Abstract
Obesity is a complex and multifactorial disease that occurs as a result of the interaction between “obesogenic” environmental factors and genetic components. Although the genetic component of obesity is clear from the heritability studies, the genetic basis remains largely elusive. Successes have been achieved in identifying the causal genes for monogenic obesity using animal models and linkage studies, but these approaches are not fruitful for polygenic obesity. The developments of genome-wide association approach have brought breakthrough discovery of genetic variants for polygenic obesity where tens of new susceptibility loci were identified. However, the common SNPs only accounted for a proportion of heritability. The arrival of NGS technologies and completion of 1000 Genomes Project have brought other new methods to dissect the genetic architecture of obesity, for example, the use of exome genotyping arrays and deep sequencing of candidate loci identified from GWAS to study rare variants. In this review, we summarize and discuss the developments of these genetic approaches in human obesity.
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References
Ahituv N et al (2007) Medical sequencing at the extremes of human body mass. Am J Hum Genet 80:779–791. doi:10.1086/513471
Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC, Hayakawa K (1996) The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord 20:501–506
Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M (2001) Genomewide scans of complex human diseases: true linkage is hard to find. Am J Hum Genet 69:936–950. doi:10.1086/324069
Amberger J, Bocchini CA, Scott AF, Hamosh A (2009) McKusick’s online Mendelian inheritance in man (OMIM). Nucleic Acids Res 37:D793–D796. doi:10.1093/nar/gkn665
American Medical Association (2013) American Medical Association: AMA adopt new policies on second day of voting at Annual Meeting (obesity as a disease). http://www.ama-assn.org/ama/pub/news/news/2013/2013-06-18-new-ama-policies-annual-meeting.page. Accessed 20 Dec 2013
Andreasen CH et al (2008a) Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18,014 Danes. PLoS ONE 3:e2872. doi:10.1371/journal.pone.0002872
Andreasen CH et al (2008b) Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 57:95–101 (db07-0910)
Armani A et al (2010) Cellular models for understanding adipogenesis, adipose dysfunction, and obesity. J Cell Biochem 110:564–572. doi:10.1002/jcb.22598
Barbier O et al (2003) The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene. J Biol Chem 278:13975–13983. doi:10.1074/jbc.M300749200
Been LF et al (2010) Replication of association between a common variant near melanocortin-4 receptor gene and obesity-related traits in Asian Sikhs. Obesity (Silver Spring) 18:425–429. doi:10.1038/oby.2009.254
Benzinou M et al (2008) Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 40:943–945. doi:10.1038/ng.177
Bergamaschi A et al (2006) Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45:1033–1040. doi:10.1002/gcc.20366
Bochukova EG et al (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463:666–670. doi:10.1038/nature08689nature08689
Bradfield JP et al (2012) A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 44:526–531. doi:10.1038/ng.2247
Carroll LS et al (2010) Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha. Mol Psychiatry 15:1101–1111. doi:10.1038/mp.2009.96mp200996
Chambers JC et al (2008) Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 40:716–718. doi:10.1038/ng.156
Chaput JP, Perusse L, Despres JP, Tremblay A, Bouchard C (2014) Findings from the Quebec Family Study on the Etiology of obesity: genetics and environmental highlights. Curr Obes Rep 3:54–66. doi:10.1007/s13679-013-0086-386
Cho YS 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. doi:10.1038/ng.357
Choi JH et al (2011) Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation. Nature 477:477–481. doi:10.1038/nature10383
Church C et al (2009) A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet 5:e1000599. doi:10.1371/journal.pgen.1000599
Church C et al (2010) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42:1086–1092. doi:10.1038/ng.713
Clement K (2006) Genetics of human obesity. C R Biol 329:608–62210. doi:10.1016/j.crvi.2005.10.009 (discussion 653–605)
Clement K et al (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401. doi:10.1038/32911
Considine RV et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295. doi:10.1056/NEJM199602013340503
Cotsapas C et al (2009) Common body mass index-associated variants confer risk of extreme obesity. Hum Mol Genet 18:3502–3507. doi:10.1093/hmg/ddp292
Cox RD, Church CD (2011) Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity. Dis Model Mech 4:155–164. doi:10.1242/dmm.000414
Croteau-Chonka DC, Marvelle AF, Lange EM, Lee NR, Adair LS, Lange LA, Mohlke KL (2011) Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women. Obesity (Silver Spring) 19:1019–1027. doi:10.1038/oby.2010.256
Dina C et al (2007) Comment on “A common genetic variant is associated with adult and childhood obesity”. Science 315:187. doi:10.1126/science.1129402 (author reply 187)
Dubern B, Bisbis S, Talbaoui H, Le Beyec J, Tounian P, Lacorte JM, Clement K (2007) Homozygous null mutation of the melanocortin-4 receptor and severe early-onset obesity. J Pediatr 150:613–617, 617 e611 (S0022-3476(07)00116-3 [pii])
Ege MJ et al (2011) Gene–environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol 127:138–144, 144 e131–134. doi:10.1016/j.jaci.2010.09.041
Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11:446–450. doi:10.1038/nrg2809
Farooqi IS (2008) Monogenic human obesity. Front Horm Res 36:1–11. doi:10.1159/0000115333
Farooqi IS et al (2002) Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093–1103. doi:10.1172/JCI15693
Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085–1095. doi:10.1056/NEJMoa022050348/12/1085
Farooqi IS et al (2006) Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55:2549–2553 (55/9/2549)
Farooqi IS et al (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356:237–247 (356/3/237)
Feng Y, Dong H, Xiang Q, Hong X, Wilker E, Zhang Y, Xu X (2007) Lack of association between rs7566605 and obesity in a Chinese population. Hum Genet 120:743–745. doi:10.1007/s00439-006-0258-2
Fesinmeyer MD et al (2013) Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. Obesity (Silver Spring) 21:835–846. doi:10.1002/oby.20268
Frayling TM 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. doi:10.1126/science.1141634
Fuentes E, Guzman-Jofre L, Moore-Carrasco R, Palomo I (2013) Role of PPARs in inflammatory processes associated with metabolic syndrome (review). Mol Med Rep 8:1611–1616. doi:10.3892/mmr.2013.1714
Galgani J, Ravussin E (2008) Energy metabolism, fuel selection and body weight regulation. Int J Obes (Lond) 32(Suppl 7):S109–S119. doi:10.1038/ijo.2008.246
Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA (2007) Thiazolidinediones improve beta-cell function in type 2 diabetic patients. Am J Physiol Endocrinol Metab 292:E871–E883 (00551.2006)
Gerhard GS et al (2013) Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity. Hum Hered 75:144–151. doi:10.1159/000351719
Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA (2004) Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826 (89/10/4821)
Glessner JT et al (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573. doi:10.1038/nature07953nature07953
Glessner JT et al (2010) A genome-wide study reveals copy number variants exclusive to childhood obesity cases. Am J Hum Genet 87:661–666. doi:10.1016/j.ajhg.2010.09.014
Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI (2011) Evolutionary evidence of the effect of rare variants on disease etiology. Clin Genet 79:199–206. doi:10.1111/j.1399-0004.2010.01535.x
Grant SF 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. doi:10.1371/journal.pone.0001746
Grant SF et al (2009) Investigation of the locus near MC4R with childhood obesity in Americans of European and African ancestry. Obesity (Silver Spring) 17:1461–1465. doi:10.1038/oby.2009.53 (oby200953)
Grarup N, Sandholt CH, Hansen T, Pedersen O (2014) Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 57:1528–1541. doi:10.1007/s00125-014-3270-4
Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X (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. doi:10.1016/j.biopsych.2006.08.025
Gray J et al (2006) Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55:3366–3371 (55/12/3366)
Green H, Meuth M (1974) An established pre-adipose cell line and its differentiation in culture. Cell 3:127–133 (0092-8674(74)90116-0)
Guerreiro RJ et al (2013) Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol 70:78–84. doi:10.1001/jamaneurol.2013.579
Hadley ME (2005) Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides 26:1687–1689. doi:10.1016/j.peptides.2005.01.023
Hainerova IA, Lebl J (2013) Treatment options for children with monogenic forms of obesity. World Rev Nutr Diet 106:105–112. doi:10.1159/000342556
Hamza TH et al (2011) Genome-wide gene–environment study identifies glutamate receptor gene GRIN2A as a Parkinson’s disease modifier gene via interaction with coffee. PLoS Genet 7:e1002237. doi:10.1371/journal.pgen.1002237
Han JC et al (2008) Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 359:918–927. doi:10.1056/NEJMoa0801119
Hassanein MT et al (2010) Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet 19:2907–2916. doi:10.1093/hmg/ddq178
Heard-Costa NL et al (2009) NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. PLoS Genet 5:e1000539. doi:10.1371/journal.pgen.1000539
Heid IM et al (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949–960. doi:10.1038/ng.685
Herbert A et al (2006) A common genetic variant is associated with adult and childhood obesity. Science 312:279–283. doi:10.1126/science.1124779
Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367. doi:10.1073/pnas.0903103106
Hinney A 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. doi:10.1371/journal.pone.0001361
Holder JL Jr, Butte NF, Zinn AR (2000) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:101–108 (ddd012)
Huang L, Teng D, Wang H, Sheng G, Liu T (2012) Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population. Eur J Endocrinol 166:727–734. doi:10.1530/EJE-11-0999
Hung CC et al (2007) Studies of the SIM1 gene in relation to human obesity and obesity-related traits. Int J Obes (Lond) 31:429–434 (0803443)
Huszar D et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141 (S0092-8674(00)81865-6 [pii])
Jackson RS et al (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303–306. doi:10.1038/ng0797-303
Jacquemont S et al (2011) Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478:97–102. doi:10.1038/nature10406
Jarick I, Vogel CI, Scherag S, Schafer H, Hebebrand J, Hinney A, Scherag A (2011) Novel common copy number variation for early onset extreme obesity on chromosome 11q11 identified by a genome-wide analysis. Hum Mol Genet 20:840–852. doi:10.1093/hmg/ddq518
Jiao H et al (2011) Genome wide association study identifies KCNMA1 contributing to human obesity. BMC Med Genomics 4:51. doi:10.1186/1755-8794-4-51
Kang SJ et al (2010) Genome-wide association of anthropometric traits in African- and African-derived populations. Hum Mol Genet 19:2725–2738. doi:10.1093/hmg/ddq154
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. doi:10.1038/ijo.2008.102
Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300. doi:10.1093/emboj/19.6.1290
Kilpelainen TO, Bingham SA, Khaw KT, Wareham NJ, Loos RJ (2009) Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study. Hum Mol Genet 18:3496–3501. doi:10.1093/hmg/ddp280
Kilpelainen TO et al (2011) Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med 8:e1001116. doi:10.1371/journal.pmed.1001116
Kim SJ, Nian C, McIntosh CH (2011) Adipocyte expression of the glucose-dependent insulinotropic polypeptide receptor involves gene regulation by PPARgamma and histone acetylation. J Lipid Res 52:759–770. doi:10.1194/jlr.M012203
Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Gruters A (2003) Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88:4633–4640. doi:10.1210/jc.2003-030502
Ku CS, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R (2012) Exome sequencing: dual role as a discovery and diagnostic tool. Ann Neurol 71:5–14. doi:10.1002/ana.22647
Kumar J, Sunkishala RR, Karthikeyan G, Sengupta S (2007) The common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population. Clin Genet 71:415–418. doi:10.1111/j.1399-0004.2007.00795.x
Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470:187–197. doi:10.1038/nature09792
Lefterova MI et al (2008) PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev 22:2941–2952. doi:10.1101/gad.1709008
Lehrke M, Lazar MA (2005) The many faces of PPARgamma. Cell 123:993–999 (S0092-8674(05)01277-8 [pii])
Leibel RL, Chung WK, Chua SC Jr (1997) The molecular genetics of rodent single gene obesities. J Biol Chem 272:31937–31940
Li H 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. doi:10.1007/s00125-011-2370-7
Lindgren CM et al (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508. doi:10.1371/journal.pgen.1000508
Ling C et al (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526. doi:10.1172/JCI21889
Liu YJ et al (2008) Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum Mol Genet 17:1803–1813. doi:10.1093/hmg/ddn072
Liu CT et al (2013) Genome-wide association of body fat distribution in African ancestry populations suggests new loci. PLoS Genet 9:e1003681. doi:10.1371/journal.pgen.1003681
Liu AY et al (2014) Genome-wide linkage and regional association study of obesity-related phenotypes: the GenSalt study. Obesity (Silver Spring) 22:545–556. doi:10.1002/oby.20469
Loktionov A (2003) Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases (review). J Nutr Biochem 14:426–451 (S0955286303000329)
Loos RJ, Barroso I, O’Rahilly S, Wareham NJ (2007) Comment on “A common genetic variant is associated with adult and childhood obesity”. Science 315:187. doi:10.1126/science.1130012 (author reply 187)
Loos RJ et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775. doi:10.1038/ng.140
Lu Y, Loos RJ (2013) Obesity genomics: assessing the transferability of susceptibility loci across diverse populations. Genome Med 5:55 (gm459)
Luo W et al (2013) Association of peroxisome proliferator-activated receptor alpha/delta/gamma with obesity, and gene–gene interaction, in the Chinese Han population. J Epidemiol 23:187–194 (DN/JST.JSTAGE/jea/JE20120110 [pii])
Maes HH, Neale MC, Eaves LJ (1997) Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27:325–351
Marian AJ (2012) Elements of ‘missing heritability’. Curr Opin Cardiol 27:197–201. doi:10.1097/HCO.0b013e328352707d
Matsunami N et al (2013) Identification of rare recurrent copy number variants in high-risk autism families and their prevalence in a large ASD population. PLoS ONE 8:e52239. doi:10.1371/journal.pone.0052239
Maures TJ, Kurzer JH, Carter-Su C (2007) SH2B1 (SH2-B) and JAK2: a multifunctional adaptor protein and kinase made for each other. Trends Endocrinol Metab 18:38–45. doi:10.1016/j.tem.2006.11.007
Merikangas AK et al (2014) The phenotypic manifestations of rare CNVs in schizophrenia. Schizophr Res. doi:10.1016/j.schres.2014.06.016
Meyre D 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. doi:10.1038/ng.301
Meyre D et al (2010) Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes 59:311–318. doi:10.2337/db09-0703db09-0703
Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES, Rosen ED (2010) Comparative epigenomic analysis of murine and human adipogenesis. Cell 143:156–169. doi:10.1016/j.cell.2010.09.006
Monda KL et al (2013) A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet 45:690–696. doi:10.1038/ng.2608
Monsalve FA, Pyarasani RD, Delgado-Lopez F, Moore-Carrasco R (2013) Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediators Inflamm 2013:549627. doi:10.1155/2013/549627
Montague CT et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908. doi:10.1038/43185
Moore SC et al (2012) Common genetic variants and central adiposity among Asian-Indians. Obesity (Silver Spring) 20:1902–1908. doi:10.1038/oby.2011.238
Moroni M et al (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6:279–286 (S1470-2045(05)70102-9)
Mutch DM, Clement K (2006) Unraveling the genetics of human obesity. PLoS Genet 2:e188 (06-PLGE-RV-0309R2)
Naidoo N, Pawitan Y, Soong R, Cooper DN, Ku CS (2011) Human genetics and genomics a decade after the release of the draft sequence of the human genome. Hum Genomics 5:577–622 (M9J614X5787X2303)
Ng MC et al (2012) Genome-wide association of BMI in African Americans. Obesity (Silver Spring) 20:622–627. doi:10.1038/oby.2011.154
Nilsson C, Raun K, Yan FF, Larsen MO, Tang-Christensen M (2012) Laboratory animals as surrogate models of human obesity. Acta Pharmacol Sin 33:173–181. doi:10.1038/aps.2011.203
Ning B et al (2014) Toxicogenomics and cancer susceptibility: advances with next-generation sequencing. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 32:121–158. doi:10.1080/10590501.2014.907460
Oberkofler H et al (2004) Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. Diabetes 53:1385–1393
Okada Y et al (2012) Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet 44:302–306. doi:10.1038/ng.1086
Patel CJ, Ioannidis JP (2014) Studying the elusive environment in large scale. JAMA 311:2173–2174. doi:10.1001/jama.2014.4129
Paternoster L et al (2011) Genome-wide population-based association study of extremely overweight young adults—the GOYA study. PLoS ONE 6:e24303. doi:10.1371/journal.pone.0024303 (PONE-D-11-06398)
Perry RJ et al (2014) Leptin reverses diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Med 20:759–763. doi:10.1038/nm.3579
Pinto D et al (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–372. doi:10.1038/nature09146
Pi-Sunyer X (2009) The medical risks of obesity. Postgrad Med 121:21–33. doi:10.3810/pgm.2009.11.2074
Rees SD et al (2011) An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabet Med 28:673–680. doi:10.1111/j.1464-5491.2011.03257.x
Rios M et al (2001) Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol 15:1748–1757. doi:10.1210/mend.15.10.0706
Rivas MA et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066–1073. doi:10.1038/ng.952
Rosskopf D et al (2007) Comment on “A common genetic variant is associated with adult and childhood obesity”. Science 315:187. doi:10.1126/science.1130571 (author reply 187)
Saeed S et al (2013) Novel LEPR mutations in obese Pakistani children identified by PCR-based enrichment and next generation sequencing. Obesity (Silver Spring). doi:10.1002/oby.20667
Sallman Almen M et al (2013) Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children. Int J Obes (Lond) 37:424–431. doi:10.1038/ijo.2012.57
Sandholt CH et al (2010) Combined analyses of 20 common obesity susceptibility variants. Diabetes 59:1667–1673. doi:10.2337/db09-1042db09-1042
Sandholt CH, Hansen T, Pedersen O (2012) Beyond the fourth wave of genome-wide obesity association studies. Nutr Diabetes 2:e37. doi:10.1038/nutd.2012.9
Saunders CL et al (2007) Meta-analysis of genome-wide linkage studies in BMI and obesity. Obesity (Silver Spring) 15:2263–2275. doi:10.1038/oby.2007.269
Scherag A 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. doi:10.1371/journal.pgen.1000916
Schmutz J et al (2004) Quality assessment of the human genome sequence. Nature 429:365–368. doi:10.1038/nature02390
Schreiber M, Dorschner M, Tsuang D (2013) Next-generation sequencing in schizophrenia and other neuropsychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 162B:671–678. doi:10.1002/ajmg.b.32156
Scuteri A et al (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115. doi:10.1371/journal.pgen.0030115
Sha BY et al (2009) Genome-wide association study suggested copy number variation may be associated with body mass index in the Chinese population. J Hum Genet 54:199–202. doi:10.1038/jhg.2009.10jhg200910
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311
Snyder EE, Walts B, Perusse L, Chagnon YC, Weisnagel SJ, Rankinen T, Bouchard C (2004) The human obesity gene map: the 2003 update. Obes Res 12:369–439. doi:10.1038/oby.2004.47
Soccio RE, Chen ER, Lazar MA (2014) Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 20:573–591. doi:10.1016/j.cmet.2014.08.005
Sofos E et al (2012) A novel familial 11p15.4 microduplication associated with intellectual disability, dysmorphic features, and obesity with involvement of the ZNF214 gene. Am J Med Genet A 158A:50–58. doi:10.1002/ajmg.a.34290
Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M (2009) Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr 90:1418–1425. doi:10.3945/ajcn.2009.27958
Speakman J, Hambly C, Mitchell S, Krol E (2008) The contribution of animal models to the study of obesity. Lab Anim 42:413–432. doi:10.1258/la.2007.006067
Speliotes EK et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948. doi:10.1038/ng.686
Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN (2013) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. doi:10.1007/s00439-013-1358-4
Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18:213–215. doi:10.1038/ng0398-213
Stunkard AJ, Harris JR, Pedersen NL, McClearn GE (1990) The body-mass index of twins who have been reared apart. N Engl J Med 322:1483–1487. doi:10.1056/NEJM199005243222102
Tabara Y, Kawamoto R, Osawa H, Nakura J, Makino H, Miki T, Kohara K (2008) No association between INSIG2 Gene rs7566605 polymorphism and being overweight in Japanese population. Obesity (Silver Spring) 16:211–215. doi:10.1038/oby.2007.25
Tao YX (2005) Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 239:1–14. doi:10.1016/j.mce.2005.04.012
Tao L et al (2012) A Common variant near the melanocortin 4 receptor is associated with low-density lipoprotein cholesterol and total cholesterol in the Chinese Han population. Mol Biol Rep 39:6487–6493. doi:10.1007/s11033-012-1476-4
Thorleifsson G et al (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24. doi:10.1038/ng.274
Tontonoz P, Spiegelman BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77:289–312. doi:10.1146/annurev.biochem.77.061307.091829
Ukkola O et al (2000) Interactions among the alpha2-, beta2-, and beta3-adrenergic receptor genes and obesity-related phenotypes in the Quebec Family Study. Metabolism 49:1063–1070. doi:10.1053/meta.2000.7708
Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253–262. doi:10.1172/JCI9238
Vasan SK et al (2012) Associations of variants in FTO and near MC4R with obesity traits in South Asian Indians. Obesity (Silver Spring) 20:2268–2277. doi:10.1038/oby.2012.64
Vasan SK, Karpe F, Gu HF, Brismar K, Fall CH, Ingelsson E, Fall T (2014) FTO genetic variants and risk of obesity and type 2 diabetes: a meta-analysis of 28,394 Indians. Obesity (Silver Spring) 22:964–970. doi:10.1002/oby.20606
Walters RG et al (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463:671–675. doi:10.1038/nature08727
Walters RG et al (2013) Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity. PLoS ONE 8:e58048. doi:10.1371/journal.pone.0058048
Wang K, Li WD, Glessner JT, Grant SF, Hakonarson H, Price RA (2010) Large copy-number variations are enriched in cases with moderate to extreme obesity. Diabetes 59:2690–2694. doi:10.2337/db10-0192 (db10-0192)
Warden CH, Yi N, Fisler J (2004) Epistasis among genes is a universal phenomenon in obesity: evidence from rodent models. Nutrition 20:74–77 (S089990070300217X [pii])
Wei WH, Hemani G, Haley CS (2014) Detecting epistasis in human complex traits. Nat Rev Genet 15:722–733. doi:10.1038/nrg3747
Wen W et al (2012) Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 44:307–311. doi:10.1038/ng.1087
Wheeler E et al (2013) Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet 45:513–517. doi:10.1038/ng.2607
Willer CJ et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34. doi:10.1038/ng.287
Wu L et al (2010) Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. Diabetes 59:3085–3089. doi:10.2337/db10-0273
Xi B, Mi J (2009) FTO polymorphisms are associated with obesity but not with diabetes in East Asian populations: a meta-analysis. Biomed Environ Sci 22:449–457. doi:10.1016/S0895-3988(10)60001-3
Xi B et al (2010) The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China. BMC Med Genet 11:107. doi:10.1186/1471-2350-11-107
Xi B, Chandak GR, Shen Y, Wang Q, Zhou D (2012) Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PLoS ONE 7:e45731. doi:10.1371/journal.pone.0045731
Yang J et al (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42:565–569. doi:10.1038/ng.608
Yang TL, Guo Y, Li SM, Li SK, Tian Q, Liu YJ, Deng HW (2013) Ethnic differentiation of copy number variation on chromosome 16p12.3 for association with obesity phenotypes in European and Chinese populations. Int J Obes (Lond) 37:188–190. doi:10.1038/ijo.2012.31
Yeo GS et al (2004) A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7:1187–1189 (nn1336)
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432. doi:10.1038/372425a0
Zucker LM (1975) Efficiency of energy utilization by the Zucker hereditarily obese rat “fatty” (38569). Proc Soc Exp Biol Med 148:498–500
Zuk O et al (2014) Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci USA 111:E455–E464. doi:10.1073/pnas.1322563111
Acknowledgments
This work was supported by High Impact Research Ministry of Higher Education (HIR-MOHE) of Malaysia Grants E000049-20001 and FL009-2011 from the University of Malaya.
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Apalasamy, Y.D., Mohamed, Z. Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity. Hum Genet 134, 361–374 (2015). https://doi.org/10.1007/s00439-015-1533-x
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DOI: https://doi.org/10.1007/s00439-015-1533-x