distribution

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Pages 417-427 | Received 11 Jul 2017, Accepted 05 Oct 2017, Published online: 17 Oct 2017

References

  • GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. Massachusetts Medical Society. 2017;377:13–27.
  • State of Obesity: Better Policies for a Healthier America [Internet]. Trust for America’s health; 2017. [cited 2017 May 25]. Available from: https://stateofobesity.org/
  • Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2014;384:766–781.
  • Prentice AM. The emerging epidemic of obesity in developing countries. Int J Epidemiol. 2006;35:93–99.
  • Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care. 2007;30(Suppl 2):S141–6.
  • Lassale C, Tzoulaki I, Moons KGM, et al. Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis. Eur Heart J. 2017.
  • US Preventive Services Task Force, Grossman DC, Bibbins-Domingo K, Curry SJ, Barry MJ, Davidson KW, et al. Screening for obesity in children and adolescents: US Preventive Services Task Force Recommendation Statement. JAMA 2017;317:2417–2426.
  • Chusyd DE, Wang D, Huffman DM, et al. Relationships between rodent white adipose fat pads and human white adipose fat depots. Front Nutr. 2016;3:10.
  • Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
  • Shungin D, Winkler TW, Croteau-Chonka DC, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187–196.
  • Fox CS, Liu Y, White CC, et al. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women. PLoS Genet. 2012;8:e1002695.
  • Randall JC, Winkler TW, Kutalik Z, et al. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. PLoS Genet. 2013;9:e1003500.
  • Aschard H, Vilhjálmsson BJ, Joshi AD, et al. Adjusting for heritable covariates can bias effect estimates in genome-wide association studies. Am J Hum Genet. 2015;96:329–339.
  • Cole SR, Platt RW, Schisterman EF, et al. Illustrating bias due to conditioning on a collider. Int J Epidemiol. 2010;39:417–420.
  • Adams SA, Matthews CE, Ebbeling CB, et al. The effect of social desirability and social approval on self-reports of physical activity. Am J Epidemiol. 2005;161:389–398.
  • Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet. 2005;6:221–234.
  • Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27:710–718.
  • Farooqi IS, Yeo GS, Keogh JM, et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 2000;106:271–279.
  • Yeo GS, Farooqi IS, Aminian S, et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20:111–112.
  • Farooqi IS, Keogh JM, Yeo GSH, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085–1095.
  • Forsythe E, Beales PL. Bardet–Biedl syndrome. Eur J Hum Genet. 2012;21:8–13. Nature Publishing Group.
  • Herrera BM, Lindgren CM. The genetics of obesity. Curr Diab Rep. 2010;10:498–505.
  • Tenesa A, Haley CS. The heritability of human disease: estimation, uses and abuses. Nat Rev Genet. 2013;14:139–149.
  • Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753.
  • Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. Jama. 1986;256:51–54.
  • Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46:1173–1186.
  • Hemani G, Yang J, Vinkhuyzen A, et al. Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs. Am Genet Am Soc Hum Genet. 2013;93:865–875.
  • Zaitlen N, Pasaniuc B, Sankararaman S, et al. Leveraging population admixture to characterize the heritability of complex traits. Nat Genet. 2014;46:1356–1362.
  • Pulit SL, Karaderi T, Lindgren CM. Sexual dimorphisms in genetic loci linked to body fat distribution. Biosci Rep. 2017;37.
  • Elks CE, Den Hoed M, Zhao JH, et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol. 2012;3:29.
  • Van Dongen J, Willemsen G, Chen W-M, et al. Heritability of metabolic syndrome traits in a large population-based sample. J Lipid Res. 2013;54:2914–2923.
  • Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005;6:95–108.
  • McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9:356–369.
  • Welter D, MacArthur J, Morales J, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42:D1001–6.
  • 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.
  • Loos RJF, 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.
  • Willer CJ, Speliotes EK, Loos RJF, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2009;41:25–34.
  • Chu AY, Deng X, Fisher VA, et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat Genet. 2017;49:125–130.
  • Pers TH, Karjalainen JM, Chan Y, et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun. 2015;6:5890.
  • Fuchsberger C, Flannick J, Teslovich TM, et al. The genetic architecture of type 2 diabetes. Nature. 2016;536:41–47.
  • Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–713.
  • Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–1283.
  • Wahl S, Drong A, Lehne B, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541:81–86.
  • Karaderi T, Drong AW, Lindgren CM. Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of obesity-related traits. Curr Diab Rep. 2015;15:83.
  • Gaulton KJ, Ferreira T, Lee Y, et al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet. 2015;47:1415–1425.
  • Dahlman I, Rydén M, Brodin D, et al. Numerous genes in loci associated with body fat distribution are linked to adipose function. Diabetes. 2016;65:433–437.
  • Claussnitzer M, Dankel SN, Klocke B, et al. Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms. Cell. 2014;156:343–358.
  • 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.
  • Wormser D, Kaptoge S, Di Angelantonio E, et al. Emerging risk factors collaboration: separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet. 2011;377:1085–1095.
  • Coutinho T, Goel K, Corrêa de Sá D, Kragelund C, et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol. 2011;57:1877–1886.
  • Phillips LK, Prins JB. The link between abdominal obesity and the metabolic syndrome. Curr Hypertens Rep. 2008;10:156–164.
  • Nazare J-A, Smith JD, Borel A-L, et al. Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile: the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity. Am J Clin Nutr Am Soc Nutrition. 2012;96:714–726.
  • Lee B-C LJ. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta. 2014;1842:446–462.
  • Misra A, Garg A, Abate N, et al. Relationship of anterior and posterior subcutaneous abdominal fat to insulin sensitivity in nondiabetic men. Obes Res. 1997;5:93–99.
  • Snijder MB, Dekker JM, Visser M, et al. Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn study. Am J Clin Nutr. 2003;77:1192–1197.
  • Tran TT, Yamamoto Y, Gesta S, et al. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 2008;7:410–420.
  • Appleton SL, Seaborn CJ, Visvanathan R, et al. Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype. Diabetes Care. 2013;36:2388–2394. American Diabetes Association.
  • Heitmann BL, Lissner L. Hurrah! Hip size inversely related to heart disease and total mortality. Obes Rev. 2011;12:478–481.
  • Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. Int J Obes. 2010;34:949–959.
  • Stefan N, Fritsche A, Schick F, et al. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016;4:789–798.
  • Stefan N, Schick F, Häring H-U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26:292–300.
  • Wajchenberg BL, Giannella-Neto D, Da Silva ME, et al. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res. 2002;34:616–621.
  • Gesta S, Blüher M, Yamamoto Y, et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci U S A. 2006;103:6676–6681.
  • Yamamoto Y, Gesta S, Lee KY, et al. Adipose depots possess unique developmental gene signatures. Obesity. 2010;18:872–878.
  • Cantile M, Procino A, D’Armiento M, et al. HOX gene network is involved in the transcriptional regulation of in vivo human adipogenesis. J Cell Physiol. 2003;194:225–236.
  • Cohen M, Syme C, Deforest M, et al. Ectopic fat in youth: the contribution of hepatic and pancreatic fat to metabolic disturbances. Obesity. 2014;22:1280–1286.
  • Grove KL, Fried SK, Greenberg AS, et al. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. Int J Obes. 2010;34:989–1000.
  • Karastergiou K, Fried SK, Xie H, et al. Distinct developmental signatures of human abdominal and gluteal subcutaneous adipose tissue depots. J Clin Endocrinol Metab. 2013;98:362–371.
  • Chau -Y-Y, Bandiera R, Serrels A, et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol. 2014;16:367–375.
  • Krueger KC, Costa MJ, Du H, et al. Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells. Stem Cell Reports. 2014;3:1147–1158.
  • Sanchez-Gurmaches J, Guertin DA. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat Commun. 2014;5:4099.
  • Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015;402:113–119.
  • Gesta S, Tseng Y-H, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007;131:242–256.
  • Berry R, Jeffery E, Rodeheffer MS. Weighing in on adipocyte precursors. Cell Metab. 2014;19:8–20.
  • Weyer C, Foley JE, Bogardus C, et al. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000;43:1498–1506.
  • Skurk T, Alberti-Huber C, Herder C, et al. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007;92:1023–1033.
  • Fang L, Guo F, Zhou L, et al. The cell size and distribution of adipocytes from subcutaneous and visceral fat is associated with type 2 diabetes mellitus in humans. Adipocyte. 2015;4:273–279.
  • Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–787.
  • Choe SS, Huh JY, Hwang IJ, et al. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders. Front Endocrinol. 2016;7:30.
  • Wernstedt Asterholm I, Tao C, Morley TS, et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 2014;20:103–118.
  • Jeffery E, Church CD, Holtrup B, et al. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol. 2015;17:376–385.
  • Arner E, Westermark PO, Spalding KL, et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes. 2010;59:105–109.
  • Wang QA, Tao C, Gupta RK, et al. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19:1338–1344.
  • Jeffery E, Wing A, Holtrup B, et al. The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab. 2016;24:142–150.
  • Kim SM, Lun M, Wang M, et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 2014;20:1049–1058.
  • Tchoukalova YD, Koutsari C, Votruba SB, et al. Sex- and depot-dependent differences in adipogenesis in normal-weight humans. Obesity. 2010;18:1875–1880.
  • Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59:1075–1088.
  • Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–1263.
  • Billon N, Iannarelli P, Monteiro MC, et al. The generation of adipocytes by the neural crest. Development. 2007;134:2283–2292.
  • Sanchez-Gurmaches J, Hung C-M, Guertin DA. Emerging complexities in adipocyte origins and identity. Trends Cell Biol. 2016;26:313–326.
  • Zhang F, Lupski JR. Non-coding genetic variants in human disease. Hum Mol Genet. 2015;24:R102–10.
  • Manolio TA. Bringing genome-wide association findings into clinical use. Nat Rev Genet. 2013;14:549–558. Nature Publishing Group.
  • Gregory AP, Dendrou CA, Attfield KE, et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature. 2012;488:508–511.
  • Claussnitzer M, Dankel SN, Kim K-H, et al. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med. 2015;373:895–907.
  • Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–380.
  • Grubert F, Zaugg JB, Kasowski M, et al. Genetic control of chromatin states in humans involves local and distal chromosomal interactions. Cell. 2015;162:1051–1065.
  • Abifadel M, Varret M, J-P R, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156.
  • Kathiresan S, Voight BF, Purcell S, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–341.
  • Ripke S, Neale BM, Corvin A, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–427.
  • Sekar A, Bialas AR, De Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–183. Nature Publishing Group.
  • Ehret GB, Ferreira T, Chasman DI, et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;48:1171–1184.
  • Lauenborg J, Grarup N, Damm P, et al. Common type 2 diabetes risk gene variants associate with gestational diabetes. J Clin Endocrinol Metab. 2009;94:145–150.
  • Monda KL, Chen GK, Taylor KC, et al. A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet. 2013;45:690–696.
  • Ng MCY, Graff M, Lu Y, et al. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium. PLoS Genet. 2017;13:e1006719.
  • Liu C-T, Monda KL, Taylor KC, et al. Genome-wide association of body fat distribution in African ancestry populations suggests new loci. PLoS Genet. 2013;9:e1003681.
  • Rosenberg NA, Huang L, Jewett EM, et al. Genome-wide association studies in diverse populations. Nat Rev Genet. 2010;11:356–366.
  • Pulit SL, Voight BF, De Bakker PIW. Multiethnic genetic association studies improve power for locus discovery. PLoS One. 2010;5:e12600.
  • Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 2016;17:157.
  • Zaitlen N, Paşaniuc B, Gur T, et al. Leveraging genetic variability across populations for the identification of causal variants. Am J Hum Genet. 2010;86:23–33.
  • Morris AP. Transethnic meta-analysis of genomewide association studies. Genet Epidemiol. 2011;35:809–822.
  • Van De Bunt M, Cortes A, Brown MA, et al. Evaluating the performance of fine-mapping strategies at common variant GWAS loci. PLoS Genet. 2015;11:e1005535.
  • Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779.
  • Siva N. UK gears up to decode 100,000 genomes from NHS patients. Lancet. 2015;385:103–104.
  • Nagano T, Lubling Y, Yaffe E, et al. Single-cell Hi-C for genome-wide detection of chromatin interactions that occur simultaneously in a single cell. Nat Protoc. 2015;10:1986–2003.
  • Rao SSP, Huntley MH, Durand NC, et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159:1665–1680.
  • Consortium G. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–660.
  • Lonsdale J, Thomas J, Salvatore M, et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–585.
  • Benfield LL, Fox KR, Peters DM, et al. Magnetic resonance imaging of abdominal adiposity in a large cohort of British children. Int J Obes. 2008;32:91–99.
  • Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–823.

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