1

Binge-eatingdisorder,anorexianervosa,andconstitutionalthinnessdifferin

theirassociationswithanthropometricandpsychiatricpolygenicscores

ChristopherHübel*,MohamedAbdulkadir*,MoritzHerle,RuthJ.F.Loos,GeromeBreen,

CynthiaM.Bulik,NadiaMicali

Hübel,BreenSocial,Genetic&DevelopmentalPsychiatryCentre,InstituteofPsychiatry,

Psychology&Neuroscience,King’sCollegeLondon,UKHübel,BreenUKNationalInstituteforHealthResearch(NIHR)BiomedicalResearchCentre

forMentalHealth,SouthLondonandMaudsleyHospital,London,UKHübel,BulikDepartmentofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,

Stockholm,SwedenMicali,HerleGreatOrmondStreetInstituteofChildHealth,UniversityCollegeLondon,

London,UKHerleDepartmentofBiostatistics&HealthInformatics,InstituteofPsychiatry,Psychology

&Neuroscience,King’sCollegeLondon,UKLoosIcahnSchoolofMedicineatMountSinai,NewYork,NewYork,USAAbdulkadir,MicaliDepartmentofPediatricsGynaecologyandObstetrics,FacultyofMedicine,

UniversityofGeneva,Geneva,SwitzerlandAbdulkadir,MicaliDepartmentofPsychiatry,FacultyofMedicine,UniversityofGeneva,

Geneva,SwitzerlandBulikDepartmentofPsychiatry,UniversityofNorthCarolinaatChapelHill,ChapelHill,

NC,USABulikDepartmentofNutrition,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,

USA

*contributedequallytothiswork

Correspondenceto:

Dr.Micali,DepartmentofPsychiatry,FacultyofMedicine,UniversityofGeneva,Geneva,

Switzerland,e-mail:nadia.micali@hcuge.ch

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2

Keywords:Eatingdisorder;AvonLongitudinalStudyofParentsandChildren(ALSPAC);

purging;constitutionalthinness,fasting,thinideal;bodydissatisfaction,UKBiobank

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Abstract(232/250,unstructured)

Genome-wideassociationstudieshaveidentifiedmultiplegeneticregionsassociated

withanorexianervosa—aneatingdisordercharacterisedbyextremelylowbodyfat,

lowfat-freemass,andrelatedbehavioursandcognitions,suchasrestrictiveeatingand

bodydissatisfaction.Relativelyfewornogenome-widestudiesofothereating

disorders,suchasbulimianervosaandbinge-eatingdisorder,havebeenperformed,

despitetheirsubstantialheritability.Weaimedtoidentifytraitsthataregenetically

associatedwithbinge-typeeatingdisorders.Wecalculatedgenome-widepolygenic

scoresfor302traitanddiseaseoutcomesusingPRSicev2.2andtheirassociationwith

anorexianervosa,bulimianervosa,andbinge-eatingdisorderinupto640casesand

17,050controlsfromtheUKBiobank.Significantassociationsweretestedfor

replicationintheAvonLongitudinalStudyofParentsandChildren(upto217casesand

3018controls).Inadditiontoeatingdisorders,weassociatedpolygenicscoreswith

constitutionalthinness,anddisordered-eatingbehavioursandcognitionsacross

adolescenceatages13,14,16,and/or18years.Individualswithbinge-typeeating

disordershadhigherpolygenicscoresforotherpsychiatricdisorders,including

depression,schizophrenia,andattentiondeficithyperactivitydisorder.Bodymass-

increasingpolygenicscoreswereassociatedwithbinge-eatingbehaviour.

Anthropometricbutnotpsychiatricpolygenicscoreswereassociatedwith

constitutionalthinness,suggestingthatitisaseparateentityfromanorexianervosa.

Ourfindingsmotivateadeeperinvestigationofsharedanduniquegenomicfactorsin

bulimianervosa,binge-eatingdisorder,constitutionalthinness,anddisordered-eating

traits.

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Introduction

Eatingdisordersarecomplexandheritablepsychiatricconditions[1].Themost

studiedisanorexianervosa,whichischaracterisedbydangerouslylowbodyweightand

extremefearofgainingweight,whileengaginginbehavioursthatinducenegative

energybalance,suchasfastingor,insomecases,excessiveexercise.[2].Individuals

withbulimianervosaandbinge-eatingdisordershowepisodesofexcessiveovereating

(i.e.,bingeeating)accompaniedbyasenseoflossofcontrol,inwhichtheyconsume

unusuallylargeamountsoffoodinashortperiodoftime.Individualswithbulimia

nervosaalsoengageinrecurrentcompensatorybehaviors(e.g.,self-inducedvomiting,

laxative,ordiureticabuse)tocounteracttheeffectsofbingeeating[3].Incontrastto

anorexianervosa,individualswithconstitutionalthinnesspresentwiththeabsenceof

disordered-eatingbehavioursandcognitions[4],buthavepersistentlylowbodymass

indices(BMIs).Itiscurrentlyunclearhowanorexianervosadiffersfromconstitutional

thinnessonageneticlevel[5].

Twin,family,andadoptionstudiesoverthepast30yearshaveshownthateating

disordersareheritable[1].Thelargestgenome-wideassociationstudy(GWAS)todate

identifiedeightgenomicregionsassociatedwithanorexianervosaandalsofounditis

geneticallycorrelatedwithobsessive-compulsivedisorder,schizophrenia,anxiety,and

majordepressivedisorder.Thisimpliesthatanorexianervosasharesgeneticrisk

variantswiththesephenotypes.However,thestudyalsofoundthatanorexianervosa

hassignificantnegativegeneticcorrelationswithanthropometrictraits,includingBMI,

fatmass,andfat-freemass.Thismeansthatanorexianervosariskvariantsareenriched

forvariantsthatresultinlowerBMI,fatmass,andfat-freemass.[6–8].TheGWAS

additionallyhighlightedasharedgeneticbasisbetweenanorexianervosaandhigh-

densitylipoproteincholesterol,fastinginsulin,aswellasinsulinsensitivity,suggesting

thatanorexianervosamayhaveametaboliccomponent.Itisunclear,however,ifbinge-

typeeatingdisordersmayalsohaveametaboliccomponent.

Althoughtwinandfamilystudiesdemonstrateapositivegeneticcorrelation

(~0.46)betweenanorexianervosaandbulimianervosa,indicatingconsiderableshared

genetics[9,10],GWASsofbulimianervosaorbinge-eatingdisorderwithsufficientsize

haveyettobeconductedtoallowwellpoweredinvestigationsoftheirmolecular

geneticcorrelationswitheachother.Furthermore,itisnotwellunderstoodhowbinge-

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5

typeeatingdisorderssharegeneticswithotherpsychiatric,anthropometric,and

metabolictraits.

Theextremesofthepopulationrangeofdisordered-eatingbehavioursor

cognitionsarecommoncomponentsymptomsofeatingdisorders(e.g.,extremefasting,

excessiveexercise,orbodydissatisfaction).Thegeneticunderpinningsofthese

componentsymptomsandtheirgeneticrelationshipswitheatingdisorders,psychiatric,

metabolic,andanthropometrictraitshavenotyetbeenexplored.

Tobetterunderstanddifferencesinthegeneticsofeatingdisordersandtheir

componentsymptoms,wehadthreeaimsinthisstudy:(1)Toconductpolygenicscore

analysestoidentifytraitsthataregeneticallyassociatedwitheitherofthethree

primaryeatingdisorders:anorexianervosa,bulimianervosa,orbinge-eatingdisorder

inasubsampleoftheUKBiobank[11]withattemptedreplicationintheAvon

LongitudinalStudyofParentsandChildren(ALSPAC)cohort;(2)investigatethe

associationofpolygenicscoreswithdisordered-eatingbehavioursandrelated

cognitionsatages13,14,16,and/or18yearsinALSPAC.Finally(3)wehypothesize

thatconstitutionalthinnesswouldshowadifferentgeneticarchitecturetothatofeating

disordersgivenitsassociationswithselectedpolygenicscores.

Methods

DiscoverysampleoftheUKBiobank

TheUKBiobank(ukbiobank.ac.uk)isauniqueepidemiologicalresourceto

improveprevention,diagnosis,andtreatmentofpsychiatricandsomaticillnesses.The

UKBiobankrecruitedparticipantsfromthegeneralpopulationbetween2006–2010.All

participantswerebetween40to69yearsold,wereregisteredwithageneral

practitionerthroughtheUnitedKingdom’sNationalHealthService,andlivedwithin

travelingdistanceofoneoftheassessmentcenters.TheUKBiobankisapprovedbythe

NorthWestMulti-centreResearchEthicsCommittee.Genomewidearraydataforthis

studywereavailablefor488,363individuals.Allparticipantsgavewrittenconsent.We

identifiednon-Europeanparticipantsby4-meansclusteringonthefirsttwoprincipal

componentsderivedfromthegenotypedata,andexcludedrelatedindividuals(KING

relatednessmetric>0.088,equivalenttoarelatednessvalueof0.25;N=7,765).

Weidentified1,488participantswhoeitherself-reportedanyofthethree

primaryeatingdisordersinthementalhealthquestionnaire[12]orhadan

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InternationalClassificationofDiseases,version10(ICD-10)[13]hospitaldiagnosisof

F50.0orF50.1foranorexianervosa,orF50.2orF50.3forbulimianervosa.This

resultedin768(4.7%)participantswithanorexianervosa,423(2.7%)withbulimia

nervosa,and561(3.5%)withbinge-eatingdisorder.Ifparticipantsself-reportedmore

thanonediagnosis,theywereassignedtoallgroups.Werandomlysampledonesetof

controlsintheratioof1to10,resultingin15,500controlsbyusingthefollowing

exclusioncriteria:Controlsmusthaveansweredthementalhealthquestionnaire,were

notdiagnosedwithapsychiatricdisorder(i.e.,self-reportorICD-10diagnosis),or

takinganypsychotropicmedication.Thefinalanalysisincluded17,050(92%female)

Europeanparticipants(SupplementaryTable1)representing3.4%ofthegenotyped

UKBiobankparticipants(n=502,682).ThisstudywascompletedundertheUK

Biobankapprovedstudyapplication27546.

SamplefromtheAvonLongitudinalStudyofParentsandChildren(ALSPAC)

TheALSPACisapopulation-basedsampleofpregnantwomenandtheirchildrenbased

intheformercountyofAvon,UK[14–16].WomenexpectedtodeliverfromApril1,

1991,untilDecember31,1992,wereinvitedtoparticipate.Childrenfrom14,541

pregnancieswereenrolledand13,988aliveat1year.Additionally,913childrenwere

enrolledatage7years.Allwomengavewritteninformedconsent.Childrenatage14

(wave14,n=10,581),16(wave16,n=9,702),and18years(wave18,n=9,505)that

hadnotwithdrawnconsentwerefollowedup.Parentsansweredquestionnaireson

7,025adolescentsatwave14andon5,656atwave16.With6,140(58%)respondingat

wave14,5,069(52%)atwave16,and3,228(34%)atwave18whichwasusedto

augmentthevalidityoftheprobableeatingdisorderdiagnoses[17].Pleasenotethatthe

studywebsitecontainsdetailsofallthedatathatisavailablethroughafullysearchable

datadictionaryandvariablesearchtool(www.bristol.ac.uk/alspac/researchers/our-

data/).Toreducepotentialconfoundingthroughgeneticrelatednessinouranalyses,we

removedrandomlyoneindividualofeachpairthatiscloselyrelated(φ>0.2)using

PLINKv1.90[18],excluding75individualsthatwereduplicates,monozygotictwins,

first-degreerelatives(i.e.,parent-offspringandfullsiblings),orsecond-degreerelatives

(i.e.,half-siblings,uncles,aunts,grandparents,anddoublecousins,Supplementary

Table2).

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Wederivedprobableeatingdisorderdiagnosesaspreviouslyreported

(SupplementaryTable3)[17],usingacombinationofadolescentself-reportaswellas

informationontheadolescentsprovidedbytheirparents,agoldstandardforchildhood

psychiatricdisorders.

EthicalapprovalfortheALSPACparticipantsofthisstudywasobtainedfromthe

ALSPACEthicsandLawCommitteeandtheLocalResearchEthicsCommittees:

www.bristol.ac.uk/alspac/researchers/research-ethics/.Consentforbiologicalsamples

hasbeencollectedinaccordancewiththeHumanTissueAct(2004)andinformed

consentfortheuseofdatacollectedviaquestionnairesandclinicswasobtainedfrom

participantsfollowingtherecommendationsoftheALSPACEthicsandLawCommittee

atthetime.

PolygenicriskscoringoneatingdisorderphenotypesinUKBiobankand

replicationinALSPAC

WeusedPRSice[19],version2.2.3.Weclumpedthesinglenucleotide

polymorphisms(SNPs)thatwerepresentbothinthesummarystatisticsofthetraitand

inthegenotypedataoftheUKBiobank(i.e.,overlappingSNPs)toobtaingenetically

independentSNPs.WeretainedtheSNPwiththesmallestpvalueineach250kilobase

windowofallthoseinlinkagedisequilibrium(r2>0.1).Wecalculated302polygenic

scoresattheiroptimalpvaluethresholdineachindividualbyscoringthenumberof

effectalleles(weightedbythealleleeffectsize)acrossthesetofremainingSNPs(fora

fulllist,seeSupplementaryTable4).Wecalculatedthepolygenicscoreusingthehigh-

resolutionscoring(i.e.,incrementallyacrossalargenumberofpvaluethresholds)

methodtoidentifythepvaluethresholdatwhichthepolygenicscoreisoptimally

associatedwiththeoutcomeandexplainsthemostvariance(i.e.,resultinginthe

highestadjustedR2forcontinuousoutcomesandNagelkerke'sR2ontheliabilityscale

forbinaryoutcomes).Weevaluatedtheassociationsbetweenpolygenicscoreand

eatingdisorderdiagnosisusinglogisticregressions,adjustedforsexandthefirstsix

principalcomponentsthatwerecalculatedontheEuropeansubsample.Toadjustfor

overfitting,wepermutedcase-controlstatusateverypvaluethreshold10,000times

and,hence,calculatedempiricalpvalues.WeconvertedtheobservedR2totheliability

scaleassumingfollowingpopulationprevalencesof3%foranorexianervosa,1.8%for

bulimianervosa,and3%forbinge-eatingdisorder[20,21].

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Tocorrectformultipletesting(i.e.,302polygenicscoreregressionmodels),we

calculatedQvaluesusingthefalsediscoveryrateapproach[22,23].Wedidnotstratify

analysesbysexbecauseofthelownumberofmaleeatingdisordercases,butincluded

sexasacovariate.WeusedtheUKBiobanksampleasourdiscoverycohortandthe

SNPsthatwereincludedinthestrongestassociatedpolygenicscorewereusedtoderive

polygenicscoresintheALSPACsample,inwhichwerepeatedtheanalysisalso

adjustingforsex,andthefirstsixancestry-informativeprincipalcomponents.

Polygenicriskscoringondisordered-eatingbehavioursandcognitionsinALSPAC

Weusedthepolygenicscoresthatweresignificantlyassociatedwitheating

disordersintheUKBiobankforafollow-upanalysisintheindependentALSPACsample.

Weinvestigatedtheassociationbetweenthesepolygenicscoresanddisordered-eating

behavioursorcognitionswhicharecomponentsymptomsofeatingdisorders.Forthese

analyses,weusedtheoptimalthresholdingmethoddescribedabove.Below,we

summarisethedisordered-eatingphenotypesthatwereassessed[17].

Disordered-eatingbehaviours

Excessiveexercise.Atage14,16,and18years,participantsreportedtheir

exercisefrequencyperweekduringthepreviousyear,iftheirexercisinginterferedwith

schoolwork,iftheyexercisedtoloseoravoidgainingweight,andiftheyexercisedeven

thoughtheyweresickorinjured.

Fasting.Atage14,16,and18years,participantsreportedthefrequencyoffasting(i.e.,

noteatingforanentireday)toloseoravoidgainingweightduringthepastyear.

Bingeeating.Atage14,16,and18years,participantsreportedthefrequencyofbinge

eatingduringthepastyear—definedaseatinganunusuallylargeamountoffood,

combinedwithafeelingofbeingoutofcontrol.

Purging.Atage14,16,and18years,participantsreportedthefrequencywithwhich

theyusedlaxativesorself-inducedvomiting,orothermedicinestoloseoravoidgaining

weightduringthepastyear.

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Disordered-eatingcognitions

Fearofweightgain.Atage14and16years,participantsreportediftheywere

afraidofgainingweightorgettingfat,iftheyavoidedfatteningfoodsorhowtheywould

feeliftheywereaskedtoputon2kilosforthesakeoftheirhealth.

Thinidealinternalization.Atage14years,adolescentgirlsreportedhowstrongly

theyagreedwiththinwomenbeingnotattractive,womenwithlonglegsbeingmore

attractive,womenwithtoned(lean)bodiesbeingmoreattractive,tallwomenbeing

moreattractive,shapelywomenbeingmoreattractiveorshort(petite)womenbeing

moreattractive.Adolescentboysreportedhowstronglytheyagreedwiththinmen

beingmoregood-looking,menwhoareinshapebeingbetterlooking,menwithtoned

(lean)bodiesbeingmoregood-looking,menwithlargepronouncedmusclesbeing

betterlooking,tallmenbeingmoregood-looking,orbodybuilders,suchasArnold

Schwarzenegger,beingbetterlooking[24].

WeightandshapeconcernAtage14years,participantsreportedhowhappytheyhad

beeninthepreviousyearwiththewaytheirbodylooked,howmuchtheirweighthad

madeadifferencetohowtheyfeelaboutthemselves,andhowmuchtheyhadworried

aboutgainingalittleweight(e.g.,1kg).

BodydissatisfactionAtage14years,participantsreportedhowsatisfiedtheywereat

thatmomentwiththeirbodybuild/breast,stomach,waist,thighs,buttocks,hips,legs,

face,hair[25].

ConstitutionalthinnessinALSPAC

Weidentifiedparticipantswithlong-termconstitutionalthinness(i.e.,persistent

thinness)analysingobjectivelymeasuredBMI(kg/m²)at10,12,14,15,and18yearsin

theALSPACusinglatentgrowthanalysis.Additionally,participantsdidneitherendorse

weightlossbehavioursnorwereaffectedbyaneatingdisorder(forfulldetails,see

SupplementaryInfo)

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Figure 1. Polygenic scores associated with eating disorders in the UK Biobank. Panel A shows psychiatric and behavioral, Panel B metabolic, and Panel C anthropometric polygenic scores that are associated with self-reported or hospital-diagnosed eating disorders in the UK Biobank sample (n = 17,050). Filled dots are statistically significant after adjustment for multiple testing through the false discovery discovery approach. Dots represent odds ratios (ORs) and error bars index 95% confidence intervals obtained via logistic regression and 10,000 permutations to obtain empirical p values.

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Results

PolygenicscoringoneatingdisorderphenotypesinUKBiobankandALSPAC

Aftercorrectingformultipletestingusingthefalsediscoveryrateadjustment,21

polygenicscoresweresignificantlyassociatedwiththethreeprimaryeatingdisorders

inthesubsampleoftheUKBiobank(Figure1).

Psychiatricdisordersandneurologicaldisease.Fivepolygenicscores

reflectingpolygenicliabilityforpsychiatricdisordersandoneneurologicaldisease

showedsignificantassociationswitheatingdisorders(SupplementaryTable4).The

schizophreniapolygenicscorewaspositivelyassociatedwithanorexianervosa(odds

ratio[OR]perstandarddeviationinpolygenicscore=1.18,95%confidenceinterval

[CI]:1.09,1.70;Q=0.03)andbinge-eatingdisorder(OR=1.23,95%CI:1.13,1.35;Q=

0.01).Themajordepressivedisorderpolygenicscorewaspositivelyassociatedwith

anorexianervosa(OR=1.20,95%CI:1.11,1.29;Q=0.01)andbinge-eatingdisorder

(OR=1.25,95%CI:1.14,1.36;Q=0.01).Additionally,theattentiondeficithyperactivity

disorderpolygenicscorewaspositivelyassociatedwithbinge-eatingdisorder(OR=

1.28,95%CI:1.17,1.39;Q=0.01).Thebipolardisorderpolygenicscore(OR=1.17,

95%CI:1.08,1.26;Q=0.04),theanorexianervosapolygenicscore(OR=1.32,95%CI:

1.22,1.42;Q=0.01),andthemigrainepolygenicscore(OR=1.17,95%CI:1.09,1.26;Q

=0.04)werepositivelyassociatedwithanorexianervosa.

Somatictraits.Severalpolygenicscoresindexingpolygenicloadfor

anthropometrictraits,includinghipcircumference(OR=1.39,95%CI:1.27,1.51;Q=

0.01),overweight(OR=1.35,95%CI:1.24,1.47;Q=0.01),obesityclass1(OR=1.38,

95%CI:1.27;1.51;Q=0.01),class2(OR=1.33,95%CI:1.22;1.45;Q=0.01)andclass3

(OR=1.21,95%CI:1.11,1.32;Q=0.04),BMI(OR=1.44,95%CI:1.32;1.56;Q=0.01)

andextremeBMI(OR=1.32,95%CI:1.22,1.44;Q=0.01)werepositivelyassociated

withbinge-eatingdisorder.However,itisimportanttonotethatthesepolygenicscores

werecorrelatedwitheachotherwithr=.10tor=.67(SupplementaryFigure2).

Additionally,thechildhoodobesitypolygenicscore(OR=1.22,95%CI:1.12,1.33;Q=

0.04)waspositivelyassociatedwithbinge-eatingdisorder,whiletheageatmenarche

polygenicscore(OR=0.79,95%CI:0.72,0.86;Q=0.01)wasnegativelyassociatedwith

binge-eatingdisorder.Neitherthechildhoodobesitynortheageatmenarchepolygenic

scorewereassociatedwithanorexianervosa.

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Theoverweightpolygenicscore(OR=1.26,95%CI:1.14,1.38;Q=0.01)andthe

waistcircumferencepolygenicscore(OR=1.25,95%CI:1.13,1.38;Q=0.02)were

positivelyassociatedwithbulimianervosa,whereastheredbloodcellcountpolygenic

scorewasnegativelyassociatedwithbulimianervosa(OR=0.80,95%CI:0.72,0.88;Q=

0.02).

Sexandagedifferences.Theadulthoodobesitypolygenicscorewasmore

stronglyassociatedwithanorexianervosathanthechildhoodobesitypolygenicscore.

Thisdifferenceinthelogoddsratioswasstatisticallysignificant(difference=-0.15,p=

0.004).Wedidnotdetectagedifferencesintheassociationsoftheobesitypolygenic

scoreswithbulimianervosaorbinge-eatingdisorder(SupplementaryTable7).We

detectednosexdifferencesintheassociationsofthebodymassindexpolygenicscore

withanorexianervosa,bulimianervosa,orbinge-eatingdisorder.

Sensitivityanalysis.Wecomparedlogisticregressionresultswhenassigning

participantstoallpossibleeatingdisorderdiagnoseswithassigningparticipants

exclusivelytooneeatingdisorderdiagnosisintheUKBiobanksample.Theeffectsizes

ofbothanalysescorrelatedwithr=0.98,indicatingthattheanalyseswerenotsensitive

toparticipantoverlap(SupplementaryFigure3).

Independentreplication.InALSPAC(SupplementaryTable8),the

overweightpolygenicscore(OR=1.38,95%CI:1.13,1.69;pempirical=0.05)andthe

obesityclass1polygenicscore(OR=1.23,95%CI:1.00;1.50;pempirical=0.001)were

positivelyassociatedwithbinge-eatingdisorder.

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Figure 2. Polygenic scores associated with purging, constitutional thinness, and binge eating in the Avon Longitudinal Study of Parents and Children. Sample sizes per outcome were purging (n cases= 398, n controls = 2962), constitutional thinness (n cases = 201, n controls = 6391), and binge eating (n cases = 840, n controls = 2151). Polygenic scores were calculated using PRSice v2. The optimal p value threshold to generate the polygenic score was obtained by calculating polygenic scores across multiple thresholds and permuting case-control status at each threshold 10,000 times. The polygenic score explaining the largest trait variance was used in logistic regressions including the first six ancestry principal components and sex as covariates. Dots represent odds ratios (OR) and error bars 95% confidence intervals (95% CI). Filled dots are those odds ratios that are significant after correction for multiple testing via calculation of false discovery rate-adjusted Q values.

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Polygenicscoresassociatedwithdisordered-eatingbehavioursandcognitions

InALSPAC,thedisordered-eatingtraitswereintercorrelatedwithr=.45-.64

(SupplementaryFigure4),explainingsomeofthesimilaritiesintheresults.

Anthropometricpolygenicscores.Severalpolygenicscoresofanthropometric

measureswerepositivelyassociatedwithdisordered-eatingbehavioursandcognitions

(Figures2,3,and4).Forinstance,theoverweightpolygenicscorewaspositively

associatedwithexcessiveexercise(OR=1.16,95%CI:1.06;1.26;Q=0.03),fasting(OR

=1.17,95%CI:1.08;1.27;Q=0.01),bingeeating(OR=1.17,95%CI:1.08;1.26;Q=

0.01),weightandshapeconcerns(β=0.13,SE=0.03;Q=6.1x10-4),body

dissatisfaction(β=0.71,SE=0.01;Q=6.1x10-4)andnegativelyassociatedwiththin

idealinternalisation(β=-0.13,SE=0.04;Q=0.03).Thesamepatternwasobserved

withadditionalpolygenicscoresforanthropometrictraitsthatareintercorrelated(r=

.06-.64,SupplementaryFigure5),includingwaistcircumference,hipcircumference,

severalcategoriesofobesity(forfullresults,seeFigures2,3,and4PanelC,and

SupplementaryTable9).Becauseofthesepropertiesweonlyreportresultsonthe

overweightpolygenicscoreinthefollowingsection.Wereportedontheassociations

betweenthebodymassindexpolygenicscoreanddisordered-eatingtraitsinALSPAC

previously,includingformalmediationanalysesandinvestigationofagedependency

[26].

Childhoodobesitypolygenicscore.Weinvestigatedtherelationshipbetween

geneticliabilityforchildhoodobesityanddisordered-eatingbehavioursandcognitions.

Thechildhoodobesitypolygenicscorewaspositivelyassociatedwithfearofweight

gain(OR=1.16,95%CI:1.07;1.25;Q=0.02),excessiveexercise(OR=1.22,95%CI:

1.13;1.32;Q=6.1x10-4),fasting(OR=1.16,95%CI:1.08;1.26;Q=0.01),bingeeating

(OR=1.19,95%CI:1.10;1.29;Q=0.002),weightshapeconcerns(β=0.17,SE=0.03;Q

=6.1x10-4),andbodydissatisfaction(β=0.80,SE=0.10;Q=6.1x10-4)inadolescence.

(SupplementaryTable10).

Sexdifferences.Overall,wedidnotdetectsexdifferences.However,onlythe

femaleBMIpolygenicscorewaspositivelyassociatedwithpurginginadolescence(OR=

1.20,95%CI:1.08;1.34;Q=0.03),butshowednodifferencesineffectsizewhen

formallytested.Nootheranthropometricorpsychiatricpolygenicscoreshowedan

associationwithpurging.

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Figure 3. Polygenic scores associated with fasting, excessive exercise, and fear of weight gain in the Avon Longitudinal Study of Parents and Children. Sample sizes per outcome were fasting (n cases = 777, n controls = 2678), excessive exercise (n cases = 628, n controls = 4596), and fear of gaining weight (n cases = 770, n controls = 2812). Polygenic scores were calculated using PRSice v2. The optimal p value threshold to generate the polygenic score was obtained by calculating polygenic scores across multiple thresholds and permuting case-control status at each threshold 10,000 times. The polygenic score explaining the largest trait variance was used in logistic regressions including the first six ancestry principal components and sex as covariates. Dots represent odds ratios (OR) and error bars 95% confidence intervals (95% CI). Filled dots are those odds ratios that are significant after correction for multiple testing via calculation of false discovery rate-adjusted Q values.

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Ageatmenarchepolygenicscore.Theageatmenarchepolygenicscorewas

negativelyassociatedwithexcessiveexercise(OR=0.86,95%CI:0.80;0.94;Q=0.02),

fasting(OR=0.87,95%CI:0.80,0.94;Q=0.02),bingeeating(OR=0.83,95%CI:0.77;

0.90;Q=0.002),weightandshapeconcerns(β=0.15,SE=0.03;Q=6.1x10-4),and

bodydissatisfaction(β=0.54,SE=0.11;Q=1.1x10-3),indicatingthatageneticliability

foralaterageatmenarcheisassociatedwithloweroddsfordisordered-eating

cognitionsorengagingindisordered-eatingbehaviour.

Psychiatricandneurologicalpolygenicscores.TheADHDpolygenicscore

waspositivelyassociatedwithfasting(OR=1.18,95%CI:1.09,1.29;Q=0.008;Figure

3,PanelB,andSupplementaryTable2,3,and4)andtheschizophreniapolygenic

scorewaspositivelyassociatedwithbingeeating(OR=1.17,95%CI:1.07;1.27;Q=

0.01).Boththemajordepressivedisorder(β=0.09,SE=0.03;Q=0.02)andthe

migrainepolygenicscores(β=0.09,SE=0.03;Q=0.03)werepositivelyassociatedwith

weightandshapeconcern.Similarly,boththedepression(β=0.40,SE=0.11;Q=0.02)

andthemigrainepolygenicscore(β=0.38,SE=0.11;Q=0.03)wereassociatedwith

bodydissatisfaction.

Polygenicscoresassociatedwithconstitutionalthinness

Theoverweightpolygenicscorewasnegativelyassociatedwithconstitutional

thinness(OR=0.63,95%CI:0.55,0.73;Q=6.1x10-4)similartootheranthropometric

polygenicscores(Figure2,PanelC)aswellasthechildhoodobesitypolygenicscore

(OR=0.54,95%CI:0.46;0.62;Q=6.1x10-4).Thechildhoodpolygenicscorewasmore

stronglyassociatedwithconstitutionalthinnessthantheadulthoodobesitypolygenic

score(pdiff=1.0x10-4),butwedidnotobservesexdifferencesforthebodymassindex

polygenicscore.Nopolygenicscoresforthepsychiatricorneurologicalillnesses

includedinouranalysiswereassociatedwithconstitutionalthinness.

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Figure 4. Polygenic scores associated with thin ideal internalization, body dissatisfaction, and weight and shape concerns in the Avon Longitudinal Study of Parents and Children. Sample sizes per outcome were thin ideal internalization (n = 4495, mean = 15.3, SD = 2.69), body dissatisfaction (n = 4624, mean = 21.85, SD = 7.75), weight and shape concerns (n = 4622, mean = 5.34, SD = 1.85). Polygenic scores were calculated using PRSice v2. The optimal p value threshold to generate the polygenic score was obtained by calculating polygenic scores across multiple thresholds and permuting case-control status at each threshold 10,000 times. The polygenic score explaining the largest trait variance was used in logistic regressions including the first six ancestry principal components and sex as covariates. Points represent odds ratios (OR) and error bars 95% confidence intervals (95% CI). Filled dots are those odds ratios that are significant after correction for multiple testing via calculation of false discovery rate-adjusted Q values.

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Discussion

Here,wefindmoleculargeneticevidencethatpsychiatricdisordersand

anthropometrictraitssharegenomicswithbinge-typeeatingdisorders(seeFigure1,

PanelC).OurUKBiobankanalysesshowedstrongpositiveassociationsbetween

bulimianervosa/binge-eatingdisorderandanthropometricpolygenicscores(e.g.,

overweightandwaistcircumference),suggestingthatbingeeatingsharesgenomic

variantswithoverweightandobesity.Bycontrast,inanorexianervosa,thedirectionof

theseassociationswasreversed.Binge-eatingdisorderalsoshowedanassociationwith

thechildhoodobesitypolygenicscorewhileanorexianervosadidnot,further

highlightingthegenomicdifferencesbetweenbinge-typeeatingdisordersandanorexia

nervosa.ThegeneticrelationshipbetweenbingeeatingandBMIhadbeenstudied

previously[27]andisreplicatedbyouranalysis,bothatthedisorderlevel(i.e.,

individualswithbinge-eatingdisorder)andsymptomlevel(i.e.bingeeating).Itis

notablethatpreviousworksuggeststhatgenomicvariantsassociatedwithBMIare

predominantlyexpressedinbraintissue[28].Ourresultsalsosuggestthatthese

genomicvariantsarerelevantforeatingdisorders,butmayactinoppositedirectionsin

binge-typeeatingdisordersandanorexianervosa.

UsingtheUKBiobankdata,wealsofoundthatpsychiatricpolygenicscores(e.g.,

schizophreniaandmajordepressivedisorder)werepositivelyassociatedwithboth

anorexianervosaandbinge-eatingdisorder(Figure1,PanelA).TheADHDpolygenic

scorewasonlysignificantlyassociatedwithbinge-eatingdisorder,whiletheanorexia

polygenicscorewasnotassociatedwithbulimianervosaorbinge-eatingdisorder.

Ourfindingsareinagreementwithpreviousstudiesthatshowedgenetic

correlationsbetweenbingeeatinganddepression[29]aswellasgeneticcorrelations

betweenanorexianervosaanddepression[7,30],migraine[31],schizophrenia[6,7],

bipolardisorder[32]andanthropometrictraits[6,7].Inlinewithourfindings,

previousGWASsshowednogenomicassociationbetweenanorexianervosaandADHD,

whereasanADHDpolygenicscorewasassociatedwithbingeeatinginaSwedishtwin

sample[33,34].Moreover,alargeevidence-basehighlightsphenotypicoverlap

betweenADHDandbingeeating[35–37].Asmostpreviousgeneticstudiesfocusedon

anorexianervosa,wepresentthefirstmoleculargeneticevidencethattheunderlying

biologybetweenbinge-typeeatingdisordersandanorexianervosadiffersandthese

differencescanbecapturedatthegenomiclevel.

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LargeGWASshaverecentlysuggestedtheinvolvementofametaboliccomponent

inanorexianervosathroughgeneticcorrelations[6,7];however,atthecurrentsample

size,wedidnotobserveassociationsbetweenmetabolicpolygenicscoresandthethree

primaryeatingdisordersintheUKBiobank(Figure1,PanelB).

Anthropometricpolygenicscores,includinganoverweightpolygenicscore,were

positivelyassociatedwithdisordered-eatingbehaviors(i.e.,bingeeating,fasting,

excessiveexercise)andcognitions(i.e.,weightandshapeconcerns,bodydissatisfaction,

andfearofweightgain)presentinthegeneralpopulation.Thisindicatesthatgenomic

propensityforgreaterbodymassisassociatedwithanegativeperceptionofone'sown

body,whichcanfurtherleadtocompensatorybehaviors.Previouslongitudinal

mediationanalysesonthissample[26]andonUSAmericanadolescentshavefound

thatphenotypicBMImediatestheassociationsbetweenaBMIpolygenicscoreand

weightlossbehaviorsandgoals[38].

Theassociationbetweenpolygenicliabilityforhigherbodymassandeating

disorders,relatedbehaviors,andcognitionsisfurthercomplicatedasitshowsage

dependence[8]andconfoundingthroughageatmenarche.Inbothcohorts,wefound

that:1)ageatmenarcheandBMIpolygenicscoreswerenegativelycorrelatedwitheach

otherand2)thedisordered-eatingtraitswhichwerepositivelyassociatedwiththeBMI

polygenicscorewerenegativelyassociatedwiththeageatmenarchepolygenicscore

andviceversa.Forexample,bodydissatisfactionshowedastrongpositiveassociation

withtheBMIpolygenicscorebutastrongnegativeassociationwiththeageatmenarche

polygenicscore(Figure4,PanelB&C).Phenotypicassociationsbetweenearly

menarcheandbulimianervosahavepreviouslybeenreported[39,40],butdonot

alwaysreplicate[41]andrelatedsymptomslikebodydissatisfactionshowaBMI-

mediatedassociationwithageatmenarche[42,43].Onageneticlevel,bingeeating

correlatednegativelywithageatmenarcheinatwinstudy[44]andanorexianervosa

wasnotgeneticallycorrelatedwithageatmenarcheinourpolygenicscoreanalysisnor

inpreviousGWASs[6,7].Thissuggeststhattheassociationbetweenageatmenarche

anddisorderedeatingmaybedrivenbysymptomsrelatedtobingeeatingratherthan

restriction.

Itisdifficulttodisentangletherelationamongageatmenarche,BMI,and

disorderedeating.PreviousMendelianrandomizationstudiesimplicateabidirectional

relationshipbetweenageatmenarcheandBMI[45,46],indicatingsharedcausal

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mechanisms.Weobservedasimilarphenomenoninouranalysis.Toacertainextentthe

magnitudeoftheassociationbetweentheageatmenarchepolygenicscoreandthe

disordered-eatingtraitsseemstobedeterminedbythemagnitudeoftheassociation

betweenthedisordered-eatingtraitsandBMI.Ingeneral,effectswereinopposite

directions(exceptforanorexianervosa)andwarrantinvestigationusingmediationand

conditionalanalyses.

Psychiatricpolygenicscoreswereassociatedwithdisordered-eatingbehaviors

andcognitions.Inoursymptom-levelALSPACanalysis,weightandshapeconcernsas

wellasbodydissatisfactionwerepositivelyassociatedwiththemajordepressive

disorderpolygenicscore,suggestingthatindividualswhocarryagenomicpropensity

fordepressivesymptomsmayperceivetheirbodymorenegatively.Furthermore,ADHD

andBMIshowapositivegeneticcorrelation[8,47]andinouranalysistheADHD

polygenicscorewasassociatedwithbinge-eatingdisorder.Atthesymptomlevel,

however,theassociationbetweentheADHDpolygenicscoreandbingeeatingwasnot

statisticallysignificantaftercorrectionformultipletesting.Nevertheless,wefounda

significantassociationbetweentheADHDpolygenicscoreandfasting.Thissuggests

thatthesharedbiologybetweenADHDandBMImaycontributetobingeeatingand

subsequentcompensatoryfasting.Thesenovelfindingswarrantfurtherresearch;

investigatinghowgenomicvariantsassociatedwithADHD,commonlycharacterizedby

inattentionandimpulsivity,arealsoassociatedwithbingeeatingandfastingand

contributetothehighcomorbiditybetweenADHDandobesity[35–37].

Ashypothesized,constitutionalthinness(characterizedbypersistentlowBMI

andnodisordered-eatingbehaviorsorcognitions)wassignificantlynegatively

associatedwithanthropometricpolygenicscoresbutwasnotassociatedwithany

psychiatricpolygenicscores.Thisclearlydelineatesconstitutionalthinnessfrom

anorexianervosa,whichincontrastissignificantlyassociatedwithseveralpsychiatric

polygenicscores(i.e.,schizophrenia,majordepressivedisorder,andbipolardisorder)

inourUKBiobankanalysis.Ourfindingsconfirmthatconstitutionalthinnessand

anorexianervosaareseparateentitiesthatmaybecharacterizedbydifferencesinan

underlyinggenomicliabilityforpsychiatricillness.

Ourfindingsmustbeinterpretedinthelightofthefollowinglimitations:The

numberofindividualswitheatingdisordersinbothsampleswasrelativelylow,someof

theeatingdisorderdiagnosesandsymptomswereself-reported,andthesamplesonly

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includedwhiteBritishparticipants.Furthermore,wewereunabletodifferentiate

betweenbinge-eating/purgingandrestrictinganorexianervosaassubtypeinformation

wasnotavailable.However,symptomsintheALSPACcohortwereobtainedbothfrom

parentsandadolescents,representingthegoldstandardinchildandadolescent

psychiatry,strengtheningthevalidityofthediagnoses.Furthermore,ouranalysis

benefittedfromtheinclusionofindividualswithconstitutionalthinnessthatwedirectly

comparedwithindividualswithanorexianervosa.Studiesoftenfocusonhighweight

andobesityandneglectthelowerendoftheweightspectrum.

Inthefuture,itwillbeimportanttocombinemeasuresofdisordered-eating

traitsandbinaryeatingdiagnoses.Usingthisapproach,researcherswillbeableto

determinewhethertheprimaryeatingdisordersmaylieonaliabilitycontinuumandif

continuousmeasuresmayfaithfullycapturetheunderlyingcontinuous"essence"of

eachdisorder,includinggenomic,biochemical,andpsychologicaltraits.Ourfindings

showforthefirsttimethatsimilaritiesexistinthegenomicpsychiatricliabilityfor

binge-typeeatingdisordersandanorexianervosa.However,wefindclear

dissimilaritiesbetweenbinge-typeeatingdisordersandanorexianervosainthe

underlyingbiologyofbodymassregulationatthegenomiclevel.Thesefindingsopenup

importantavenuesfortranslationalresearchrelevanttoEDphenotypesandoverlap

betweeneatingdisorders.

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Acknowledgements

Weareextremelygratefultoallthefamilieswhotookpartinthisstudy,themidwives

fortheirhelpinrecruitingthem,andthewholeALSPACteam,whichincludes

interviewers,computerandlaboratorytechnicians,clericalworkers,researchscientists,

volunteers,managers,receptionistsandnurses.Thisstudywascompletedaspartof

approvedUKBiobankstudyapplications27546toProfBreen.

Funding

ThisstudyrepresentsindependentresearchpartfundedbytheUKNationalInstitute

forHealthResearch(NIHR)BiomedicalResearchCentreatSouthLondonandMaudsley

NHSFoundationTrustandKing’sCollegeLondon.Theviewsexpressedarethoseofthe

author(s)andnotnecessarilythoseoftheUKNHS,theNIHRortheDepartmentof

Health.Highperformancecomputingfacilitieswerefundedwithcapitalequipment

grantsfromtheGSTTCharity(TR130505)andMaudsleyCharity(980).Thisworkwas

supportedbytheUKMedicalResearchCouncilandtheMedicalResearchFoundation

(ref:MR/R004803/1).TheUKMedicalResearchCouncilandWellcome(Grantref:

102215/2/13/2and217065/Z/19/Z)andtheUniversityofBristolprovidecore

supportforALSPAC.AcomprehensivelistofgrantsfundingisavailableontheALSPAC

website(http://www.bristol.ac.uk/alspac/external/documents/grant-

acknowledgements.pdf);ThisresearchwasspecificallyfundedbytheNIHR

(CS/01/2008/014),theNIH(MH087786-01).GWASdatawasgeneratedbySample

LogisticsandGenotypingFacilitiesatWellcomeSangerInstituteandLabCorp

(LaboratoryCorporationofAmerica)usingsupportfrom23andMe.NMandCB

acknowledgefundingfromtheNationalInstituteofMentalHealth(R21MH115397).CB

acknowledgesfundingfromtheSwedishResearchCouncil(VRDnr:538-2013-8864),

theNationalInstituteofMentalHealth(R21MH115397;R01MH109528;

R01MH120170;R01MH119084).Thecontentissolelytheresponsibilityoftheauthors

anddoesnotnecessarilyrepresenttheofficialviewsoftheNationalInstitutesofHealth.

Thefunderswerenotinvolvedinthedesignorconductofthestudy;collection,

management,analysis,orinterpretationofthedata;orpreparation,review,orapproval

ofthemanuscript.

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Conflictofinterest

Dr.BreenhasreceivedgrantfundingfromandservedasaconsultanttoEliLilly,has

receivedhonorariafromIlluminaandhasservedonadvisoryboardsforOtsuka.Dr.

BulikisagrantrecipientfromandhasservedonadvisoryboardsforShireandisa

consultantforIdorsia.ShereceivesroyaltiesfromPearson.Allotherauthorshave

indicatedtheyhavenoconflictsofinteresttodisclose.

AuthorContribution

CH,MA,MHanalysedthedata.CH,MA,MHdraftedthemanuscript.CMB,NM,RFL,and

GBsupervisedthework.Allauthorssubstantiallycontributedtotheconceptionand

interpretationofthework,revisedthemanuscriptforimportantintellectualcontent

andapprovedthefinalversion.Allauthorsagreetobeaccountableforallaspectsofthis

work.

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24

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