DOI: 10.1542/peds.2011-2717; originally published online June 4, 2012;Pediatrics

Melania Manco and Bruno DallapiccolaGenetics of Pediatric Obesity

  

  http://pediatrics.aappublications.org/content/early/2012/05/29/peds.2011-2717

located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

Genetics of Pediatric Obesity

abstractOnset of obesity has been anticipated at earlier ages, and prevalencehas dramatically increased worldwide over the past decades. Epi-demic obesity is mainly attributable to modern lifestyle, but familystudies prove the significant role of genes in the individual’s predis-position to obesity. Advances in genotyping technologies have raisedgreat hope and expectations that genetic testing will pave the way topersonalized medicine and that complex traits such as obesity will beprevented even before birth. In the presence of the pressing offer ofdirect-to-consumer genetic testing services from private companiesto estimate the individual’s risk for complex phenotypes includingobesity, the present review offers pediatricians an update of the stateof the art on genomics obesity in childhood. Discrepancies with re-spect to genomics of adult obesity are discussed. After an appraisal offindings from genome-wide association studies in pediatric popula-tions, the rare variant–common disease hypothesis, the theoreticalsoil for next-generation sequencing techniques, is discussed as op-posite to the common disease–common variant hypothesis. Next-generation sequencing techniques are expected to fill the gap of“missing heritability” of obesity, identifying rare variants associatedwith the trait and clarifying the role of epigenetics in its heritability.Pediatric obesity emerges as a complex phenotype, modulated byunique gene–environment interactions that occur in periods of lifeand are “permissive” for the programming of adult obesity. With theadvent of next-generation sequencing techniques and advances inthe field of exposomics, sensitive and specific tools to predict theobesity risk as early as possible are the challenge for the next decade.Pediatrics 2012;130:1–11

AUTHORS: Melania Manco, MD, PhD, and BrunoDallapiccola, MD

Scientific Directorate, “Bambino Gesù” Pediatric Hospital, IstitutoDi Ricovero e Cura a Carattere Scientifico, Rome, Italy

KEY WORDSchildhood, genome-wide association study, heritability, obesity,metabolic programming

ABBREVIATIONSALSPAC—Avon Longitudinal Study of Parents and ChildrenGWAS—genome-wide association studyPA—physical activitySNP—single-nucleotide polymorphism

Dr Manco conceived and drafted the manuscript; Dr Dallapiccolarevised it critically for important intellectual content; and bothauthors approved the final version of the draft and take publicresponsibility for its content.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-2717

doi:10.1542/peds.2011-2717

Accepted for publication Mar 2, 2012

Address correspondence to Melania Manco, MD, PhD, FACN,Scientific Directorate, Bambino Gesù Pediatric Hospital, PiazzaSanOnofrio 4, 00165, Rome, Italy. E-mail: melania.manco@opbg.net

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: No external funding.

PEDIATRICS Volume 130, Number 1, July 2012 1

STATE-OF-THE-ART REVIEW ARTICLE

at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

Prevalence of overweight and obesityhas dramatically increased worldwidein children and adolescents over thepast 3 decades. Recent estimates sug-gest that 1 child in 2 in the United Statesand 1 in 3 in Europe is overweight.1

Therefore, childhood obesity has turnedinto a major health problem in Westerncountries, despite policies targeted atreducing its prevalence.1

Obesity is a complex trait that stemsfrom a complicated network of con-tributory components, encompassinggenomic (see glossary in Table 1) andenvironmental factors, which in ag-gregate increase the probability ofdisease. Sedentary behaviors and high-calorie diets are major environmentalfactors driving epidemic obesity.

Studies in twins, nontwin siblings, andadoptees have shown that genetic com-ponents contribute from 40% to 70% tothe interindividual variation in common

obesity.2 With no doubt, the obese phe-notype runs prevalently in families, butmost of the causative genes are still un-discovered. Findings from genome-wideassociation studies (GWAS) explain avery few of the obesity heritability. Themost recent meta-analysis of GWASdata identified 18 new loci associatedwith BMI, thus setting the number ofgenes likely associated with obesityup to 42.3 It is disappointing that eachof these alleles explained only a verysmall portion of the interindividual vari-ability in BMI, contributing to an increasein BMI of ∼0.17 kg/m2.3 Shortcomingsof GWAS in explaining such heritabilityare often referred to as the “missingheritability.”

As estimated by GWAS, the genetic com-ponent of obesity encompasses the smallcontribution of many single-nucleotidepolymorphisms (SNPs; Table 1). Apartfrom common variants, rare and private

variants determine jointly the humangenetic variation of BMI, but they can-not be identified by current GWAS. Asfar as the role of copy number variantsis concerned, there is no evidence sup-porting their role in explaining someof the BMI variation. Evidence is alsolacking on gene-by-gene or, more spe-cifically, variant-by-variant interactions(a phenomenon also termed “epista-sis”) that contribute to BMI variability.Indeed, analyses to detect epistaticinteractions suffer from a substantiallyincreased multiple testing burdens thathamper detection and interpretation. Todate, these investigations have focusedonly on those SNPs with significantmarginal effects,4 but future collabo-rative studies should provide evidenceon gene-by-gene interactions.

The cumulative risk to develop the dis-ease relies not only on the individual’sgenotype, but also on nongenetic deter-minants, mainly epigenetic (Table 1) andenvironmental factors.

As to environmental factors, the notionof “environment” has been evolving be-yond the classic idea of parental andnonparental influences on the child’slifestyle, mood, and behavior. Maternalinfluences on the child’s phenotypeoriginate before birth (in the intra-uterine environment) and continueduring the first 6 years of life,5 whenBMI trajectories are programmed bythe mother’s genetic, hormonal, and be-havioral factors.5,6 Intrauterine and earlypostnatal life are “permissive” windowswhen maternal and nonmaternal envi-ronmental factors will up or down mod-ulate the phenotypic expression of thechild’s genotype.6 Similarly, age of adi-posity rebound and puberty are “per-missive" periods.7

Genetics of pediatric obesity is pecu-liar with respect to genetics of adultobesity.8,9 The joint effects of genesand environment change sizably frombirth toward adulthood and are affectedby sex-limited effects.8 Two phases of

TABLE 1 Glossary

Copy number variants(CNVs)

They are variants that change the number of base pairs in the genome.

Less common variants Alleles with a minor allele frequency between 1% and 5%Effect size The increase in risk that is conferred by a given causal variantsEpigenetics The study of heritable changes in gene expression that are not due to changes

in DNA sequence. Epigenetic modifications include changes in the localizedor global density of DNAmethylation (also termed “methylome”), incorrecthistone modifications, or altered distribution or function of chromatin-modifying proteins that, in turn, lead to aberrant gene expression. Threekinds of genomic targets are susceptible to gene-expression changesowing to environmental perturbations of epigenetic marks: the promoterregion of certain housekeeping genes; genes with metastable epialleles,which are loci particularly sensible to environmental factors; andimprinted genes.

Epistasis The phenomenon in which the effect of a gene or variant on a trait is notindependent of the effect on the trait of another gene or variant.

Exome The proportion of the genome that is translated into proteins (1% of thewhole genome).

Exposome It is the sum of all the individual’s exposures in his/her lifetime and estimateshow those exposures relate to disease.

Exposomics The sciencewhich aims at studying association among factors, the exposome,which can influence the individual’s health.

Heritability It measures the fraction of the total phenotypic variance of a quantitative traitattributable to genes in a specified environment.

Minor allele frequency(MAF)

The proportion of alleles at a locus, that consists of the less frequent alleles,and ranges from 0% to 50%.

Private variants Alleles restricted to probands and immediate relatives.Rare variants Alleles with a minor allele frequency ,1%Single-nucleotidepolymorphisms (SNPs)

Single base changes in the DNA

Very common variants Alleles with a minor allele frequency between 5% and 50%

2 MANCO and DALLAPICCOLA at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

infancy, 0.5 to 1.5 years and 5 to 6 years,are considered as 2 particularly crit-ical periods regarding BMI develop-ment, whose direction is crucially fixedduring those time periods.5 Afterward,sex-limited genetic effects will addcomplexity to the dynamic picture ofdifferential genetic expression of obe-sity as a function of age.8 The sets ofgenes contributing to BMI variation arenot identical in men and women.9 Twinstudies demonstrated that sex-specificeffects modulate genetically drivengrowth patterns7 and influences ofshared and nonshared environmentalfactors on BMI heritability.10 These ef-fects become evident when fat massdistribution and hormonal milieu dif-ferentiate between the 2 genders.8

Recognitionofage- andgender-dependentgene effects is pivotal to explain someof the inconsistencies in GWAS findingsbetween young and adult individuals.

The growing inventory of human geneticvariation is facilitating an understandingof why susceptibility to common dis-eases varies among individuals andpopulations. It represents the rationaleto the development of “personalizedmedicine.” Individuals, when presentedwith information about their personal-ized, gene-based "disease risk profile"seem to better adapt their lifestyles soas to reduce their chances of developingconditions for which they have an “in-creased” risk.11 In the presence of thepressing offer of direct-to-consumergenetic testing services from privatecompanies to estimate the individual’srisk for complex phenotypes, ie, obesity,caution must be paid in interpretingresults of such tests.

COMMON DISEASE–COMMONVARIANT HYPOTHESIS AND GWASIN PEDIATRIC POPULATIONS

Based on the common disease–commonvariant hypothesis, which posits thatmultiple common alleles contribute tothe disease risk, the approach to genetic

studies of obesity has entailed preva-lently GWAS.

In GWAS, larger and larger samples ofcases and controls have been geno-typed for hundreds of thousands ofcommon variants, typically 300 000 to1 000 000 of SNPs with the aim ofdetecting the largest number of at riskvariants.12 The allele or genotype fre-quencies have been evaluated fordifferences between groups or for cor-relations with continuous traits. Despitesuch apparent simplicity, results of GWASmay be subject to multiple-hypothesistesting because of typing a very largenumber of alleles. They need correctionto exclude random association attrib-utable to multiple testing, which canturn spurious associations out. Draw-backs to GWAS include also the need forreplication of results in independentstudy populations and complementa-tion with robust mechanistic studies toelucidate the biological mechanisms re-sponsible for the genetic association.13

Despite shortcomings, GWAS have pro-vided robust evidence for a role of somevariants, particularly FTO, MC4R, andTMEM18 loci, in the development ofobesity. Table 2 reports genes so farassociated with pediatric obesity, theiracronyms, and functions, wheneverknown.

In the study by Willer et al14 the first,analysis was conducted in the AvonLongitudinal Study of Parents and Chil-dren (ALSPAC) study sample (N = 4951with BMI information at age 11) andconfirmed significant associations ofvariants in/near FTO, MC4R, TMEM18,KCTD15, and GNPDA2 with BMI. Succes-sively, data were replicated in the cohortof obese children (N = 1038) from theSevere Childhood Onset Obesity ProjectUnited Kingdom cohort and an increasedrisk of extreme childhood obesity wasrevealed for the BMI-increasing allelesnear TMEM18, GNPDA2, NEGR1.14

In the European Youth Heart Study(1252 children and 790 adolescents),

associations of 15 variants (NEGR1,SEC16B, LYPLAL1, TMEM18, ETV5,GNPDA2,TFAP2B, MSRA, BDNF, MTCH2, BCDIN3D,NRXN3, SH2B1, FTO, MC4R, and KCTD15)with BMIwere similar to those observedin adults.15 In a meta-analysis of datafrom 13 071 children and adolescentssignificant associations with BMI werefound for 9 of 13 variants and the nearTMEM18 variant had the strongest ef-fect. Effect sizes for BMI tended to bemore pronounced for variants in/nearSEC16, TMEM18, and KCTD15 in childrenand adolescents than in adults.16

FTO

The association between FTO polymor-phisms and obesity-related traits (ie,BMI, adiposity, circulating leptin, energyintake, impaired control of energy bal-ance, satiety sensitivity, and food re-sponsiveness) is one of the most robustassociation reported for complex traitsand has been firmly established in chil-dren.15–36 Nevertheless, functional rele-vance of FTO for the pathogenesis ofobesity remains elusive.17,18,21,25–31

It is worth mentioning that this associa-tion shows clearly sex-limited effects8,9

and an age-dependent expression inthat gene expression changes devel-opmentally.15,19,24,29,34,36 At birth, no as-sociation exists between FTO variantsand birth weight,15,17,18,32,33 but it appearssoon within the first weeks of life34 andpersists through the passage fromchildhood into adolescence.17,19,29,35 Inthis regard, Hebebrand37 hypothesizedthat the intrauterine environment hasa strong influence on anthropometricvariables of newborns and infants,thus tempering the effect of FTO var-iants on the infant ’s body weight,whereas, successively at 2 to 3 years,the effect of the genetic makeup be-comes discernible. The associationstrengthens from 4 years of age onwardover the lifespan.15,38 BMI developmentduring infancy can influence later theadult BMI.29 In a Dutch cohort of children

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 130, Number 1, July 2012 3 at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

TABLE 2 Genes Near/in Which Variants Have Been Associated With Increased BMI and Pediatric Populations

Nearest Genes(Acronym)

Locus AssociationWith BMI or BW

Major Cohort Studiesand Meta-analyses

Functions (Whenever It Is Known)/Sites of Expression

ADCY583 3q13.2-q21 BW Meta-analysis83 Adenylate cyclase 5. The gene encodes amemberof themembrane-boundadenylyl cyclase enzymes. Adenylyl cyclasesmediate G protein-coupledreceptor signaling through the synthesis of the second messengercAMP. Activity of theencodedprotein is stimulatedby theGsa subunit ofG protein-coupled receptors and is inhibited by protein kinase A,calcium, and Gi a subunits. Single-nucleotide polymorphisms in thisgene may be associated with low BW and type 2 diabetes. Alternatively,spliced transcript variants that encode different isoforms have beenobserved for this gene.

BDNF16,49,59,60,80 11p4 BMI/BW EYHS16 Brain-derived neurotrophic factor. The protein encoded by this gene isa member of the nerve growth factor family. It is induced by corticalneurons, and is necessary for survival of striatal neurons in the brain.Expression of this gene is reduced in patients with Alzheimer’s andHuntington disease. This gene may play a role in the regulation ofstress response and in the biology of mood disorders The gene hasa complex pattern of expression in the brain. Its high expression in theventromedial hypothalamus is regulated by nutritional state andMC4R signaling.

Obeldicks intervention59

Beijing Child and AdolescentMetabolic Syndrome Study60

ABC80

CCNL183 3q25.31 BW Meta-analysis83 Cyclin L1 protein kinase binding. Nothing is currently known about themechanism behind the association with obesity.

ETV516,49 3q27 BMI EYHS16 Ets variant gene 5. It is a transcription factor that plays a role indevelopment and cancer, highly expressed in brain and pancreas. Itstranscript levels are tightly regulatedduringhuman fetal development.

FAIM260 12q13 BMI Beijing Child and AdolescentMetabolic Syndrome Study60

Fas apoptotic inhibitorymolecule 2. Nothing is currently known about themechanism behind the association with obesity.

FTO14–38,59,63,64,84 16q12 BMI/BW ALSPAC and SCOOP-UK14 Fatmass-andobesity-associatedgene.Thisgene isanuclearproteinof theAlkB related non-heme iron and 2-oxoglutarate-dependent oxygenasesuperfamilybut theexactphysiologic functionof thisgene isnotknown.Studies in mice and humans indicate a role in nervous andcardiovascularsystemsandastrongassociationwithBMI, obesity risk,and type2diabetes.Thegene is involved inprocessessuchas fattyacidsmetabolism, and highly expressed in the hypothalamic nuclei.

EYHS16

Northern Finland BirthCohort 196629

GINI and LISA24

National Longitudinal Studyon Adolescent Health8,9

Obeldicks intervention59

GENESIS and GENDAI63,64

Meta-analysis84

GNPDA214,16,49 4p12 BMI ALSPAC and SCOOP-UK14 EYHS16 Glucosamine-6-phosphate deaminase 2. It catalyzes the reversibleconversion of D-glucosamine-6-phosphate into D-fructose-6-phosphateand ammonium.

KCNJ1180 11p15.1 BW ABC80 Potassiuminwardlyrectifyingchannel,subfamilyJ,member11Potassiumchannels are present inmostmammalian cells, where they participatein a wide range of physiologic responses. The protein encoded by thisgene is an integral membrane protein and inward-rectifier–typepotassium channel.

KCTD1514,16,49 19q13 BMI ALSPAC and SCOOP-UK14 Potassium channel tetramerization domain containing 15 gene. It isexpressed in the pituitary and carries out sulfation of carbohydrates,which confers highly specific functions on glycoproteins, glycolipids,and proteoglycans, pivotal for signal transduction and embryonicdevelopment.

EYHS16

MCR414,16,39–52,59,60 18q21 BMI ALSPAC and SCOOP-UK14 Melanocortin receptor 4. The preopiomelanocortin-deriveda-melanocyte-stimulating hormone from the arcuate nucleus binds toMCR4 in the paraventricular nucleus of the hypothalamus and isresponsible for increase in energy intake and decrease in food intake.

EYHS16

Meta-analysis studies48–50

Obeldicks intervention59

Beijing Child and AdolescentMetabolic Syndrome Study60

MTCH216,84 11p11.2 BMI/BW EYHS16 Mitochondrial carrier homolog 2. Nothing is currently known about themechanism behind the association with obesity.Meta-analysis84

NEGR118,49 1p31 BMI ALSPAC and SCOOP-UK18 Neuronalgrowth regulator-1gene. Theencodedprotein isamemberof theimmunoglobulin superfamily. Through its function as cell adhesionmolecule, the protein participates in the regulation of neuriteoutgrowth in the developing brain.

4 MANCO and DALLAPICCOLA at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

followed with yearly collection of dataon anthropometry from birth to age 7and on anthropometry, body composi-tion, leptin concentrations, physicalactivity (PA), hours watching television,and attitude toward eating from ages12 to 17, researchers observed thatat 17 years, 20% of the children wereoverweight/obese and 88% of theoverweight/obese children had the Aallele in contrast to 45% of the leanchildren.36 The A allele carriers hadhigher ratio of fat mass to height. TheFTO allele was associated with higherBMI, fat ratio, and leptin concentrationsfrom the age of 12 years, whereas the

associations showed a dip at ages 13 to14 years, probably because of the pu-bertal hormonal storm. The associa-tion became stronger at age 17 years.Such results were in keeping withreports from the German Infant Nutri-tional Intervention, the Lifestyle-relatedfactors on the Immune System and theDevelopment of Allergies in Childhoodbirth cohorts,24 and a twin study.19 Inthe German Infant Nutritional Interven-tion and Lifestyle-related factors on theImmune System and the Development ofAllergies in Childhood birth cohorts,2732 term newborns were genotyped(rs1558902 or rs9935401) and followed

from birth up to age 6 years. BMI tra-jectories varied by genotype status anddifferences become recognizable againfrom the age of 3 years onward. In 3582twin pairs, Haworth et al19 reporteda progressively larger heritability es-timate of BMI over time and, again, anage-dependent stronger association forthe common variant rs9939609 of FTOwith BMI, which became significant asof age 4.

As to mechanisms of the associationbetween FTO variants and fatness, ina sample of 2726 Scottish children (age4–10 years), the variant rs9939609 wasassociated with both adiposity and food

TABLE 2 Continued

Nearest Genes(Acronym)

Locus AssociationWith BMI or BW

Major Cohort Studiesand Meta-analyses

Functions (Whenever It Is Known)/Sites of Expression

PFKP80 10p15.3-p15.2 BW ABC80 ThePFKPgeneencodes theplatelet isoformofphosphofructokinase (PFK).PFK catalyzes the irreversible conversion of fructose 6-phosphate tofructose 1,6-bisphosphate and is a key regulatory enzyme in glycolysis.

PTER80 10p12 BW ABC80 Phosphotriesterase. Nothing is currently known about the mechanismbehind the association with obesity.

SDCCAG859 1q43 BMI Obeldicks intervention59 Serologically defined colon cancer antigen 8. This gene encodesa centrosome-associated protein. This protein may be involved inorganizing thecentrosomeduring interphaseandmitosis.Mutations inthis gene are associated with retinal-renal ciliopathy.

SEC16B16 1q25 BMI EYHS16 Located in intron 15 of the Mammalian Homolog of Saccharomycescerevisiae Sec1 gene. The protein encoded is required for organizationof transitional endoplasmic reticulum sites and protein export.

SH2B116,80 16p11.2 BMI EYHS16 Scr-homology-2 (SH2) domain containing putative adapter protein 1. Thisgene encodes a member of the SH2 domain. The encoded proteinmediates activation of various kinases andmay function in cytokine (ie,leptin) and growth factor receptor signaling and cellulartransformation.

ABC80

TFAP2B16 6p12 BMI EYHS16 Transcription factor AP-2 b or activating enhancer-binding protein 2 b isa member of the AP-2 family of transcription factors. AP-2 proteinsform homo- or heterodimerswith other AP-2 familymembers and bindspecific DNA sequences. They are thought to stimulate cellproliferation and suppress terminal differentiation of specific celltypes during embryonic development. The encoded transcriptionfactor is expressed in adipose tissue. Its overexpression leads toincreased lipid accumulation and decreased expression ofadiponectin. Thus, TFAP2B may have an effect on fat accumulation atmultiple sites.

TMEM1814,16,49 2p25 BMI ALSPAC and SCOOP-UK14 Transmembrane protein 18. The gene is highly conserved among speciesand expressed in the brain, particularly at the nucleus site.EYHS16

TNJK/MSRA16,59 8p23.1 BMI EYHS16 This protein is ubiquitous and highly conserved. It carries out theenzymatic reduction ofmethionine sulfoxide tomethionine. Humanandanimal studies have shown the highest levels of expression in kidneyand nervous tissue. Its proposed function is the repair of oxidativedamage to proteins to restore biological activity. Three transcriptvariants encoding different isoforms have been found for this gene.

Obeldicks intervention59

Functions and sites of expression are reported as in the Reference Sequence (RefSeq) collection.90 BW, body weight; ABC, Auckland Birth weight Collaborative study; EYHS, European YouthHeart Study; GINI, German Infant Nutritional Intervention; LISA, Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; SCOOP-UK, Severe ChildhoodObesity Onset Project-United Kingdom; SGA, small-for-gestational birth weight.

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 130, Number 1, July 2012 5 at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

intake, whereas no association wasfound with energy expenditure in asubgroup of 97 subjects.21 Scuteri et al25

suggested that the FTO variants mighthave a role in the control of food intakeand food choice, because children car-rying FTO variants are hyperphagic andprefer energy-dense foods. A more re-cent study in 655 European adolescentsprovided evidence for an association ofthe minor A allele of the FTO rs9939609with increased levels of leptin, andthis association was independent ofadiposity.30

MC4R in Common and MonogenicObesity

The melanocortin pathway plays a piv-otal role in the central regulation ofenergy homeostasis. MC4R deficiencyresulting from the disruption of one orboth MC4R alleles represents the mostcommonmonogenic form of early-onsetobesity, affecting 4% to∼6% of severelyobese French and British populations,respectively.39–42 More than 90 differentobesity-associated mutations of MC4R,most of which are missense mutations,have been reported so far.43 Phenotypeof carriers varies considerably.43,44 Ho-mozygous individuals typically exhibit amore severe phenotype than heterozy-gous do, but penetrance and expres-sivity may vary in affected families, withvariable age of onset and severity ofobesity.45

Children carrying MC4R mutationspresent with early-onset severe obesity,persistent food-seeking behavior from6 months of age, increased fat and leanmasses, hyperinsulinemia and hyper-phagia, which ameliorate with aging,higher stature, increased growth ve-locity, and older bone age (ie, exceed-ing the chronological age by 1–5 years)than matched obese controls.46,47

Findings from GWAS have proved thatvariants in/near MC4R contribute fre-quently to complex obesity, with a non-negligible size effect in the general

population. The increasing BMI size ef-fect ranged from 18% to 31% for car-riers of rs2229616 variant, whereascarriers of rs52820871 had ∼20% re-duced risk of obesity.48 A recent meta-analysis of data from 13 004 youngEuropeans demonstrated that eachadditional risk allele of the near/inMCR4 locus increases BMI by ∼7% SD.16

No association was found betweenvariants in/near MCR4 gene and birthweight48 and/or early weight gain.49,50

On the contrary, the association withBMI becomes significant by age 6 to 7years.38

TMEM18

The TMEM18 gene might be powerfullyinvolved in the modulation of energyhomeostasis, because it is widely ex-pressed and detected in the majority ofneurons in all major brain regions.51

Interestingly, variants near/in TMEM18were significantly associated with BMIin adult3,14 and pediatric populations.51–53

The most recent case-control study of502 obese and 525 control Swedishchildren (age 6–20 years) found a sig-nificant association of rs6548238 andrs756131 variants with obesity. In thisstudy, the odds ratio for the locus nearTMEM18 was as high as that reportedfor the FTO locus. Interestingly, homo-zygous carriers of the major allelesshowed a trend for lower birth weightand length.51 Variants near/in TMEM18were also significantly associated withweight gain in infancy49 and early-onset obesity.53

GENE-BY-PA AND DIETINTERACTIONS

The obesity-increasing effect of somepolymorphisms may be attenuated inindividuals who are physically active.54

Variants in FTO have been the mostfrequently analyzed with respect to gene-by-PA interactions, but results have beencontradictory.31,55–58 In population-basedcohorts of 4762 Finnish adolescents, low

PA was found to accentuate the effect ofFTO variant (rs1421085), whereas noclear interactions with PA were seen in3167 French adults,55 in a population ofDanish children (rs7566605) stratifiedfor PA,56 in young European and AfricanAmerican patients (rs9939609) in 1978,57

and in 19 268 children from a meta-analysis of 9 studies.58 The latter meta-analysis demonstrated that PA attenu-ates the influence of FTO variants onobesity risk by 30% in adults.58

No significant interaction was ob-served as well between M4CR variant(rs17782313) and PA in the afore-mentioned Finnish cohort.55 The inter-actions of 10 SNPs at 5 loci (in/near FTO,MC4R, TMEM 18, SDCCAG8, and TNJK/MSRA) with 1-year lifestyle interventionwas explored in 401 overweight chil-dren and adolescents (“Obeldicks” in-tervention). Homozygous carriers ofobesity risk alleles of SDCCAG8 lost lessweight than heterozygous or homozy-gous carriers of other alleles. Suchfindings were not confirmed in adults.59

In the Beijing Child and AdolescentMetabolic Syndrome Study, the associ-ations between FAIM2, NPC1, FTO, MCR4,BDNF, and GNPDA2 and obesity risk wasmodulated by PA. A higher risk of obesitywas observed in children who carriedthe high-risk alleles of the 6 SNPs andengaged in sedentary behavior$2 hoursper day outside of school or participatedin low or moderate PA.60

Heterogeneity between study in geneticarchitecture and environmental factors,differences in methods of measuring PA,and accuracy of the phenotype mea-surements make it difficult to studyinteractions between gene variants andPA. Differences with reports in adultsmay be due tomore intensive PA in youngand age-related effects.61

In relation to nutritional effects, no in-teraction was found between FTO allele(rs9939609) and dietary energy den-sity in the ALSPAC study.62 On the con-trary, fat intake modified the age- and

6 MANCO and DALLAPICCOLA at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

gender-specific association of thePro12Ala polymorphism with adiposityin preschoolers and periadolescents(data from the growth, exercise, andNutrition Epidemiologic Study, GENESIS;and the Gene diet Attica Investiga-tion on childhood obesity, GENDAI,respectively).63,64 In children, an age-dependent and gender-limited gene-by-diet effect was found at the age of 48months when the gene-by-diet effectdifferentiated in the 2 genders.64

Ideally, future GWA studies should beperformed in large study samples withsuperior characterization of lifestylefactors to take into account gene-by-environment interactions and thus fa-cilitate thedetectionof low-impact genevariants, of which there are expected tobe numerous variants with importantbut modest effects on obesity.

RARE VARIANT–COMMON DISEASEHYPOTHESIS ANDNEXT-GENERATION SEQUENCING

As opposite to the common variant–common disease hypothesis, the rarevariant–common disease hypothesissuggests that rare variants contributesignificantly to complex traits. Com-mon and rare variants are expected toexert their effects on adiposity by fol-lowing a gradient ranging from negli-gible to severe along a continuum. In allprobability, the obese phenotype is theconsequence of additive effects andinteractions among multiple alleleswith varying magnitude of effect, var-iants acting as modifier alleles, non-coding RNA, microRNA, splice variants,and regulatory elements in trans bywhich the genome governs various bi-ological processes.

Indeed, based on today’s knowledge,only 1% of the human genome is tran-scribed into mRNA and translated intoproteins. An additional 0.5% serves astemplate for noncoding RNA and theregulatory regions that control geneexpression. Functions of the remaining

98.5% of the genome remain un-known.12,65

GWAS, as they have been designed dodate, are unable to detect rare andprivate variants and to provide in-formation on the other genomic ele-ments that modulate the phenotypicexpression.12 On the contrary, rare andprivate variants might be identified bymassive genotyping or deep sequenc-ing in large families. Novel techniquesthat sequence millions of DNA strandsin parallel and at low cost have beendeveloped. These new technologies arecollectively referred to as the next-generation sequencing techniques. Inthe next few years, a rapid shift fromwhole exome (Table 1) to whole ge-nome sequencing as the desirable ap-proach to identify obesity-associatedvariants is expected.

EPIGENETICS ANDDEVELOPMENTAL ORIGIN OFOBESITY

Understanding the functional contentof the genome necessitates knowledgebeyond the complete genome sequence,including also information on epigenome(Table 1). Strong evidence is accumu-lating that the environment can altergene expression and influence theindividual’s phenotype mostly by mod-ifying the epigenome.66 Interest in epi-genetics has been increasing in thepast few years, because it may providea molecular mechanism for metabolicprogramming that links genes, prenatalenvironment, intrauterine growth, andsubsequent susceptibility to disease.

Epigenetic changes occur most com-monly during gestation, neonatal de-velopment, and puberty. They seem tocarry “memory” of early life experi-ences, triggering reversible, but alsoheritable disease susceptibility in laterlife. Indeed, they can be heritable acrosscell divisions in somatic cells and po-tentially inherited across several gen-eration (“epimutations”).6,66

Studies in animal models supportstrongly the concept that experi-ences during the intrauterine life canmodulate the phenotypes of progenyindependently of its genotype. In par-ticular, maternal nutrition67–70 andhormonal cues71 can influence the fe-tus’ gene expression by altering theextent of DNA methylation in genepromoters and histone acetylation inthe chromatin structure. This phenom-enon continues immediately after thebirth. Early modulation of the child’sphenotype may occur mostly through2 mechanisms that encompass theeffects of both thematernal epigenomeand the epigenetic programming of theplacenta in response to nutrient avail-ability and hormonal cues (recentlyrevised in ref 6). Epigenetic program-ming of the placenta, in turn, will resultin structural and functional changes,72

which can up- or downmodulate nutri-ent transport to the fetus and, hence, tofetal growth restriction or vice versa toovergrowth.

However, evidence in humans of mech-anisms by which epigenetics affect de-velopment of complex traits such asobesity and how such changes passacross generations are limited to a fewclinical observations.73–76 In particular,the Dutch famine birth cohort repre-sents a unique “natural” experience ofheritability of epigenetic changes acrossgenerations due to a condition of ma-ternal undernutrition.76 Very recently,Godfrey et al75 reported the first evi-dence that methylation status of genepromoters in utero affects related phe-notypes later in the child’s development.The authors first measured the meth-ylation status of CpGs in the promotersof 78 candidate genes in DNA extractedfrom umbilical cord tissue obtainedat birth in children who were laterassessed for adiposity at age 9 years.Measurements of perinatal DNA meth-ylation were related to adiposity inlater childhood and to information on

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 130, Number 1, July 2012 7 at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

mother’s diet during pregnancy. Asso-ciations of genes (retinoid X receptor-a,RXRA; endothelial nitric oxide synthase,eNOS; superoxide dismutase-1, SOD1;interleukin-8, IL8; and phosphoinositide-3-kinase, catalytic,d-polypeptide,PI3KCD)that had associations of comparablestrength between childhood body com-position and both methylation of overallgene promoters and of individual olig-omers, were replicated in a secondand independent group of children.Methylation status of the promoter re-gion of RXRA correlated strongly in the 2cohorts and was inversely associatedwith maternal carbohydrate intake inthe first months of pregnancy.

LOW BIRTH WEIGHT ANDINCREASED RISK FOR OBESITY

Advances in thefieldofepigeneticsshednew light on old concepts and hypoth-eses. Conditions of metabolic disad-vantage associated with intrauterinegrowth retardation and low birth weight,a surrogate marker of such metabolicdisadvantage, are significantly associ-ated with adult obesity, diabetes, andcardiovascular disease as demon-strated by a number of epidemiologicaland clinical studies (reviewed in ref 6).Barker77 first hypothesized and demon-strated the disadvantaged conditionsof intrauterine growth that result ina small-for-gestational birth weight,as having significant effects on a per-son’s weight over a lifetime. Even so,birth weight can depend on the indi-vidual’s predisposing genotype, be-cause small-for-gestational-birth weightbirths tend to cluster in families and torecur in successive generations.78,79

The Auckland Birth weight Collabo-rative 80 and the ALSPAC49 studiesidentified common risk alleles associ-ated with both low birth weight andobesity. The Auckland Birth weightCollaborative study explored the asso-ciation of birth weight with 54 SNPs incandidate genes formerly associated

with obesity. Genetic variation in KCNJ11,BDNF, PFKP, PTER, and SEC16B (Table 2)were associated with a small weight atbirth.81 The ALSPAC investigated asso-ciations of 10 different risk alleles forobesity (in/near FTO; MC4R, TMEM18,GNPDA2, KCTD15, NEGR1, BDNF, andETV5; Table 2) in 7146 children, whoseanthropometrics were assessed frombirth to age 11 years. An obesity–risk-allele score was derived for each child.The score was poorly associated withbirth weight, but had an apparentlymuch larger positive effect on earlyinfancy weight gain, hence, suggestingthat some variants, although they areeffective against the newborn’s failureto thrive, conversely make the infantprone to develop obesity.49

Ameta-analysis82 of 6 GWAS, performedin 10 623 Europeans from pregnancy-birth cohorts, identified a significantassociation between 2 variants (ADCY5and CCNL1) never implicated beforewith fetal growth and birth weight. Theassociations were independent of ma-ternal intrauterine environment. Amorerecent meta-analysis of obesity sus-ceptibility loci in 28 219 individualsconfirmed an association only forMTCH2and FTO with lower and higher birthweight, respectively. The associations,however, were no longer statisticallysignificant after correction for multi-ple testing.83

ENVIRONMENT AND EXPOSOMICS

Understanding heritability of obesityrequires a deeper knowledge of thecomplex dynamic between gene-by-geneandgene-by-environment interactions.81

The extent of these associations variessignificantly along the different periodsof the human life.16,84

Studies on sibling and twin pairs haveput attention on shared and nonsharedenvironmental factors, mostly withinthe family, to tryanswering thequestionof how much genetics contributes tothe complex trait. Environmental factors

within the familyhave includedparentaleating and physical exercise behaviors,mental constructs, socioeconomical sta-tus, and other shared experiences ofsiblings and twins. In this light, twinstudies allowed the estimate of the extentto which the family environment makesfamilymembersmoresimilar thanwouldbe expected from their genetic relat-edness (the shared-environment effect)and dissecting those nongenetic effectsthat come from environmental factorsthat are unique to each person (the non–shared-environment effects).85 However,because twins experience more com-monality in indirect genetic effects thanfull siblings because they share both thestable and idiosyncratic parts of thehome environment, but full siblingsshare only the common component, twinstudies can have inflated heritabilityof obesity.86 The effect of the homeenvironment clearly diminishes whenchildren grow older and become moreindependent to make their own choices,which will reflect the effect of new spe-cific environmental pressures.87 Per-ception of all these pressures may differin each individual and in twins as well,hence, contributing significantly to thephenotype variance. Siblings generallyattend the same school, but members ofa sibling pair perceive their school andclassroom experience differently, evenidentical twins in the same class room.87

Thus, the question becomeswhy siblingsand twins are so different despite thecommon genetic background.88 Under-standing how the individual’s exposuresto the environmental factors (alsotermed as “exposome”) interactwith its unique characteristics, suchas its genetic makeup, resulting inthe obese phenotype is pivotal toestimate heritability.89 “Omics” tech-niques and deep sequencing providea huge amount of data, then, analyzedby data-mining techniques, with theaim of finding statistical associationsbetween exposome, effects of expo-sures, and genetics.

8 MANCO and DALLAPICCOLA at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

CONCLUSIONS

Results from GWAS have strength-ened the idea that the genetic heri-tage of obesity is strong, but still awide gap exists between heritability,

as demonstrated by family studies,and variance of body fatness, as esti-

mated by numbers and odd ratios of

identified risk alleles. Although some

genes have been found for pediatric

obesity, there is still a lot more to belearned, and the future involves look-

ing at rare variants, gene-by-gene and

gene-by-environment interactions, and

epigenetic factors.

REFERENCES

1. Han JC, Lawlor DA, Kimm SY. Childhoodobesity. Lancet. 2010;375(9727):1737–1748

2. Maes HH, Neale MC, Eaves LJ. Genetic andenvironmental factors in relative body weightand human adiposity. Behav Genet. 1997;27(4):325–351

3. Speliotes EK, Willer CJ, Berndt SI, et al.Association analyses of 249,796 individu-als reveal 18 new loci associated withbody mass index. Nat Genet. 2010;42(11):937–948

4. Stranger BE, Stahl EA, Raj T. Progress andpromise of genome-wide association stud-ies for human complex trait genetics. Ge-netics. 2011;187(2):367–383

5. Brune BC, Gerlach MK, Seewald MJ, BruneTG. Early postnatal BMI adaptation is reg-ulated during a fixed time period andmainly depends on maternal BMI. Obesity(Silver Spring). 2010;18(4):798–802

6. Hochberg Z, Feil R, Constancia M, et al.Child health, developmental plasticity, andepigenetic programming. Endocr Rev. 2011;32(2):159–224

7. Salsberry PJ, Reagan PB. Effects of herita-bility, shared environment, and nonsharedintrauterine conditions on child and ado-lescent BMI. Obesity (Silver Spring). 2010;18(9):1775–1780

8. Haberstick BC, Lessem JM, McQueen MB,et al. Stable genes and changing environ-ments: body mass index across adoles-cence and young adulthood. Behav Genet.2010;40(4):495–504

9. Schousboe K, Willemsen G, Kyvik KO, et al.Sex differences in heritability of BMI:a comparative study of results from twinstudies in eight countries. Twin Res. 2003;6(5):409–421

10. Lajunen HR, Kaprio J, Keski-Rahkonen A,et al. Genetic and environmental effects onbody mass index during adolescence: a pro-spective study among Finnish twins. Int J Obes(Lond). 2009;33(5):559–567

11. Loos RJ. Genetics: genome-wide risk pro-files - will they change your life(style)? NatRev Endocrinol. 2011;7(5):252–254

12. Manolio TA, Collins FS, Cox NJ, et al. Findingthe missing heritability of complex dis-eases. Nature. 2009;461(7265):747–753

13. Marian AJ, Belmont J. Strategic approachesto unraveling genetic causes of cardiovas-cular diseases. Circ Res. 2011;108(10):1252–1269.

14. Willer CJ, Speliotes EK, Loos RJ, et al;Wellcome Trust Case Control Consortium;Genetic Investigation of ANthropometricTraits Consortium. Six new loci associatedwith body mass index highlight a neuronalinfluence on body weight regulation. NatGenet. 2009;41(1):25–34

15. den Hoed M, Ekelund U, Brage S, et al. Ge-netic susceptibility to obesity and relatedtraits in childhood and adolescence: in-fluence of loci identified by genome-wideassociation studies. Diabetes. 2010;59(11):2980–2988

16. Frayling TM, Timpson NJ, Weedon MN, et al.A common variant in the FTO gene is as-sociated with body mass index and pre-disposes to childhood and adult obesity.Science. 2007;316(5826):889–894

17. Dina C, Meyre D, Gallina S, et al. Variation inFTO contributes to childhood obesity andsevere adult obesity. Nat Genet. 2007;39(6):724–726

18. Jess T, Zimmermann E, Kring SI, et al. Im-pact on weight dynamics and generalgrowth of the common FTO rs9939609:a longitudinal Danish cohort study. Int JObes (Lond). 2008;32(9):1388–1394

19. Haworth CM, Carnell S, Meaburn EL, DavisOS, Plomin R, Wardle J. Increasing herita-bility of BMI and stronger associations withthe FTO gene over childhood. Obesity (SilverSpring). 2008;16(12):2663–2668

20. Kring SI, Holst C, Zimmermann E, et al. FTOgene associated fatness in relation to bodyfat distribution and metabolic traits through-out a broad range of fatness. PLoS ONE. 2008;3(8):e2958

21. Cecil JE, Tavendale R, Watt P, HetheringtonMM, Palmer CN. An obesity-associated FTOgene variant and increased energy intakein children. N Engl J Med. 2008;359(24):2558–2566

22. Wardle J, Llewellyn C, Sanderson S, PlominR. The FTO gene and measured food intakein children. Int J Obes (Lond). 2009;33(1):42–45

23. Wardle J, Carnell S, Haworth CM, FarooqiIS, O’Rahilly S, Plomin R. Obesity associatedgenetic variation in FTO is associated withdiminished satiety. J Clin Endocrinol Metab.2008;93(9):3640–3643

24. Rzehak P, Scherag A, Grallert H, et al; GINIand LISA Study Group. Associations be-tween BMI and the FTO gene are age de-pendent: results from the GINI and LISAbirth cohort studies up to age 6 years.Obes Facts. 2010;3(3):173–180

25. Scuteri A, Sanna S, Chen WM, et al. Genome-wide association scan shows genetic variantsin the FTO gene are associated with obesity-related traits. PLoS Genet. 2007;3(7):e115

26. Ohashi J, Naka I, Kimura R, et al. FTO poly-morphisms in oceanic populations. J HumGenet. 2007;52(12):1031–1035

27. Grant SF, Li M, Bradfield JP, et al. Associa-tion analysis of the FTO gene with obesity inchildren of Caucasian and African ancestryreveals a common tagging SNP. PLoS One.2008;3(3):e1746

28. Li H, Wu Y, Loos RJ, et al. Variants in the fatmass- and obesity-associated (FTO) geneare not associated with obesity in a Chi-nese Han population. Diabetes. 2008;57(1):264–268

29. Kaakinen M, Läärä E, Pouta A, et al. Life-courseanalysis of a fat mass and obesity-associated(FTO) gene variant and body mass index inthe Northern Finland Birth Cohort 1966 usingstructural equation modeling. Am J Epi-demiol. 2010;172(6):653–665

30. Labayen I, Ruiz JR, Ortega FB, et al. As-sociation between the FTO rs9939609polymorphism and leptin in European ado-lescents: a possible link with energy balancecontrol. The HELENA study. Int J Obes. 2011;35(1):66–71

31. Scott RA, Bailey ME, Moran CN, et al. FTOgenotype and adiposity in children: physi-cal activity levels influence the effect ofthe risk genotype in adolescent males. EurJ Hum Genet. 2010;18(12):1339–1343

32. Hinney A, Nguyen TT, Scherag A, et al. Ge-nome wide association (GWA) study forearly onset extreme obesity supports therole of fat mass and obesity associated gene(FTO) variants. PLoS ONE. 2007;2(12):e1361

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 130, Number 1, July 2012 9 at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

33. Hunt SC, Stone S, Xin Y, et al. Association ofthe FTO gene with BMI. Obesity (SilverSpring). 2008;16(4):902–904

34. López-Bermejo A, Petry CJ, Díaz M, et al. Theassociation between the FTO gene and fatmass in humans develops by the postnatalage of two weeks. J Clin Endocrinol Metab.2008;93(4):1501–1505

35. Hakanen M, Raitakari OT, Lehtimäki T, et al.FTO genotype is associated with body massindex after the age of seven years but notwith energy intake or leisure-time physicalactivity. J Clin Endocrinol Metab. 2009;94(4):1281–1287

36. Rutters F, Nieuwenhuizen AG, Bouwman F,Mariman E, Westerterp-Plantenga MS. Asso-ciations between a single nucleotide poly-morphism of the FTO Gene (rs9939609)and obesity-related characteristics overtime during puberty in a Dutch childrencohort. J Clin Endocrinol Metab. 2011;96(6):E939–E942

37. Hebebrand J. Putting the greater dimen-sions of obesity into perspective. ObesFacts. 2010;3(6):341–342

38. Hardy R, Wills AK, Wong A, et al. Life coursevariations in the associations between FTOand MC4R gene variants and body size.Hum Mol Genet. 2010;19(3):545–552

39. Krude H, Biebermann H, Gruters A. Mutationsin the human proopiomelanocortin gene. AnnN Y Acad Sci. 2003;994:233–239

40. Lubrano-Berthelier C, Dubern B, LacorteJM, et al. Melanocortin 4 receptor muta-tions in a large cohort of severely obeseadults: prevalence, functional classifica-tion, genotype-phenotype relationship, andlack of association with binge eating. J ClinEndocrinol Metab. 2006;91(5):1811–1818

41. Loos RJ, Lindgren CM, Li S, et al; Prostate,Lung, Colorectal, and Ovarian (PLCO) CancerScreening Trial; KORA; Nurses’ Health Study;Diabetes Genetics Initiative; SardiNIA StudyWellcome Trust Case Control Consortium;FUSION. Common variants near MC4R areassociated with fat mass, weight and riskof obesity. Nat Genet. 2008;40(6):768–775

42. Grant SF, Bradfield JP, Zhang H, et al. In-vestigation of the locus near MC4R withchildhood obesity in Americans of Euro-pean and African ancestry. Obesity (SilverSpring). 2009;17(7):1461–1465

43. Tao YX. Molecular mechanisms of the neu-ral melanocortin receptor dysfunction insevere early onset obesity. Mol Cell Endo-crinol. 2005;239(1-2):1–14

44. Vaisse C, Clément K, Durand E, HercbergS, Guy-Grand B, Froguel P. Melanocortin-4receptor mutations are a frequent andheterogeneous cause of morbid obesity.J Clin Invest. 2000;106(2):253–262

45. Dempfle A, Hinney A, Heinzel-GutenbrunnerM, et al. Large quantitative effect ofmelanocortin-4 receptor gene mutationson body mass index. J Med Genet. 2004;41(10):795–800

46. Farooqi IS, Keogh JM, Yeo GSH, Lank EJ,Cheetham T, O’Rahilly S. Clinical spectrumof obesity and mutations in the melano-cortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–1095

47. Martinelli CE, Keogh JM, Greenfield JR,et al. Obesity due to melanocortin 4 re-ceptor (MC4R) deficiency is associated withincreased linear growth and final height,fasting hyperinsulinemia, and incompletelysuppressed growth hormone secretion.J Clin Endocrinol Metab. 2011;96(1):E181–E188

48. Loos RJ. The genetic epidemiology ofmelanocortin 4 receptor variants. EurJ Pharmacol. 2011;660(1):156–164

49. Elks CE, Loos RJ, Sharp SJ, et al. Geneticmarkers of adult obesity risk are associ-ated with greater early infancy weight gainand growth. PLoS Med. 2010;7(5):e1000284

50. Petry CJ, López-Bermejo A, Díaz M, et al.Association between a common variantnear MC4R and change in body mass indexdevelops by two weeks of age. Horm ResPaediatr. 2010;73(4):275–280

51. Almén MS, Jacobsson JA, Shaik JH, et al.The obesity gene, TMEM18, is of ancientorigin, found in majority of neuronal cellsin all major brain regions and associatedwith obesity in severely obese children.BMC Med Genet. 2010;11:58

52. Zhao J, Bradfield JP, Li M, et al. The role ofobesity-associated loci identified in genome-wide association studies in the determina-tion of pediatric BMI. Obesity (Silver Spring).2009;17(12):2254–2257

53. Scherag A, Dina C, Hinney A, et al. Two newLoci for body-weight regulation identified ina joint analysis of genome-wide associationstudies for early-onset extreme obesity inFrench and German study groups. PLoSGenet. 2010;6(4):e1000916

54. Ruiz JR, Labayen I, Ortega FB, et al; HELENAStudy Group. Attenuation of the effect of theFTO rs9939609 polymorphism on total andcentral body fat by physical activity inadolescents: the HELENA study. Arch PediatrAdolesc Med. 2010;164(4):328–333

55. Cauchi S, Stutzmann F, Cavalcanti-ProençaC, et al. Combined effects of MC4R and FTOcommon genetic variants on obesity inEuropean general populations. J Mol Med(Berl). 2009;87(5):537–546

56. Vimaleswaran KS, Franks PW, Brage S, et al.Lack of association between PCK1 poly-morphisms and obesity, physical activity,and fitness in European Youth Heart Study

(EYHS). Obesity (Silver Spring). 2010;18(10):1975–1980

57. Liu G, Zhu H, Lagou V, et al. FTO variantrs9939609 is associated with body mass in-dex and waist circumference, but not withenergy intake or physical activity in European-and African-American youth. BMC Med Genet.2010;11:57

58. Kilpeläinen TO, Qi L, Brage S, et al. Physicalactivity attenuates the influence of FTOvariants on obesity risk: a meta-analysis of218,166 adults and 19,268 children. PLoSMed. 2011;8(11):e1001116

59. Scherag A, Kleber M, Boes T, et al. SDCCAG8obesity alleles and reduced weight lossafter a lifestyle intervention in overweightchildren and adolescents. Obesity (SilverSpring). 2011;20(2):466–470

60. Xi B, Shen Y, Zhang M, et al. The commonrs9939609 variant of the fat mass andobesity-associated gene is associated withobesity risk in children and adolescents ofBeijing, China. BMC Med Genet. 2010;11:107

61. Troiano RP, Berrigan D, Dodd KW, Mâsse LC,Tilert T, McDowell M. Physical activity in theUnited States measured by accelerometer.Med Sci Sports Exerc. 2008;40(1):181–188

62. Johnson L, van Jaarsveld CH, Emmett PM,et al. Dietary energy density affects fatmass in early adolescence and is notmodified by FTO variants. PLoS ONE. 2009;4(3):e4594

63. Lagou V, Scott RA, Manios Y, et al. Impact ofperoxisome proliferator-activated recep-tors gamma and delta on adiposity intoddlers and preschoolers in the GENESISStudy. Obesity (Silver Spring). 2008;16(4):913–918

64. Dedoussis GV, Manios Y, Kourlaba G, et al.An age-dependent diet-modified effect ofthe PPARg Pro12Ala polymorphism in chil-dren. Metabolism. 2011;60(4):467–473

65. Blaxter M. Genetics. Revealing the darkmatter of the genome. Science. 2010;330(6012):1758–1759

66. Lillycrop KA, Burdge GC. Epigenetic changesin early life and future risk of obesity. Int JObes (Lond). 2011;35(1):72–83

67. Wolff GL, Kodell RL, Moore SR, Cooney CA.Maternal epigenetics and methyl supple-ments affect agouti gene expression in Avy/a mice. FASEB J. 1998;12(11):949–957

68. Feil R. Environmental and nutritional effectson the epigenetic regulation of genes. MutatRes. 2006;600(1-2):46–57

69. Gallou-Kabani C, Vigé A, Gross MS, et al.Resistance to high-fat diet in the femaleprogeny of obese mice fed a control dietduring the periconceptual, gestation, andlactation periods. Am J Physiol EndocrinolMetab. 2007;292(4):E1095–E1100

10 MANCO and DALLAPICCOLA at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

70. Howie GJ, Sloboda DM, Kamal T, Vickers MH.Maternal nutritional history predicts obesityin adult offspring independent of postnataldiet. J Physiol. 2009;587(pt 4):905–915

71. Anway MD, Cupp AS, Uzumcu M, SkinnerMK. Epigenetic transgenerational actions ofendocrine disruptors and male fertility.Science. 2005;308(5727):1466–1469

72. Fowden AL, Ward JW, Wooding FP, ForheadAJ, Constancia M. Programming placentalnutrient transport capacity. J Physiol. 2006;572(pt 1):5–15

73. Gluckman PD, Hanson MA, Cooper C,Thornburg KL. Effect of in utero and early-life conditions on adult health and disease.N Engl J Med. 2008;359(1):61–73

74. Filiberto AC, Maccani MA, Koestler D, et al.Birthweight is associated with DNA pro-moter methylation of the glucocorticoidreceptor in human placenta. Epigenetics.2011;6(5):566–572

75. Godfrey KM, Sheppard A, Gluckman PD,et al. Epigenetic gene promoter methyla-tion at birth is associated with child’s lateradiposity. Diabetes. 2011;60(5):1528–1534

76. Heijmans BT, Tobi EW, Stein AD, et al. Persis-tent epigenetic differences associated withprenatal exposure to famine in humans. ProcNatl Acad Sci USA. 2008;105(44):17046–17049

77. Barker DJ. The fetal and infant origins ofadult disease. BMJ. 1990;301(6761):1111

78. Wang X, Zuckerman B, Coffman GA, CorwinMJ. Familial aggregation of low birth weightamong whites and blacks in the UnitedStates. N Engl J Med. 1995;333(26):1744–1749

79. Magnus P, Bakketeig LS, Hoffman H. Birthweight of relatives by maternal tendency torepeat small-for-gestational-age (SGA) birthsin successive pregnancies. Acta ObstetGynecol Scand Suppl. 1997;165:35–38

80. Morgan AR, Thompson JM, Murphy R, et al.Obesity and diabetes genes are associatedwith being born small for gestational age:results from the Auckland Birthweight Col-laborative study. BMC Med Genet. 2010;11:125

81. Chung WK, Leibel RL. Considerations re-garding the genetics of obesity. Obesity(Silver Spring). 2008;16(suppl 3):S33–S39

82. Freathy RM, Mook-Kanamori DO, Sovio U,et al. Variants in ADCY5 and near CCNL1 areassociated with fetal growth and birthweight. Nat Genet. 2010;42(5):430–435

83. Kilpeläinen TO, den Hoed M, Ong KK, et al;Early Growth Genetics Consortium. Obesity-susceptibility loci have a limited influenceon birth weight: a meta-analysis of up to28,219 individuals. Am J Clin Nutr. 2011;93(4):851–860

84. Silventoinen K, Kaprio J. Genetics of track-ing of body mass index from birth to latemiddle age: evidence from twin and familystudies. Obes Facts. 2009;2(3):196–202

85. Wardle J, Carnell S, Haworth CM, Plomin R.Evidence for a strong genetic influence onchildhood adiposity despite the force of theobesogenic environment. Am J Clin Nutr.2008;87(2):398–404

86. Hopper JL, Bishop DT, Easton DF. Population-based family studies in genetic epidemiology.Lancet. 2005;366(9494):1397–1406

87. Silventoinen K, Rokholm B, Kaprio J, SørensenTI. The genetic and environmental influenceson childhood obesity: a systematic review oftwin and adoption studies. Int J Obes (Lond).2010;34(1):29–40

88. Plomin R. Commentary: Why are children inthe same family so different? Non-sharedenvironment three decades later. Int JEpidemiol. 2011;40(3):582–592

89. Exposome and exposomics. Atlanta, GA:Centers for Disease Control and Preven-tion. Available at: www.cdc.gov/niosh/topics/exposome/ Accessed September 6, 2011

90. NCBI RefSeq. NCBI Reference Sequences.Bethesda, MD: National Center for Bio-technology Information. Available at: www.ncbi.nlm.nih.gov/RefSeq/ Accessed December15, 2011

STATE-OF-THE-ART REVIEW ARTICLE

PEDIATRICS Volume 130, Number 1, July 2012 11 at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from

DOI: 10.1542/peds.2011-2717; originally published online June 4, 2012;Pediatrics

Melania Manco and Bruno DallapiccolaGenetics of Pediatric Obesity

  

ServicesUpdated Information &

/peds.2011-2717http://pediatrics.aappublications.org/content/early/2012/05/29including high resolution figures, can be found at:

Subspecialty Collections

nd_dysmorphologyhttp://pediatrics.aappublications.org/cgi/collection/genetics_aGenetics & Dysmorphologythe following collection(s):This article, along with others on similar topics, appears in

Permissions & Licensing

tmlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhtables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,

Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

at Bambino Gesu Childrens Hospital on June 15, 2012pediatrics.aappublications.orgDownloaded from