Section of Genomic Medicine (A.I.F.B., P.F.), Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom; and Centre National de la Recherche Scientifique 8090-Institute of Biology (P.F.), Pasteur Institute, BP 245-59019 Lille, France
Address all correspondence and requests for reprints to: Professor Philippe Froguel, Section of Genomic Medicine, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, East Acton, London W12 0NN, United Kingdom. E-mail: p.froguel{at}imperial.ac.uk.
Context: To design rational management regimes and identifynovel therapeutic targets, it is essential to understand thebiological drivers of the current epidemic of obesity. Thisreview describes our current knowledge of genetic factors inobesity, drawing functional parallels in the underlying neuroendocrinemechanisms and suggesting promising new directions for research.
Evidence Acquisition: Published literature, addressing boththe current knowledge of genetics of monogenic and syndromicforms of extreme obesity, and the emerging literature on geneticfactors associated with more common forms of obesity are analyzed.
Evidence Synthesis: The current genetic evidence in obesityunderlines the importance of neuroendocrine mechanisms of appetiteregulation. Monogenic forms of disease explain 6% of childrenwith extreme obesity, having hyperphagia associated with defectsin the leptin-melanocortin pathway, as a central feature. Candidategene association studies indicate that more subtle variationsof the same genes also contribute to common forms of obesity.Well-powered genome-wide association studies recently identifiedFTO as a strong contributor to both childhood and adult obesity,demonstrating the power of such hypothesis-free analysis toprovide new insights into the underlying pathogenic mechanismsof a common complex disease.
Conclusions: Although there has been some very heartening recentprogress in elucidating genetic mechanisms underlying obesity,we are still a long way from explaining the high heritabilityof adiposity. Investigations of different forms of variation,such as copy number polymorphism, may extend our understandingof this condition.
As obesity becomes ever more widespread and severe in westernizedpopulations, presenting a growing burden for health care provision(1), the imperative to identify drivers for our burgeoning adipositybecomes increasingly urgent. The future does not look optimistic.The U.S. Center for Disease Control and Prevention reports thatin 2007, not only had not one U.S. state reached the A HealthyPeople 2010 target to reduce the proportion of obese adultsto 15%, but also in contrast, self-reported adult obesity hadincreased by 1.7% since 2005 (2). These trends are mirroredglobally. In a recent report, the absolute numbers of obeseindividuals were projected to total 2.16 billion overweightand 1.12 billion obese by 2030 (3).
It is abundantly clear that despite intensive efforts to reduceadiposity by various programs of dietary restraint, exerciseregimens, public health education, and drug therapies, thereis currently no effective, long-term therapy for morbid obesity,other than bariatric surgery. Elucidation of the genetic contributionto the etiology of the condition, and definition of subtypesof obesity amenable to different approaches to management, maybe our best hope of developing a nonsurgical therapy for thischronic disabling, disfiguring and often life-threatening condition.
Over the past three decades, there have been substantial changesin the human environment, including increased access to highlypalatable, calorie-dense foodstuffs and decreased need for physicalactivity in daily lives. We may be the first generation of humansto live in an environment of such long-term gustatory abundanceand leisure, and these conditions present a significant challengeto our metabolic regulatory systems, with 25.6% of U.S. adultsbeing obese in 2007 (1), and the number of "super obese" individuals,with body mass index (BMI) greater than 50 kg/m2, increasing6-fold in the last decade. The consequences of obesity for theindividual concerned are severe and wide ranging, includingsocial stigmatization and financial detriment (4, 5, 6), aswell as increased risk of diabetes, cardiovascular disease,osteoarthritis, respiratory disease, and a range of cancers(7). In addition, obesity is associated with an increased incidenceof psychiatric disease (8, 9) and with decreased cognitive function(10, 11), although the mechanisms underlying these phenomenaremain to be elucidated (12). It is clear that this escalatingepidemic is related to the recent environmental changes, butthe relationship is not a simple one. Not all people are affectedequally by our unhealthy lifestyles; some are protected fromthe deleterious effects of the obesogenic environment, whereasothers carry gene variants rendering them particularly sensitiveto it.
So What Is the Evidence that Genes Are Involved at All?
In fact, it is very robust, with twin studies giving heritabilityestimates of around 0.7 for BMI in adults and children (13),and comparable levels for other measures of adiposity: skinfoldthickness, waist circumference, and total and regional fat distribution(14, 15, 16, 17, 18). This means that around 70% of the individualvariation in adiposity between people is apparently due to geneticfactors. People at high genetic risk for obesity are more susceptibleto the effects of an unhealthy environment. Thus, as expoundedby Wardle et al. (13), "Targeting the family may be vital forobesity prevention in the earliest years, but longer-term weightcontrol will require a combination of individual engagementand society-wide efforts to modify the environment, especiallyfor children at high genetic risk."
Can’t Obese People Lose Weight if They Just Eat Less and Exercise More?
Well clearly this is at least partly true, but we may be substantiallyoverestimating our powers of self-determination with referenceto certain aspects of behavior. Long term, almost no one canmaintain significant weight loss after dieting (19) becauseeating behavior is under neuroendocrine control, and intakecannot be permanently repressed by conscious effort. The studyof ob/ob and db/db strains of mice that spontaneously becomeobese because of hyperphagia, as well as suffering infertilityand immunological deficit, highlights the role of leptin incontrol of food intake (20). Because these mice are not subjectto the type of social effects commonly thought to be associatedwith obesity in humans (poor education, dysfunctional familysituations, social exclusion, childhood sexual abuse, emotionalstress, fast food outlets, or excessive use of television andcomputer games), they represented the first proof that it waspossible to have a purely biologically based appetite dysregulation.The cloning of the leptin and leptin receptor genes was a realbreakthrough in the understanding of appetite control and wasswiftly followed by identification of the first examples ofhuman monogenic obesity (21, 22). Individuals with severe defectsin the leptin or leptin receptor genes are uncommon, but othermonogenic forms of obesity caused by defects involving the hypothalamicleptin-melanocortin pathway are observed at a higher frequency:1.8% of obese adults and up to 6% of early-onset severely obesechildren have dominant monogenic obesity caused by mutationsin the gene encoding the melanocortin-4 receptor (23, 24), andother rare recessive mutations in the proopiomelanocortin andprohormone convertase 1 genes also result in hyperphagia andsevere early-onset obesity (25, 26). Acting downstream of theleptin-melanocortin pathway, mutations in the neurotrophic tyrosinekinase receptor type 2 gene, which encodes the receptor forbrain-derived neurotrophic factor (BDNF), also result in monogenicearly-onset obesity (27). Individually, most mutations in theleptin-melanocortin and related pathways are uncommon, but eachhas a strong effect, leading inexorably to the phenotype ofextreme obesity.
Other rare causes of severe obesity have also helped to pinpointgenes or genomic regions important for the maintenance of bodyweight. These have also tended to have a neuroendocrine basis,mediated largely through appetite dysregulation. The best-knownexample of this is Prader-Willi syndrome, in which the absenceof the paternally inherited copy of a region on the long armof chromosome 15 leads to insatiable hunger, obsessive food-seekingbehavior, and consequent severe obesity, along with learningdisability and dysmorphic features. The precise mechanism underlyingthe hyperphagia in humans remains to be determined, but recentanalysis of a murine model of Prader-Willi syndrome has narroweddown the genomic region of interest. Mice with a deletion ofthe small nucleolar RNA cluster, Snord116, exhibit a defectin meal termination mechanisms, characterized by extended feedingduration and hyperghrelinemia (28). Some Prader-Willi-like patientshave had a defect involving haploinsufficiency for the single-mindedhomolog 1 gene on chromosome 6, which encodes a transcriptionfactor essential for formation of the hypothalamic paraventricularnucleus, and which was also identified as a candidate gene forchildhood obesity in studies (29, 30, 31).
In another microdeletion syndrome, Wilms’ tumor, aniridia,genitourinary abnormalities, and mental retardation (WAGR) (adeletion of a region of chromosome 11p13, including the Wilms’tumor suppressor and PAX6 genes, and characterized by WAGR),only around 50% of patients become obese. The explanation forthis is found in the size of each patient’s mutation;in cases in which the deletion also included the adjacent BDNFgene, there was haploinsufficiency for BDNF (32), which actsdownstream of the leptin-melanocortin pathway (33). Gray etal. (34) had already provided evidence that disruption of BDNFcauses human obesity, and the WAGR data support this. Animalstudies further support these data. Heterozygous Bdnf knockoutmice exhibit hyperphagia and obesity, which is reversible byintracerebroventricular infusion of BDNF protein (35).
Another knockout mouse model has increased our understandingof appetite dysregulation in Bardet-Biedl syndrome, a ciliopathywith complex genetic etiology involving at least 12 genes, someof which may interact (36). The protein products of two of thehomologous mouse genes, Bbs2 and Bbs4, are required for thecorrect localization of somatostatin receptor type 3 and melanin-concentratinghormone receptor 1 in central neurons, providing a potentialmolecular mechanism for the hyperphagia in Bardet-Biedl syndrome(37).
It is clear from the study of rare obesity syndromes that themajority of molecular defects discovered so far are neuroendocrinein nature, with profound effects on feeding behavior resultingin severe early-onset obesity. The situation with common formsof obesity may differ. Most fat children go on to become fatadults, but many more people only become obese in adult life,particularly in middle age. Although subtle variants in thegenes discussed previously are obvious candidates for contributionto common obesity, distinct genetic mechanisms may also be inplay in adult-onset disease. In addition, different factorsare likely to be involved in extreme adult obesity than in morecommon forms.
As with other complex diseases, a large number of candidategene association studies, of variable power, have been performedin obesity and related phenotypes (reviewed in Ref. 38). Byfar the most strongly replicated candidate gene from these analysesis melanocortin 4 receptor, but other replicated associationsinclude those with adipokine and adipokine receptor genes (includingthose encoding leptin and its receptor, adiponectin, resistin,TNF-, and IL-6). In contrast to studies of rare childhood obesitysyndromes, genes concerned with energy utilization have alsobeen implicated in common obesity, with replicated associationswith the genes encoding β-adrenergic receptors 2 and 3,hormone-sensitive lipase, and mitochondrial uncoupling proteins1, 2, and 3 (38). Underlining the central role of behavioralstimuli in obesity, alleles of genes encoding dopamine, serotonin,and cannabinoid receptors (DRD2, HTR2C, and CBI) (38, 39, 40,41) are also reported to be associated with feeding behaviorand related traits.
The last 2 yr have seen a revolution in our approach to thestudy of complex disease as well-powered, hypothesis-free genome-wideassociation (GWA) studies have led to the identification ofnew candidate genes in various disorders, including type 2 diabetesand obesity. In the course of these studies, a new gene forobesity, FTO, was also identified simultaneously by three separategroups (42, 43, 44). This association has subsequently beenconfirmed by a number of GWA or candidate gene association analyses(45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61). The contribution of the FTO variant is fairly modest,with adult homozygotes for the risk allele having only a 2-to 3-kg increase in weight (43), but the obesity high-risk alleleis common in Caucasian populations. Its effects begin earlyin life. Higher fat mass is observable from the age of 2 wk(61), and carriage of the allele is associated with higher BMIand reduced satiety in children (62). However, the most significantlyassociated single nucleotide polymorphism (SNP) is intronic,and the molecular mechanisms underlying the association remainunclear. The gene encodes a 2-oxoglutarate-dependent nucleicacid demethylase (63); the gene is widely expressed but at particularlyhigh levels in the hypothalamus. There are contradictory reportsof up-regulation and down-regulation in response to feedingand fasting between rats and mice (64, 65). In studies of humanswith different genotypes, other workers report effects on insulinsensitivity in the brain (66) and on peripheral lipolysis (67).A third possibility is that the observed effect attributed toFTO is, in fact, a result of a ciliopathy resulting from dysregulationof an adjacent gene, FTM (68). Further work is required to determinewhich mechanisms are producing the major effect.
In addition to the studies reported previously, there are reportsof association with the genes encoding b-catenin-like protein1 (69), insulin-induced gene 2 (70) myotubularin-related protein-9(71), ganglioside induced differentiation associated protein1, and somastatin-receptor-2 (72), but these await independentreplication by other researchers.
In general, the yield from GWA studies of obesity has been lowso far, and some findings await independent replication. Mostcurrent GWA studies have only moderate power to detect commonvariants associated with a binary trait with a relative riskof around 1.2 or above, and it has been estimated that studiesof 50,000 subjects or above are necessary to provide 90% powerto detect variants with genetic effects of around that magnitude(73). Currently, the only feasible approach to increasing poweris through large-scale metaanalyses, and we anticipate thatsuch investigations will increase the yield of obesity associatedloci.
All of the genes currently known to cause monogenic or syndromicobesity are expressed in the brain and appear to exert theireffects by modulation of feeding behavior. Common SNPs in severalof these genes are associated with common obesity and with mildabnormalities in food intake behavior. The evidence for involvementof other mechanisms, such as altered energy utilization, ismuch less compelling. In this respect there is little evidenceso far for the existence of "thrifty genes" (74), so that analternative hypothesis proposed by Speakman (75), that accumulationof genetic factors predisposing to obesity results largely fromgenetic drift after the relaxation of selection resulting fromlack of predation, is gaining additional credibility.
Our efforts to identify genetic factors in obesity have yieldedsome notable successes, but we are still a long way from explainingthe high heritability of the condition. Most genetic associationstudies have been predicated on the idea that common geneticvariants in relevant genes alter their function in relativelysubtle ways, having a cumulative effect on risk of obesity.This is the "common variant-common disease hypothesis." However,there is an alternative possibility: that there exist in thepopulation a large number of more deleterious variations, eachone being individually quite rare (76, 77), although initialsuch studies of well-known candidate genes have not shown variationin coding sequences that would account for a significant fractionof obesity (78). Extensive resequencing will be required toidentify such variants. Alternatively, the missing heritabilitymay be accounted for by other genetic factors. One possibilityis that a recently appreciated form of genetic polymorphism,genomic copy number variation, might make a major contributionto interindividual phenotypical differences (79). Copy numbervariation is widespread in the genome, including many genesand regulatory regions, and it has been estimated to accountfor around 18% of variation in gene expression between normalindividuals (80, 81), but is nontrivial to genotype in the large-scalestudies required to firmly establish potential associationswith obesity. Other genetic effects, including epigenetic modifications,may also contribute to phenotypical variability. Our knowledgeof genetic factors predisposing to obesity has increased rapidlyover recent years, and the pace of this should accelerate astechnologies for genome resequencing, detection of structuralvariants, and ultra high-throughput SNP genotyping continueto mature.
Footnotes
Disclosure Statement: The authors have nothing to disclose.
Abbreviations: BDNF, Brain-derived neurotrophic factor; BMI,body mass index; GWA, genome-wide association; SNP, single nucleotidepolymorphism; WAGR, Wilms’ tumor, aniridia, genitourinaryabnormalities, and mental retardation.
Wolf AM, Colditz GA 1998 Current estimates of the economic cost of obesity in the United States. Obes Res 6:97–106[Medline]
Centers for Disease Control and Prevention (CDC) 2008 State-specific prevalence of obesity among adults—United States, 2007. MMWR Morb Mortal Wkly Rep 57:765–768[Medline]
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[CrossRef][Medline]
Gortmaker SL, Must A, Perrin JM, Sobol AM, Dietz WH 1993 Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med 329:1008–1012[Abstract/Free Full Text]
Sarlio-Lähteenkorva S, Stunkard A, Rissanen A 1995 Psychosocial factors and quality of life in obesity. Int J Obes Relat Metab Disord 19(Suppl 6):S1–S5
Flegal KM, Graubard BI, Williamson DF, Gail MH 2007 Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 298:2028–2037[Abstract/Free Full Text]
Petry NM, Barry D, Pietrzak RH, Wagner JA 2008 Overweight and obesity are associated with psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychosom Med 70:288–297[Abstract/Free Full Text]
McLaren L, Beck CA, Patten SB, Fick GH, Adair CE 2008 The relationship between body mass index and mental health. A population-based study of the effects of the definition of mental health. Soc Psychiatry Psychiatr Epidemiol 43:63–71[CrossRef][Medline]
Li Y, Dai Q, Jackson JC, Zhang J 2008 Overweight is associated with decreased cognitive functioning among school-age children and adolescents. Obesity (Silver Spring) 16:1809–1815[CrossRef][Medline]
Wolf PA, Beiser A, Elias MF, Au R, Vasan RS, Seshadri S 2007 Relation of obesity to cognitive function: importance of central obesity and synergistic influence of concomitant hypertension. The Framingham Heart Study. Curr Alzheimer Res 4:111–116[CrossRef][Medline]
Walley AJ, Blakemore AI, Froguel P 2006 Genetics of obesity and the prediction of risk for health. Hum Mol Genet 15(Spec No 2):R124–R130
Wardle J, Carnell S, Haworth CM, Plomin R 2006 Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 87:398–404
Selby JV, Newman B, Quesenberry Jr CP, Fabsitz RR, King MC, Meaney FJ 1989 Evidence of genetic influence on central body fat in middle-aged twins. Hum Biol 61:179–194[Medline]
Turula M, Kaprio J, Rissanen A, Koskenvuo M 1990 Body weight in the Finnish Twin Cohort. Diabetes Res Clin Pract 10(Suppl 1):S33–S36
Moll PP, Burns TL, Lauer RM 1991 The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study. Am J Hum Genet 49:1243–1255[Medline]
Katzmarzyk PT, Malina RM, Perusse L, Rice T, Province MA, Rao DC, Bouchard C 2000 Familial resemblance in fatness and fat distribution. Am J Hum Biol 12:395–340[CrossRef][Medline]
Malis C, Rasmussen EL, Poulsen P, Petersen I, Christensen K, Beck-Nielsen H, Astrup A, Vaag AA 2005 Total and regional fat distribution is strongly influenced by genetic factors in young and elderly twins. Obes Res 13:2139–2145[Medline]
Mann T, Tomiyama AJ, Westling E, Lew AM, Samuels B, Chatman J 2007 Medicare’s search for effective obesity treatments: diets are not the answer. Am Psychol 62:220–233[CrossRef][Medline]
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[CrossRef][Medline]
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908[CrossRef][Medline]
Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401[CrossRef][Medline]
Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, Balkau B, Potoczna N, Horber F, O'Rahilly S, Farooqi IS, Froguel P, Meyre D 2008 Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 57:2511–2518[Abstract/Free Full Text]
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[Abstract/Free Full Text]
Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157[CrossRef][Medline]
Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S 1997 Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303–306[CrossRef][Medline]
Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS 2004 A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7:1187–1189[CrossRef][Medline]
Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, Francke U 2008 SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS ONE 3:e1709
Holder Jr JL, Butte NF, Zinn AR 2000 Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:101–108[Abstract/Free Full Text]
Faivre L, Cormier-Daire V, Lapierre JM, Colleaux L, Jacquemont S, Geneviéve D, Saunier P, Munnich A, Turleau C, Romana S, Prieur M, De Blois MC, Vekemans M 2002 Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J Med Genet [Erratum (2004) 41:320] 39:594–596[CrossRef]
Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P 2004 A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 53:803–811[Abstract/Free Full Text]
Han JC, Liu QR, Jones M, Levinn R, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan MD, Uhl GR, Rennert OM, Yanovski JA 2008 Brain derived neurotrophic factor and obesity in WAGR syndrome. N Engl J Med 359:918–927[Abstract/Free Full Text]
Levin BE 2007 Neurotrophism and energy homeostasis: perfect together. Am J Physiol Regul Integr Comp Physiol 293:R988–R991
Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM, Yanovski JA, El Gharbawy A, Han JC, Tung YC, Hodges JR, Raymond FL, O'Rahilly S, Farooqi IS 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[Abstract/Free Full Text]
Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M 2007 Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behaviour and obesity. J Neurosci 27:14265–14274[Abstract/Free Full Text]
Adams M, Smith UM, Logan CV, Johnson CA 2008 Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. J Med Genet 45:257–267[Abstract/Free Full Text]
Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K 2008 Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA 105:4242–4246[Abstract/Free Full Text]
Li S, Loos RJ 2008 Progress in the genetics of common obesity: size matters. Curr Opin Lipidol 19:113–121[Medline]
Peeters A, Beckers S, Mertens I, Van Hul W, Van Gaal L 2007 The G1422A variant of the cannabinoid receptor gene (CNR1) is associated with abdominal adiposity in obese men. Endocrine 31:138–141[CrossRef][Medline]
Russo P, Strazzullo P, Cappuccio FP, Tregouet DA, Lauria F, Loguercio M, Barba G, Versiero M, Siani A 2007 Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men. J Clin Endocrinol Metab 92:2382–2386[Abstract/Free Full Text]
Benzinou M, Chèvre JC, Ward KJ, Lecoeur C, Dina C, Lobbens S, Durand E, Delplanque J, Horber FF, Heude B, Balkau B, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O, Meyre D, Froguel P 2008 Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations. Hum Mol Genet 17:1916–1921[Abstract/Free Full Text]
Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P, Carlsson LMS, Kiess W, Vatin V, Lecoeur C, Deplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougneres P, Kovacs P, Marre M, Balkau B, Cauchi S, Chevre JC, Froguel P 2007 Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39:724–726[CrossRef][Medline]
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI 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[Abstract/Free Full Text]
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR 2007 Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115
Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H, Hebebrand J 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
Cha SW, Choi SM, Kim KS, Park BL, Kim JR, Kim JY, Shin HD 2008 Replication of genetic effects of FTO polymorphisms on BMI in a Korean population. Obesity (Silver Spring) 16:2187–2189[CrossRef][Medline]
Chu X, Erdman R, Susek M, Gerst H, Derr K, Al-Agha M, Wood GC, Hartman C, Yeager S, Blosky MA, Krum W, Stewart WF, Carey D, Benotti P, Still CD, Gerhard GS 2008 Association of morbid obesity with FTO and INSIG2 allelic variants. Arch Surg 143:235–240[Abstract/Free Full Text]
Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC 2008 Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes 57:1147–1150[Abstract/Free Full Text]
Grant SF, Li M, Bradfield JP, Kim CE, Annaiah K, Santa E, Glessner JT, Casalunovo T, Frackelton EC, Otieno FG, Shaner JL, Smith RM, Imielinski M, Eckert AW, Chiavacci RM, Berkowitz RI, Hakonarson H 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
Haupt A, Thamer C, Machann J, Kirchhoff K, Stefan N, Tschritter O, Machicao F, Schick F, Häring HU, Fritsche A 2008 Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss. Obesity (Silver Spring) 16:1969–1972[CrossRef][Medline]
Hotta K, Nakata Y, Matsuo T, Kamohara S, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Masuzaki H, Yoneda M, Nakajima A, Miyazaki S, Tokunaga K, Kawamoto M, Funahashi T, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Nakao K, Sakata T, Matsuzawa Y, Tanaka K, Kamatani N, Nakamura Y 2008 Variations in the FTO gene are associated with severe obesity in the Japanese. J Hum Genet 53:546–553[CrossRef][Medline]
Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP, Hopkins PN, Adams TD 2008 Association of the FTO gene with BMI. Obesity (Silver Spring) 16:902–904[CrossRef][Medline]
Kring SI, Holst C, Zimmermann E, Jess T, Berentzen T, Toubro S, Hansen T, Astrup A, Pedersen O, Sørensen TI 2008 FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS ONE 3:e2958
Marvelle AF, Lange LA, Qin L, Adair LS, Mohlke KL 2008 Association of FTO with obesity-related traits in the Cebu Longitudinal Health and Nutrition Survey (CLHNS) Cohort. Diabetes 57:1987–1991[Abstract/Free Full Text]
Ng MC, Park KS, Oh B, Tam CH, Cho YM, Shin HD, Lam VK, Ma RC, So WY, Cho YS, Kim HL, Lee HK, Chan JC, Cho NH 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[Abstract/Free Full Text]
Peeters A, Beckers S, Verrijken A, Roevens P, Peeters P, Van Gaal L, Van Hul W 2008 Variants in the FTO gene are associated with common obesity in the Belgian population. Mol Genet Metab 93:481–484[CrossRef][Medline]
Price RA, Li WD, Zhao H 2008 FTO gene SNPs associated with extreme obesity in cases, controls and extremely discordant sister pairs. BMC Med Genet 9:4
González-Sánchez JL, Zabena C, Martínez-Larrad MT, Martínez-Calatrava MJ, Pérez-Barba M, Serrano-Ríos M 27 June 2008 Variant rs9939609 in the FTO gene is associated with obesity in an adult population from Spain. Clin Endocrinol (Oxf) 10.1111/j.1365-2265.2008.03335x
Qi L, Kang K, Zhang C, van Dam RM, Kraft P, Hunter D, Lee CH, Hu FB 22 July 2008 FTO gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test. Diabetes 10.2337/db08-0006
Tan JT, Dorajoo R, Seielstad M, Sim X, Rick OT, Seng CK, Yin WT, Saw SM, Kai CS, Aung T, Tai ES 3 July 2008 FTO variants are associated with obesity in the Chinese and Malay populations in Singapore. Diabetes 57:2851–2857[Abstract/Free Full Text]
Villalobos-Comparán M, Teresa Flores-Dorantes M, Teresa Villarreal-Molina M, Rodríguez-Cruz M, García-Ulloa AC, Robles L, Huertas-Vázquez A, Saucedo-Villarreal N, López-Alarcón M, Sánchez-Muñoz F, Domínguez-López A, Gutiérrez-Aguilar R, Menjivar M, Coral-Vázquez R, Hernández-Stengele G, Vital-Reyes VS, Acuña-Alonzo V, Romero-Hidalgo S, Ruiz-Gómez DG, Riaño-Barros D, Herrera MF, Gómez-Pérez FJ, Froguel P, García-García E, Teresa Tusié-Luna M, Aguilar-Salinas CA, Canizales-Quinteros S 31 July 2008 The FTO gene is associated with adulthood obesity in the Mexican population. Obesity (Silver Spring) 16:2296–2301[CrossRef][Medline]
López-Bermejo A, Petry CJ, Díaz M, Sebastiani G, de Zegher F, Dunger DB, Ibáñez L 2008 The association between the FTO gene and fat mass in humans develops by the postnatal age of two weeks. J Clin Endocrinol Metab 93:1501–1505[Abstract/Free Full Text]
Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R 2008 Obesity-associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab 93:3640–3643[Abstract/Free Full Text]
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ 2007 The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318:1469–1472[Abstract/Free Full Text]
Fredriksson R, Hägglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schiöth HB 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[Abstract/Free Full Text]
Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, Zeltser LM, Chung WK, Leibel RL 2008 Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294:R1185–R1196
Tschritter O, Preissl H, Yokoyama Y, Machicao F, Häring HU, Fritsche A 2007 Variation in the FTO gene locus is associated with cerebrocortical insulin resistance in humans. Diabetologia 50:2602–2603[CrossRef][Medline]
Wåhlén K, Sjölin E, Hoffstedt J 2008 The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res 49:607–611[Abstract/Free Full Text]
Liu YJ, Liu XG, Wang L, Dina C, Yan H, Liu JF, Levy S, Papasian CJ, Drees BM, Hamilton JJ, Meyre D, Delplanque J, Pei YF, Zhang L, Recker RR, Froguel P, Deng HW 2008 Genome-wide association scans identified CTNNBL1 as a novel gene for obesity. Hum Mol Genet 17:1803–1813[Abstract/Free Full Text]
Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB, Colditz G, Hinney A, Hebebrand J, Koberwitz K, Zhu X, Cooper R, Ardlie K, Lyon H, Hirschhorn JN, Laird NM, Lenburg ME, Lange C, Christman MF 2006 A common genetic variant is associated with adult and childhood obesity. Science 312:279–283[Abstract/Free Full Text]
Yanagiya T, Tanabe A, Iida A, Saito S, Sekine A, Takahashi A, Tsunoda T, Kamohara S, Nakata Y, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Masuzaki H, Yoneda M, Nakajima A, Miyazaki S, Tokunaga K, Kawamoto M, Funahashi T, Hamaguchi K, Tanaka K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Nakao K, Sakata T, Matsuzawa Y, Kamatani N, Nakamura Y, Hotta K 2007 Association of single-nucleotide polymorphisms in MTMR9 gene with obesity. Hum Mol Genet 16:3017–3026[Abstract/Free Full Text]
Fox CS, Heard-Costa N, Cupples LA, Dupuis J, Vasan RS, Atwood LD 2007 Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project. BMC Med Genet 8(Suppl 1):S18
Altshuler D, Daly M 2007 Guilt beyond a reasonable doubt. Nat Genet 39:813–815[CrossRef][Medline]
Neel JV 1962 Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet 14:353–362[Medline]
Speakman JR 2007 A non-adaptive scenario explaining the genetic predisposition to obesity: the "predation release" hypothesis. Cell Metab 6:5–12[CrossRef][Medline]
Pritchard JK, Cox NJ 2002 The allelic architecture of human disease genes: common disease-common variant... or not? Hum Mol Genet 11:2417–2423[Abstract/Free Full Text]
Reich DE, Lander ES 2001 On the allelic spectrum of human disease. Trends Genet 17:502–510[CrossRef][Medline]
Beckmann JS, Estivill X, Antonarakis SE 2007 Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 8:639–646[CrossRef][Medline]
Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Martin J, Hebert S, Doelle H, Ersoy B, Kryukov G, Schmidt S, Yosef N, Ruppin E, Sharan R, Vaisse C, Sunyaev S, Dent R, Cohen J, McPherson R, Pennacchio LA 2007 Medical sequencing at the extremes of human body mass. Am J Hum Genet 80:779–791[CrossRef][Medline]
de Smith AJ, Tsalenko A, Sampas N, Scheffer A, Yamada NA, Tsang P, Ben-Dor A, Yakhini Z, Ellis RJ, Bruhn L, Laderman S, Froguel P, Blakemore AI 2007 Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Hum Mol Genet 16:2783–2794[Abstract/Free Full Text]
Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME, Dermitzakis ET 2007 Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315:848–853[Abstract/Free Full Text]
Top
Abstract
Introduction
, and IL-6). In contrast to studies of rare childhood obesity syndromes, genes concerned with energy utilization have also been implicated in common obesity, with replicated associations with the genes encoding β-adrenergic receptors 2 and 3, hormone-sensitive lipase, and mitochondrial uncoupling proteins 1, 2, and 3 (