tyrrell, j., richmond, r. c., palmer, t. m., feenstra, b...
TRANSCRIPT
Tyrrell, J., Richmond, R. C., Palmer, T. M., Feenstra, B., Rangarajan, J.,Metrusky, S., ... Freathy, R. M. (2016). Genetic Evidence for CausalRelationships Between Maternal Obesity-Related Traits and Birth Weight.JAMA - Journal of the American Medical Association, 315(11), 1129-1140.https://doi.org/10.1001/jama.2016.1975
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Dateofrevision:11February2016
Wordcount(text):3837
Geneticevidenceforcausalrelationshipsbetweenmaternalobesity-related
traitsandbirthweight
JessicaTyrrell,PhD1,2;RebeccaC.Richmond,PhD3,4,12;TomM.Palmer,PhD5,6*;BjarkeFeenstra,
PhD7;JananiRangarajan,MS8;SarahMetrustry,MSc9;AlanaCavadino,MSc10,11;LaviniaPaternoster,
PhD12;LorenL.Armstrong,PhD13;N.ManekaG.DeSilva,PhD12;AndrewR.Wood,PhD1;Momoko
Horikoshi,MD,PhD14,15;FrankGeller,MSc7;RonnyMyhre,PhD16;JonathanP.Bradfield,BS17;Eskil
Kreiner-Møller,MD18;VilleHuikari,MSc19;JodieN.Painter,PhD20;Jouke-JanHottenga,PhD21,22;
CatherineAllard,BSc23,24;DianeJ.Berry,PhD11;LuigiBouchard,PhD,MBA24-26;ShiktaDas,PhD27;
DavidM.Evans,PhD3,12,28;HakonHakonarson,MD,PhD17,29,30;M.GeoffreyHayes,PhD13;Jani
Heikkinen,MSc31;AlbertHofman,PhD32;BridgetKnight,PhD1;PenelopeA.Lind,PhD20;MarkI.
McCarthy,MD,PhD14,15,33;GeorgeMcMahon,PhD3;SarahE.Medland,PhD20;MadsMelbyeMD,
DMSc7,34;AndrewP.Morris,PhD15,35;MichaelNodzenski,MS8;ChristophReichetzeder,MD36,37;
SusanM.Ring,PhD3,12;SylvainSebert,PhD19,38;VerenaSengpiel,PhD39;ThorkildI.A.Sørensen,
MD12,40,41;GonnekeWillemsen,PhD21,22;EcoJ.C.deGeus,PhD21,22;NicholasG.Martin,PhD20;Tim
D.Spector,MD9;ChristinePower,PhD11;Marjo-RiittaJärvelin,MD,PhD19,38,42-44;HansBisgaard,MD,
DMSci18;StruanF.A.Grant,PhD17,29,30;EllenA.Nohr,PhD45;VincentW.Jaddoe,PhD4,32,46;Bo
Jacobsson,MD,PhD16,39;JeffreyC.Murray,MD47;BertholdHocher,MD,PhD36,48;AndrewT.
Hattersley,DM1;DeniseM.Scholtens,PhD8;GeorgeDaveySmith,DSc3,12;Marie-FranceHivert,
MD49-51;JanineF.Felix,PhD4,32,46;ElinaHyppönen,PhD11,52,53;WilliamL.Lowe,Jr.,MD13;TimothyM.
Frayling,PhD1*;DebbieA.Lawlor,PhD3,12*;andRachelM.Freathy,PhD1,12*fortheEarlyGrowth
Genetics(EGG)Consortium
1. InstituteofBiomedicalandClinicalScience,UniversityofExeterMedicalSchool,RoyalDevonand
ExeterHospital,BarrackRoad,Exeter,EX25DW,UK.2. EuropeanCentreforEnvironmentandHumanHealth,UniversityofExeter,TheKnowledgeSpa,
Truro,TR13HD.3. SchoolofSocialandCommunityMedicine,UniversityofBristol,OakfieldHouse,OakfieldGrove,
Bristol,BS82BN,UK.4. TheGenerationRStudyGroup,ErasmusMC,UniversityMedicalCenterRotterdam,P.O.Box2040,
3000CA,Rotterdam,theNetherlands.5. DivisionofHealthSciences,WarwickMedicalSchool,UniversityofWarwick,Coventry,UK.6. DepartmentofMathematicsandStatistics,LancasterUniversity,Lancaster,UK.7. DepartmentofEpidemiologyResearch,StatensSerumInstitut,Copenhagen,Denmark.
2
8. DepartmentofPreventiveMedicine,NorthwesternUniversityFeinbergSchoolofMedicine.9. DepartmentofTwinResearch,King'sCollegeLondon,St.Thomas'Hospital,London,UK.10. CentreforEnvironmentalandPreventiveMedicine,WolfsonInstituteofPreventiveMedicine,
BartsandtheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon.11. Population,PolicyandPractice,UCLInstituteofChildHealth,UniversityCollegeLondon,UK.12. MedicalResearchCouncilIntegrativeEpidemiologyUnitattheUniversityofBristol,UK.13. DivisionofEndocrinology,MetabolismandMolecularMedicine,NorthwesternUniversity
FeinbergSchoolofMedicine14. OxfordCentreforDiabetes,EndocrinologyandMetabolism,UniversityofOxford,UK.15. WellcomeTrustCentreforHumanGenetics,UniversityofOxford,Oxford,UK.16. DepartmentofGenesandEnvironment,DivisionofEpidemiology,NorwegianInstituteofPublic
Health,Oslo,Norway.17. CenterforAppliedGenomics,TheChildren’sHospitalofPhiladelphia,Philadelphia,Pennsylvania,
USA.18. CopenhagenProspectiveStudiesonAsthmainChildhood(COPSAC),FacultyofHealthSciences,
UniversityofCopenhagen,Copenhagen,Denmark&DanishPediatricAsthmaCenter,CopenhagenUniversityHospital,Gentofte,Denmark.
19. InstituteofHealthSciences,UniversityofOulu,Oulu,Finland20. QIMRBerghoferMedicalResearchInstitute,LockedBag2000,RoyalBrisbaneHospital,Herston,
Qld4029,Australia.21. EMGOInstituteforHealthandCareResearch,VUUniversityMedicalCenter,Amsterdam,The
Netherlands.22. DepartmentofBiologicalPsychology,VUUniversityAmsterdam,VanderBoechorststraat1,1081
BTAmsterdam,TheNetherlands.23. DepartmentofMathematics,UniversitedeSherbrooke,QC,Canada.24. CentrederechercheduCentreHospitalierUniversitairedeSherbrooke,Sherbrooke,QC,Canada.25. ECOGENE-21andLipidClinic,ChicoutimiHospital,Saguenay,QC,Canada.26. DepartmentofBiochemistry,UniversitédeSherbrooke,Sherbrooke,QC,Canada.27. DepartmentofPrimaryCareandPublicHealth,ImperialCollegeLondon.28. UniversityofQueenslandDiamantinaInstitute,TranslationalResearchInstitute,Brisbane,
Queensland,Australia.29. DivisionofHumanGenetics,TheChildren’sHospitalofPhiladelphia,Philadelphia,Pennsylvania,
USA.30. DepartmentofPediatrics,PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,
Pennsylvania,USA.31. FIMMInstituteforMolecularMedicineFinland,HelsinkiUniversityHelsinki,FI-00014,Finland.32. DepartmentofEpidemiology,ErasmusMC,UniversityMedicalCenterRotterdam,P.O.Box2040,
3000CA,Rotterdam,theNetherlands.33. OxfordNationalInstituteforHealthResearch(NIHR)BiomedicalResearchCentre,Churchill
Hospital,Oxford,UK.34. DepartmentofMedicine,StanfordUniversitySchoolofMedicine,Stanford,California,USA.35. DepartmentofBiostatistics,UniversityofLiverpool,LiverpoolL693GA,UK.36. InstituteofNutritionalScience,UniversityofPotsdam,Germany37. CenterforCardiovascularResearch/Charité,Berlin,Germany.38. DepartmentofEpidemiologyandBiostatistics,SchoolofPublicHealth,MedicalResearch
Council-HealthProtectionAgencyCentreforEnvironmentandHealth,FacultyofMedicine,ImperialCollegeLondon,UK
39. DepartmentofObstetricsandGynecology,SahlgrenskaAcademy,SahgrenskaUniversityHospital,Gothenburg,Sweden.
40. InstituteofPreventiveMedicine,BispebjergandFrederiksbergUniversityHospital,CapitalRegion,Copenhagen,Denmark
41. NovoNordiskFoundationCenterforBasicMetabolicResearchandDepartmentofPublicHealth,FacultyofHealthandMedicalSciences,UniversityofCopenhagen,Copenhagen,Denmark
42. DepartmentofChildrenandYoungPeopleandFamilies,NationalInstituteforHealthandWelfare,Aapistie1,Box310,FI-90101Oulu,Finland.
43. BiocenterOulu,UniversityofOulu,Oulu,Finland.
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44. UnitofPrimaryCare,OuluUniversityHospital,Kajaanintie50,P.O.Box20,FI-90220Oulu,90029OYS,Finland.
45. ResearchUnitofObstetrics&Gynecology,InstituteofClinicalResearch,UniversityofSouthernDenmark,Odense,Denmark.
46. DepartmentofPediatrics,ErasmusMC,UniversityMedicalCenterRotterdam,P.O.Box2040,3000CA,Rotterdam,theNetherlands.
47. DepartmentofPediatrics,UniversityofIowa,IowaCity,Iowa,USA.48. TheFirstAffiliatedHospitalofJinanUniversity,Guangzhou,510630,China.49. DepartmentofPopulationMedicine,HarvardPilgrimHealthCareInstitute,HarvardMedical
School,Boston,MA.50. DiabetesCenter,MassachussettsGeneralHospital,Boston,MA.51. DepartmentofMedicine,UniversitedeSherbrooke,QC,Canada.52. CentreforPopulationHealthResearch,SchoolofHealthSciences,andSansomInstitute,
UniversityofSouthAustralia,Adelaide,Australia.53. SouthAustralianHealthandMedicalResearchInstitute,Adelaide,Australia.
*Theseauthorsjointlydirectedthiswork
Correspondingauthors:Dr.RachelM.FreathyUniversityofExeterMedicalSchoolRoyalDevonandExeterHospitalBarrackRoadExeter,UKTel:+44(0)1392408238Email:r.freathy@ex.ac.ukProf.DebbieA.LawlorMRCIntegrativeEpidemiologyUnitattheUniversityofBristolOakfieldHouse,OakfieldRoad,Bristol,UKTel:+44(0)1173310096Email:d.a.lawlor@bristol.ac.ukProf.TimothyM.FraylingUniversityofExeterMedicalSchoolRoyalDevonandExeterHospitalBarrackRoadExeter,UKTel:+44(0)1392408256Email:[email protected]
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Structuredabstract
Importance:Neonatesborntooverweight/obesewomenarelargerandathigherriskofbirth
complications.Manymaternalobesity-relatedtraitsareobservationallyassociatedwithbirth
weight,butthecausalnatureoftheseassociationsisuncertain.
Objective:Totestforgeneticevidenceofcausalassociationsofmaternalbodymassindex(BMI)and
relatedtraitswithbirthweight.
Design,SettingandParticipants:WeusedMendelianrandomizationtotestwhethermaternalBMI
andobesity-relatedtraitsarecausallyrelatedtooffspringbirthweight.Mendelianrandomization
makesuseofthefactthatgenotypesarerandomlydeterminedatconceptionandarethusnot
confoundedbynon-geneticfactors.Datawereanalysedon30,487womenfrom18studies.
ParticipantswereofEuropeanancestryfrompopulation-orcommunity-basedstudieslocatedin
Europe,NorthAmericaorAustraliaandparticipatingintheEarlyGrowthGenetics(EGG)
Consortium.Live,term,singletonoffspringbornbetween1929and2013wereincluded.Wetested
associationsbetweenageneticscoreof30BMI-associatedsinglenucleotidepolymorphisms(SNPs)
and(i)maternalBMIand(ii)birthweight,toestimatethecausalrelationshipbetweenBMIandbirth
weight.Analyseswererepeatedforotherobesity-relatedtraits.
Exposures:GeneticscoresforBMI,fastingglucoselevel,type2diabetes,systolicbloodpressure
(SBP),triglyceridelevel,HDL-cholesterollevel,vitaminDstatusandadiponectinlevel.
MainOutcome(s)andMeasure(s):Offspringbirthweightmeasuredbytrainedstudypersonnel(n=2
studies),frommedicalrecords(n=10studies)orfrommaternalreport(n=6studies).
Results:Amongthe30,487newbornsthemeanbirthweightinthevariouscohortsrangedfrom
3325gto3679g.ThegeneticscoreforBMIwasassociatedwitha2g(95%CI:0,3g)higheroffspring
birthweightpermaternalBMI-raisingallele(P=0.008).Thematernalgeneticscoresforfasting
glucoseandSBPwerealsoassociatedwithbirthweightwitheffectsizesof8g(95%CI:6,10g)per
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glucose-raisingallele(P=7x10-14)and-4g(95%CI:-6,-2g)perSBP-raisingallele(P=1x10-5),
respectively.A1standarddeviation(1SD≈4kg/m2)geneticallyhighermaternalBMIwasassociated
witha55g(95%CI:17,93g)higherbirthweight.A1-SDgeneticallyhighermaternalfastingglucose
(≈0.4mmol/L)orSBP(10mmHg)wereassociatedwitha114g(95%CI:80,147g)higheror-208g(95%
CI:-394,-21g)lowerbirthweight,respectively.ForBMIandfastingglucosethesegenetic
associationswereconsistentwiththeobservationalassociations,butforSBP,thegeneticand
observationalassociationswereinoppositedirections.
ConclusionsandRelevance:InthisMendelianrandomizationstudyofmorethan30,000women
withsingletonoffspringfrom18studies,geneticallyelevatedmaternalBMIandbloodglucoselevels
werepotentiallycausallyassociatedwithhigheroffspringbirthweight,whereasgeneticallyelevated
maternalsystolicbloodpressurewasshowntobepotentiallycausallyrelatedtolowerbirthweight.
Ifreplicated,thesefindingsmayhaveimplicationsforcounselingandmanagingpregnanciestoavoid
adverseweight-relatedbirthoutcomes.
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Introduction
Neonatesborntooverweightorobesewomenaremorelikelytobelargeforgestationalage.1The
precisemechanismsunderlyingthisassociationandtheextenttowhichconfoundingfactors
contributearepoorlyunderstood.Itisimportanttounderstandwhichmaternaltraitsarecausally
associatedwithbirthweightbecausethismay(i)facilitatetargeteddevelopmentofinterventionsto
betestedinrandomizedcontrolledtrials,and(ii)enableclear,evidence-basedrecommendationsin
pregnancy.
Maternaloverweightandobesityarekeyriskfactorsforgestationaldiabetes.2Evenintheabsence
ofdiabetes,obesewomenhavehigherglucoselevelsthannormalweightwomen,despitea
controlleddiet.3Theassociationbetweengestationaldiabetesandhigherbirthweightiswell
documented4,andmaternalglucoselevelsbelowthosediagnosticofdiabetesalsoshowstrong
associationswithbirthweight.5
Thefetusofanoverweightorobesewomanmaybeexposedtotheconsequencesofhigher
maternaltriglyceridelevelsandbloodpressure,lowerlevelsofHDL-cholesterol(HDLc)and
adiponectinandlowervitaminDstatus1,6,7(Box1).Thesematernalobesity-relatedtraitshavebeen
variablyassociatedwithbirthweightinobservationalstudies:highertriglyceridesandlowerHDLc
withhigherbirthweight8,9;higherbloodpressurewithlowerbirthweight10;lowervitaminDstatus
withlowerbirthweight11;andloweradiponectinwithhigherbirthweight12.However,associations
arenotalwaysconsistentlyobservedandmaybeconfounded,forexamplebymaternal
socioeconomicstatusandassociatedbehaviourssuchassmokinganddiet.Furthermore,thehigh
inter-correlationofobesity-relatedtraitscomplicatesdeterminationofcausalrelationshipsinan
observationalsetting.
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MaternalgenotypesmaybeusedinaMendelianrandomization13,14approachtoprovideevidenceof
apotentialcausalassociationbetweenmaternaltraitsandbirthoutcomes(Figure1).Mendelian
randomizationisanalogoustoarandomizedcontrolledtrial:genotypes,whicharerandomly
allocatedatconception,arelargelyfreefromconfoundingandcanbeusedtoestimatethepossible
causaleffectsofmaternaltraits.Inthisstudy,geneticvariantswereselectedtocalculategenetic
scoresrepresentingmaternalBMIandeachof7obesity-relatedmaternaltraits.Thepotentialcausal
relationshipbetweenmaternalBMIandeachrelatedtraitwasestimatedbytestingassociations
betweenmaternalgeneticriskscoresandoffspringbirthweights.
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Methods
Studyparticipants
Singlenucleotidepolymorphism(SNP)genotypedatawereusedfromatotalof30,487womenfrom
18population-orcommunity-basedstudieslocatedinEurope,NorthAmericaorAustralia.Thebirth
weightofonechildpermotherwasincluded(seeeTable1forfulldetailsofparticipant
characteristicsandeTable2forgenotypinginformation).Birthweightwasmeasuredbytrained
studypersonnel(n=2studies),frommedicalrecords(n=10studies)orfrommaternalreport(n=6
studies).Theoffspringyearsofbirthwerefrom1929to2013.Multiplebirths,stillbirths,congenital
anomalies,birthsbefore37weeksgestationandindividualsofnon-Europeanancestrywere
excluded.Informedconsentwasobtainedfromallparticipants,andstudyprotocolswereapproved
bythelocalregionalorinstitutionalethicscommittees.
Selectionofmaternalobesity-relatedtraitsandSNPs
InadditiontoBMI,traitswereselectedthatareassociatedwithmaternalobesityandmayaffect
fetalgrowththroughtheintrauterineenvironment.Theireffectsweremodelledinthedirections
hypothesisedbytheirrelationshipstomaternalBMI(Box1)
SNPsknowntoberobustlyassociated(P<5x10-8)withBMIandeachobesity-relatedtraitwere
selected.FulldetailsoftheselectedSNPsareprovidedineTable3.SNPsassociatedwith(i)fasting
glucoseand(ii)type2diabeteswereusedtorepresentmaternalglycemia.TheType2diabetesSNPs
wereconsideredtorepresentexposuretomaternaldiabetesinpregnancy,includinggestational
diabetes,givenoverlapbetweentype2andgestationaldiabetesgeneticsusceptibilityvariants.15For
bloodpressure,SNPswereselectedthatareprimarilyassociatedwithsystolicbloodpressure(SBP),
thoughallalsoshowstrongevidenceofassociationwithdiastolicbloodpressure.ForvitaminD
status,twoSNPswithhypothesisedrolesinvitaminDsynthesiswereusedtorepresent25(OH)D
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levels(anindicatorofoverallvitaminDstatus),aspreviouslyrecommended.16,17Furtherdetailsof
SNPselectionareprovidedintheeMethods.
Aweightedgeneticscorewascalculatedforeachmaternaltrait(seeeMethodsforfulldetails).Very
fewoftheselectedSNPshavebeentestedinpregnancy.Geneticscoreswerevalidatedby
confirmingthateachwasassociatedwithitsrespectivematernaltrait,measuredduringpregnancy
(withtheexceptionofBMI,forwhichthepre-pregnancyvaluewasused).Maternalpre-pregnancy
BMIwasavailablefromregistrydata(N=2studies)orcalculatedfromself-reportedweightand
height(N=3studies).IntheAvonLongitudinalStudyofParentsandChildren(ALSPAC)study,the
self-reportwasvalidatedwithaclinicmeasure18.Detailsoftraitsmeasuredinpregnancyandtheir
sourcesaregivenineTable4.Ineachavailablestudy,linearregressionofthematernaltrait(e.g.
BMI)againstthegeneticscorewasperformed,adjustingformaternalage.Toconfirmthat
associationsbetweeneachgeneticscoreanditsrespectivematernaltraitweresimilarinthesame
individualsduringandafterpregnancy,availabledatawereusedfromtwolongitudinalstudies(the
AvonLongitudinalStudyofParentsandChildren[ALSPAC]andtheExeterFamilyStudyofChildhood
Health[EFSOCH]).TocheckthatthestrategyforSNPselectionhadresultedingeneticscoresthat
werespecifictoeachmaternaltrait,theassociationwastestedbetweeneachofthe8geneticscores
andtheothermaternaltraits,andindicatorsofmaternalsocio-economicstatusandsmoking.
TestingthehypothesisthatmaternalBMIandobesity-relatedtraitsareassociatedwithbirth
weightthroughtheintra-uterineenvironment.
ForBMIandeachrelatedmaternaltrait,twoMendelianrandomizationapproacheswereusedto
testthehypothesis.First,associationsweretestedbetweengeneticscoresrepresentingmaternal
traitsandoffspringbirthweightusingthemaximumnumberofparticipants(i.e.foreachtrait,those
withgeneticscoreandoffspringbirthweightdataavailable,irrespectiveofwhethertheyhadthe
maternaltraitmeasured).Anassociationofthegeneticscorewithbirthweightwouldsupporta
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possiblecausalrelationshipbetweenthetrait(e.g.pre-pregnancyBMI)andbirthweight,butwould
notprovideinformationonthesizeofthatassociation.Second,weperformedanalysesinthosewith
themeasuredtraitthatenabledanestimateofthesizeofapossiblecausalrelationship.The
analysestookintoaccounttheassociationbetweeneachgeneticscoreandthematernaltraitit
represented(e.g.BMI),inadditiontotheassociationbetweenthesamegeneticscoreandbirth
weight.Thesetworesultswereusedtocalculateanassociationbetweenthematernaltrait(e.g.
BMI)andbirthweightthatwasfreefromconfounding.Thissecondapproachmeasuresthe
relationshipbetweenvariationinmaternalBMI(orBMI-relatedtrait)andbirthweightthatis
attributableonlytogeneticfactors(seeFigure1foranexplanationofthemethod).Foreach
approachmeta-analysiswasusedtocombinedatafromindividualstudies(seeeMethods).
Usingthefirstapproach,weinvestigatedtheassociationbetweeneachgeneticscoreand(i)birth
weightand(ii)ponderalindex(anindexofneonatalleanness,measuredinkg/m3).Withineach
study,birthweightorponderalindexZ-scoreswereregressedagainsteachmaternalgeneticscore,
adjustedforoffspringsexandgestationalage.Analysesusingthetype2diabetesgeneticscorewere
repeatedafterexcludingparticipantswithpre-existingandgestationaldiabetes.Analysesusingthe
SBPgeneticscorewererepeatedafterexcludingparticipantswithpre-eclampsiaandexistingor
gestationalhypertension.
Thegeneticestimateoftheassociationbetweeneachmaternaltraitandbirthweight/ponderal
indexfromthesecondapproachwascomparedwiththecorrespondingobservationalassociation.
Toobtaintheobservationalestimateslinearregressionwasperformedusingbirthweightor
ponderalindexasthedependentvariable,andeachof7maternaltraitsasindependentvariables,
adjustingforsexandgestationalage.Therewasinsufficientinformationonmaternaltype2diabetes
prevalence,soitwasnotpossibletoestimatethecausalrelationshipforthattrait.Fulldetailsofthe
analysisareprovidedintheeMethods.
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EstimatinghowmuchoftheassociationbetweenmaternalBMIandbirthweightismediatedby
fastingglucose
Availabledatawereusedtoestimatetheapproximatecausalrelationshipbetweena1SD(≈4kg/m2)
highermaternalBMIand(i)fastingglucoseand(ii)SBP.Usingeachofthoseestimates,theresultsof
theMendelianrandomizationanalyseswererescaledtorepresenttheeffectsoffastingglucoseand
SBPthatcouldbedirectlycomparedwiththecausalrelationshipbetweena1SDhigherBMIand
birthweight(seeeMethodsforadetaileddescriptionofthemethod).
Correctingfordirectfetalgenotypeeffects
Genotypesofmaternal-fetalpairswereavailableinupto8studies(N=upto11,494).Analyseswere
repeatedincludingthefetalgenotypeateachSNPinthemodel,tocorrectforpotentialconfounding
causedbydirecteffectsofthefetalgenotype.
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Results
Thecharacteristicsofincludedparticipantsfromthe18contributingstudiesareshowninTable1.
Amongthe30,487newbornsthemeanbirthweightrangedfrom3325gto3679g.Themeanpre-
pregnancyBMIwasavailablein11studiesandrangedfrom22.78kg/m2to24.83kg/m2.Themean
maternalageatdelivery,availablein16studies,rangedfrom24.5yearsto31.5years.
Therewasevidenceofassociationbetweeneachgeneticscoreanditscorrespondingmaternaltrait
measuredinpregnancy(P≤0.003;Table2).ForBMI,fastingglucoseandSBP,datafrommultiple
studiesweremeta-analysed,withsimilareffectestimatesbetweenstudiesforBMIandfasting
glucose(Phet>0.05)andevidenceofheterogeneityforSBP(Phet=0.04).Theeffectsizesofassociations
betweenmaternaltraitsandtheirrespectivegeneticscoreswereverysimilarwhencomparedinthe
sameindividualsduringandoutsidepregnancy,withtheexceptionoftheSBPgeneticscorewhich
hadaweakereffectduringpregnancy(eTable5).Therewasnoevidenceofassociationbetweenany
geneticscoreandpotentiallyconfoundingvariables.Noindividualgeneticscorewasassociatedwith
anyoftheothermaternaltraits,exceptforthegeneticscoreforBMI,whichwaspositively
associatedwithSBP(P<0.003Bonferroni-correctedfor15tests;eTable6).
GeneticevidenceforapossiblecausalassociationbetweenhighermaternalBMIandhigherbirth
weight
ThematernalBMIgeneticscorewasassociatedwithhigherbirthweight(Table3)andponderal
index(eTable7)withsimilareffectsizesbeforeandafteradjustingforpossibleeffectsoffetal
genotype.Usingthegeneticscoretoquantifythepossiblecausalassociation,a1SDgenetically
highermaternalBMI(equivalentto4kg/m2)wasassociatedwitha55g(95%CI:17,93)higher
offspringbirthweight.Afteradjustingforfetalgenotype,theestimatedeffectwas104g(95%CI:32,
176)(Table4).TheseMendelianrandomizationcausalestimatesweresimilartotheobservational
13
associationof62g(95%CI:56,70)per1SD(4kg/m2)highermaternalBMI(Figure2).Similarresults
wereobtainedforponderalindex(eTable8andeFigure1).
Geneticevidenceforapossiblecausalassociationbetweenhighermaternalfastingglucoseand
higherbirthweight,butnoassociationwithmaternallipidsoradiponectin
Thematernalfastingglucoseandtype2diabetesgeneticscoreswereassociatedwithhigherbirth
weight(Table3)andponderalindex(eTable7)withsimilareffectsizeestimatesbeforeandafter
adjustingforfetalgenotype,andbeforeandafterexcludingpre-existingandgestationaldiabetes.
Usingthegeneticscoretoestimatethepossiblecausalrelationship,a1SD(0.4mmol/L)genetically
highermaternalglucosewasassociatedwitha114g(95%CI:80,147)higherbirthweight.After
adjustingforfetalgenotype,theassociationwas145g(95%CI:91,199)(Table4).Thesegenetic
estimatesweresimilartotheobservationalassociationof92g(95%CI:80,104)per1SD(0.4mmol/L)
highermaternalglucose(Figure2).Similarresultswereobtainedforponderalindex(eTable8and
eFigure1).
Thematernaltriglyceridegeneticscorewasnotassociatedwithoffspringbirthweight(Table3)or
ponderalindex(eTable7).Usingthegeneticscoretoestimatethepossiblecausalrelationship,a
geneticallyhighermaternaltriglyceridelevelwasnotassociatedwithoffspringbirthweightandthe
95%confidenceintervalsaroundthegeneticestimateexcludedtheobservationalassociation
betweenmaternaltriglyceridesandbirthweight(P=0.007testingdifferencebetweengeneticand
observationalassociation;Table4;Figure2).Likewise,thegeneticestimateofthepossibleeffectof
maternaladiponectinlevelsonoffspringbirthweightwasdifferentfromtheobservational
association(P=0.002).ThegeneticscoreforHDLcwasnotassociatedwithbirthweightorponderal
indexandtheanalysiswasconsistentwithnocausalrelationship,howeverthiscouldnotbe
distinguishedfromthenegativeobservationalassociationbetweenmaternalHDLcandbirthweight.
14
Geneticevidenceforapossiblecausalassociationbetweenhighersystolicbloodpressureand
lowerbirthweight
ThematernalSBPgeneticscorewasassociatedwithlowerbirthweight(Table3)andponderalindex
(eTable7)withsimilareffectsizeestimatesbeforeandafteradjustingforfetalgenotype,andbefore
andafterexcludingmaternalpre-eclampsiaandhypertension.Usingthegeneticscoretoestimate
thepossiblecausalrelationship,a1SD(10mmHg)geneticallyhighermaternalSBPwasassociated
witha-208g(95%CI;-394,-21)loweroffspringbirthweight.Afteradjustingforfetalgenotype,the
estimatedeffectwas-151g(95%CI:-390,89)(Table4).Thegeneticestimateoftheassociation
betweenmaternalSBPandbirthweightinthefullsampleofwomenwasintheoppositedirectionto
theobservationalassociation(P=0.01fordifferencebetweengeneticandobservationalassociations;
Table4;Figure2).Similarresultswereobtainedforponderalindex(eTable8andeFigure1).
ThematernalgeneticscoreforlowervitaminDstatuswasassociatedwithlowerbirthweight
(P=0.03;Table3).However,theestimatedcausalrelationshipwasnotsignificantlydifferentfrom
zero(theestimatedchangeinbirthweightfora10%geneticallylowermaternal25[OH]Dlevelwas-
26g(95%CI:-54,2);Table4,Figure2).
Associationsbetweenthegeneticscoresandbirthweightwereconsistentacrossstudies
Associationsbetweenmaternalgeneticscoresandoffspringbirthweightweresimilarbetween
studiesinthemeta-analysis(Table3;Phet>0.05).Wheredatawerecombinedfromobservational
analyses,theassociationsbetweenmaternalfastingglucoseorSBPandbirthweightweresimilar
(Phet>0.05),andtherewasevidenceofheterogeneityfortheBMI-birthweightobservational
association(Table4;Phet=0.03).
Exposureofthefetustohighermaternalfastingglucoseisunlikelytoexplainalloftheassociation
betweenhighermaternalBMIandhigheroffspringbirthweight
15
ToestimatehowmuchoftheassociationbetweenmaternalBMIandbirthweightmightbe
mediatedbyfastingglucose,theBMIandfastingglucosegeneticscoreswereused:a1SD(≈4
kg/m2)geneticallyhighermaternalBMIwasassociatedwitha0.34SD(≈0.14mmol/L)higher
maternalfastingglucose.FromtheMendelianrandomizationanalyses,1SD(≈0.4mmol/L)
geneticallyhighermaternalfastingglucosewasassociatedwitha114g(95%CI:80,147)higherbirth
weight.Consequently,itwaspredictedthata0.34SDhigherfastingglucosewouldbeassociated
witha114g×0.34=39g[95%CI:27,50]higherbirthweight.Thisapproximationisbroadlysimilarto
thetotalestimatedeffectofa1SDhigherBMIonbirthweight(55g[95%CI:17,93]).However,using
thesamemethodwiththeBMIandSBPgeneticscoresweestimatedthata1SDhighermaternalBMI
wouldbeassociatedwitha-40g[95%CI:-75,-4]lowerbirthweightviaitsassociationwithmaternal
SBP(eFigure2),whichwouldopposethepositiveassociationwithmaternalfastingglucose.
16
Discussion
ThisstudyprovidesevidenceforapossiblecausalassociationbetweenmaternalBMIandoffspring
birthweight.A4kg/m2geneticallyhighermaternalBMI(a1SDrise)wasassociatedwitha55g(95%
CI:17,93)higheroffspringbirthweight.Inaddition,a0.4mmol/l(1SD)geneticallyhighercirculating
maternalfastingglucosewasassociatedwitha114g(95%CI:80,147)higherbirthweight,whilea10
mmHggeneticallyhighermaternalSBPwasassociatedwitha-208g(95%CI:-394,-21)lowerbirth
weight.TheseresultsprovideevidencethatgeneticallyelevatedmaternalglucoseandSBPhave
directionallyoppositecausalassociationswithbirthweight.Theestimatedassociationsbetween
thesematernaltraitsandbirthweight(eitherincreasedorreduced)aresubstantialandofclinical
importance.Theysupporteffortstomaintainhealthygestationalglucoseandbloodpressurelevels
toensurehealthyfetalgrowth.ThepositiveassociationbetweenmaternalBMIandbirthweight
maybepartiallymediatedbytheeffectofhigherBMIoncirculatingmaternalfastingglucose.There
wasnoevidenceofassociationwithageneticscoreformaternaltriglycerides,whichhavealsobeen
hypothesisedtobeimportantcontributorstohigherbirthweightinoverweightorobesewomen.
Otherlipids,orspecificsubclassesoftriglycerides,mightbeimportantbutrequirefurtherstudy.
Theseresultsprovidegeneticevidenceofacausalassociationbetweenmaternalglycemiaandbirth
weightandponderalindex,eveninwomenwithnopre-existingorgestationaldiabetes,whichis
consistentwithpublishedobservationaldata.5Apossibleexplanationforthisfindingisthatwomen
withahighergeneticscorefortype2diabeteshaverelativelyhigherglucoselevelsinpregnancy,as
aresultofinadequatebetacellcompensationinresponsetogestationalinsulinresistance,19,20
leadingtoincreasedplacentalglucosetransferandfetalinsulinsecretion,21andconsequentlyhigher
birthweight.
Thesedatadidnotsupportacausalassociationbetweenmaternaltriglyceride,HDLcoradiponectin
levelsandbirthweightorponderalindex.Thegeneticassociationsbetweenmaternaltriglycerides
17
andadiponectinandbirthweightwerenull,incontrasttotheobservationalassociations,suggesting
thattheobservationalassociationsseenhere,andinotherpublishedstudies8,9,12,areconfounded.
TheMendelianrandomizationanalysisshowedthatthepositiveobservationalassociationbetween
SBPandbirthweightisconfounded,mostlikelybyBMI,whichisbothanimportantriskfactorfor
higherSBPinpregnancyandpositivelyassociatedwithbirthweight.1Usinggeneticvariantsthatare
independentofconfoundingbyBMI,itwasdemonstratedthatgeneticallyhighermaternalSBPis
associatedwithlowerbirthweight,evenafterexcludingpre-eclampsiaandhypertension.The
precisionofourestimateofthechangeinbirthweightper1SDinmaternalSBPcouldbeaffectedby
theheterogeneitybetweenstudiesinthegeneticscore-SBPassociation(P=0.04,I2=76.0%;Table2).
However,associationsbetweentheSBPgeneticscoreandbirthweightwereconsistentacrossall13
meta-analyzedstudies(P=0.14,I2=30.4%;Table3)andsupportiveofacausalassociationbetween
highermaternalSBPandlowerbirthweight.Thesefindingssupportobservationalassociations
betweenmaternalSBPandbirthweightthatwereadjustedforawiderangeofconfounders,22and
areconsistentwithlaboratoryandpopulationstudiessuggestingalinkbetweenhypertensive
disordersofpregnancyandimpairedfetalgrowthduetoplacentalpathology.23Thereareincreasing
concernsabouttheeffecttheobesityepidemicmighthaveonbirthsize,viagreatermaternalBMI.
However,thefocusofthatconcernhasbeenlargelyonincreasedbirthsizeasaresultofgreater
maternalglucoseandotherfetalnutrients.Ourfindingssuggestthatthereareopposingeffectsof
maternalbloodpressureandglucose.
PublishedMendelianrandomizationanalysesprovideevidencethathigherBMIiscausallyassociated
withlowervitaminDstatus,6andevidencefrommultipleobservationalstudiessuggeststhatlower
maternalvitaminDisassociatedwithlowerbirthweight.11,24OuranalysisofthevitaminDgenetic
scoreprovidedsomeevidencetosupportapossiblecausalassociationwithbirthweight,butthis
requiresfurtherexplorationinlargernumbersofpregnancies.
18
Socio-economicfactorsandrelatedbehaviourssuchassmokingarekeyconfoundersof
observationalassociationsbetweenmaternalBMI(orBMI-relatedtraits)andoffspringbirthweight,
sincetheyareassociatedwithbothvariables(seeeTable9forademonstrationoftheseassociations
intheALSPACstudy).Thegeneticscoresusedinouranalyseswerenotassociatedwithsocio-
economicfactorsorsmoking,andthisillustratesakeystrengthoftheMendelianrandomization
approach:sincegenotypesaredeterminedatconception,suchconfoundingisavoided.
Therearesomelimitationstothisstudy.Despiteattemptstomaximisespecificityofthegenetic
scores,wecannotfullyexcludethepossibilitythattheselectedgeneticvariantsactonmorethan
onematernaltrait.Althoughallavailableinformationwasused,therewaslimitedpowertodetect
associationsbetweenthegeneticscoresandothertraits.Forexample,theknownassociation
betweenBMI-associatedvariantsandtriglyceridelevelswasnotdetected.25Withthepotentialfor
high-throughputmetabolomicstudiesandagrowingpublicdatabaseofgeneticassociations,26-28
futurestudieswillimprovethespecificity(fordifferentlipidsub-fractions)ofselectedgenetic
variants.
Despitethelargesampleinthisstudy,statisticalpowertodetectcausalrelationshipswaslimitedfor
somematernaltraits(seeeMethodsandeTable10forpowercalculations).Thetotalsample
provided>99%powertodetectassociationsatP<0.05betweenbirthweightandgeneticscoressuch
asfastingglucoseandsystolicbloodpressurethatexplainatleast0.1%varianceinbirthweight.
However,largersamples(N>80,000)willbeneededtoconfidentlydetectorruleout(i)the
associationwithvitaminDstatussuggestedbyourdata,or(ii)smallerpositiveornegativecausal
associationsbetweenmaternaltriglycerides,HDLcoradiponectinandbirthweight.
19
Whileadjustingforthefetalgeneticscoreswasnecessarytoseparatematernaleffectsfromthe
directeffectsofgeneticvariantsinthefetus,thiscouldpotentiallyintroducebiasviaassociation
withpaternalgenotypes.AssortativematingforBMIcouldadditionallyresultinacorrelation
betweenmaternalandpaternalgenotypes,leadingtosimilarbias.However,afather’sgeneticscore
wouldonlyconfoundtheMendelianrandomizationestimatesifthefather’sphenotypewererelated
tobirthweight,andwefoundonlyveryweakassociationsoffathersBMIandrelatedtraitswith
offspringbirthweight(eTable11).Anotherpotentialbiascouldbeinducedbytheuseofthegenetic
scoreforSBP,whichwasderivedfromagenome-wideassociationstudyofbloodpressure
conditionalonBMI.SinceBMIisalsoassociatedwithbirthweight,thiscouldbiastheresults.
However,similarresultswereobtainedusinganalternativegeneticscorethatwasunadjustedfor
BMI(eMethods).
InMendelianrandomizationanalysis,aweakstatisticalassociationbetweenageneticscoreanda
maternaltrait(duetolowvarianceexplainedand/orsmallsamplesize)hasthepotentialtocause
weakinstrumentbiastowardstheobservationalresults.29Theproportionsofmaternaltraitvariance
explainedbythegeneticscoresaremodestinourstudy(Table2).However,thelargeoverallsample
sizeensuredthatthepossiblecausalassociationsidentifiedareunlikelytobeduetoweak
instrumentbias(seeeMethods).
OuranalysesassumethatmaternalBMIandrelatedtraitsarelinearlyassociatedwithoffspringbirth
weight.Wehavenottestedfornon-linearassociationswhich,inaMendelianrandomizationdesign,
wouldrequireverylargenumbers30.However,formaternalBMI,fastingglucoseandsystolicblood
pressure,thereisobservationalevidenceofsuchlinearassociationsacrossthedistribution,withno
evidenceofthresholdorcurvilinearassociations5,10,31.
20
Conclusions
InthisMendelianrandomizationstudyofmorethan30,000womenwithsingletonoffspringfrom18
studies,geneticallyelevatedmaternalBMIandbloodglucoselevelswerepotentiallycausally
associatedwithhigheroffspringbirthweight,whereasgeneticallyelevatedmaternalsystolicblood
pressurewasshowntobepotentiallycausallyrelatedtolowerbirthweight.Ifreplicated,these
findingsmayhaveimplicationsforcounselingandmanagingpregnanciestoavoidadverseweight-
relatedbirthoutcomes.
21
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24
ARTICLEINFORMATION
AuthorContributionsDr.FreathyandProfsLawlorandFraylinghadfullaccesstoallofthedataintheALSPAC,EFSOCHandHAPO(non-GWAS)studiesandaccesstosummarydatafromallcontributingstudiesandtakeresponsibilityfortheintegrityofthedataandaccuracyofthedataanalysis.Studyconceptanddesign:J.Tyrrell,D.A.Lawlor,T.M.Frayling&R.M.FreathyAnalysisandinterpretationofdata:J.Tyrrell,R.C.Richmond,S.Metrustry,B.Feenstra,A.Cavadino,E.Hyppönen,M-FHivert,J.F.Felix,W.L.Lowe,D.A.Lawlor,T.M.Frayling&R.M.FreathyDraftingmanuscript:J.Tyrrell,R.C.Richmond,S.Metrustry,B.Feenstra,A.Cavadino,E.Hyppönen,M-FHivert,J.F.Felix,W.L.Lowe,D.A.Lawlor,T.M.Frayling&R.M.Freathy
Criticalrevisionofmanuscriptforimportantintellectualcontent:Allauthors
Statisticalanalysis:N.M.G.DeSilva,A.R.Wood,G.McMahon,D.M.Evans,E.Kreiner-Møller,F.Geller,C.Allard,J-J.Hottenga,J.P.Bradfield,M.G.Hayes,D.M.Scholtens,L.L.Armstrong,J.Rangaraja,M.Horikoshi,M.I.McCarthy,M.Nodzenski,L.Paternoster,S.Das,V.Huikari,J.N.Painter,S.E.Medland,P.A.Lind,D.J.Berry,R.Myhre,V.Sengpiel,J.Tyrrell,R.C.Richmond,S.Metrustry,B.Feenstra,A.Cavadino,J.F.Felix,D.A.Lawlor&R.M.Freathy
Genotyping:D.M.Evans,S.M.Ring,J.C.Murray,L.Bouchard,J.F.Felix,J-J.Hottenga,H.Hakonarson,T.I.A.Sørensen,N.G.Martin,E.A.Nohr,T.D.Spector,S.F.Grant,D.A.Lawlor,T.M.Frayling&R.M.Freathy
Individualstudydesign:T.D.Spector,B.Jacobsson,C.Power,N.G.Martin,S.Serbert,T.I.A.Sørensen,M.Järvelin,B.Hocher,M.G.Hayes,W.L.Lowe,S.F.Grant,H.Hakonarson,J.P.Bradfield,E.J.C.deGeus,V.W.Jaddoe,A.Hofman,M.Melbye,J.C.Murray,H.Bisgaard,G.DaveySmith,A.T.Hattersley,E.Hyppönen,M-FHivert,J.F.Felix,W.L.Lowe,D.A.Lawlor,&T.M.Frayling
Phenotypingincontributingstudies:T.D.Spector,B.Jacobsson,C.Power,E.Hyppönen,N.G.Martin,T.I.A.Sørensen,E.A.Nohr,C.Reichetzeder,B.Hocher,S.F.Grant,H.Hakonarson,J.P.Bradfield,G.Willemsen,V.W.Jaddoe,M-FHivert,M.Melbye,F.Geller,B.Feenstra,E.Kreiner-Møller,H.Bisgaard,G.DaveySmith,S.M.Ring,D.A.Lawlor,B.Knight,A.T.Hattersley
25
ConflictsofInterestandFinancialDisclosuresNoconflictsofinterestwerereported.Funding/SupportFunding/supportofauthorsisasfollows(fundingdetailsforindividualstudiesarereportedintheSupplementaryMaterial).T.M.FandA.R.WaresupportedbytheEuropeanResearchCouncilgrant:323195SZ-24550371-GLUCOSEGENES-FP7-IDEAS-ERC;A.T.H.andM.I.M.areWellcomeTrustSeniorInvestigators;M.I.M.isanNIHRSeniorInvestigator.R.M.F.isaSirHenryDaleFellow(WellcomeTrustandRoyalSocietygrant:104150/Z/14/Z);J.T.isfundedbytheERDFandaDiabetesResearchandWellnessFoundationFellowship;RCRisfundedbytheWellcomeTrust4-yearstudentship(GrantCode:WT083431MF).D.A.L.,G.D-S.,D.M.E.andS.R.allworkinaUnitthatreceivesfundingfromtheUniversityofBristolandtheUKMedicalResearchCouncil(MC_UU_1201/1/5,MC_UU_1201/1andMC_UU_1201/4).D.A.L.issupportedbyawardsfromtheWellcomeTrust(WT094529MAandWT088806),USNationalInstituteofHealth(R01DK10324)andisanNIHRSeniorInvestigator(NF-SI-0611-10196).D.M.EandS.E.M.weresupportedbyAustralianResearchCouncilFutureFellowship(FT130101709andFT110100548).B.FissupportedbyanOakFoundationScholarship.L.B.isajuniorresearchscholarfromtheFondsdelarechercheensantéduQuébec(FRQS)andamemberoftheFRQS-fundedCentrederechercheduCHUS.M.F.H.isaFRQSresearchscholarsandwasawardedaClinicalScientistAwardbytheCanadianDiabetesAssociationandtheMaudMentenAwardfromtheInstituteofGenetics–CanadianInstituteofHealthResearch(CIHR).C.A.wasawardedtheCIHR-FrederickBantingandCharlesBestCanadaGraduateScholarships.V.W.J.issupportedbytheNetherlandsOrganizationforHealthResearchandDevelopment(ZonMw–VIDI016.136.361).A.P.M.isaWellcomeTrustSeniorResearchFellow(grantnumberWT098017).T.S.isholderofanERCAdvancedPrincipalInvestigatoraward.RoleoftheSponsorsThefundingagencieshadnoroleinthedesignandconductofthestudy;collection,management,analysisandinterpretationofdata;preparation,review,approvalofmanuscript;ordecisiontosubmitmanuscriptforpublication.PreviousPresentationsThisworkwaspresentedattheDiabetesUKAnnualProfessionalConference2014,5-7March,Liverpool,UK.AdditionalContributionsWeareextremelygratefultotheparticipantsandfamilieswhocontributedtoallofthestudiesandtheteamsofinvestigatorsinvolvedineachone.Theseincludeinterviewers,computerandlaboratorytechnicians,clericalworkers,researchscientists,volunteers,managers,receptionistsandnurses.Foradditionalstudy-specificacknowledgements,pleaseseeSupplementaryMaterial.ThisresearchhasbeenconductedusingtheUKBiobankresource.
26
FIGURE/BOXLEGENDS
Box1.Thematernalobesity-relatedtraitshypothesizedtocauseincreasedordecreasedfetalgrowth,
based on observational associations with birth weight: body mass index (BMI)1; fasting glucose5;
gestationalortype2diabetes32;triglycerides9;HDL-cholesterol8;systolicbloodpressure10;vitaminD
status(asindicatedby25-hydroxyvitaminD,25[OH]Dlevel)11;adiponectin12.
Figure1
PrincipleofMendelianrandomization:Ifamaternaltraitcausallyinfluencesoffspringbirthweight,
thenariskscoreofgeneticvariantsassociatedwiththattraitwillalsobeassociatedwithbirth
weight.Sincegenotypeisdeterminedatconception,itshouldnotbeassociatedwithfactorsthat
normallyconfoundtheassociationbetweenmaternaltraitsandbirthweight(e.g.socio-economic
status).Estimatesofthegeneticscore-maternalphenotypeassociation(w)andthegeneticscore-
birthweightassociation(x)maybeusedtoestimatetheassociationbetweenthematernaltrait
variationthatisduetogeneticscore,andbirthweight(y=x/w),whichisexpectedtobefreefrom
confounding.Iftheestimatedcausalrelationship,y,isdifferentfromtheobservationalassociation
betweenthemeasuredmaternalphenotypeandbirthweight,thiswouldsuggestthatthe
observationalassociationisconfounded(assumingthattheassumptionsoftheMendelian
randomizationanalysesarevalid).14Thedashedlineconnectingmaternaltraitwithfetalgrowthhas
noarrow,toindicatethatthecausalnatureoftheassociationisuncertain.Itisimportanttoadjust
forpossibledirecteffectsoffetalgenotype(z).
Figure2.Comparisonoftheobservationalwiththegeneticchangeinbirthweight(ingrams)fora1
standarddeviation(SD)changeineachmaternalobesity-relatedtrait.For25[OH]Dandadiponectin,
wepresentthechangeinbirthweightfora10%changeinmaternaltraitlevelbecausethese
variableswereloggedforanalysis.ThegeneticchangewasestimatedfromMendelian
randomizationanalysis,inwhichageneticscorewasusedtoestimatethepossiblecausal
27
relationshipbetweenthematernaltraitandbirthweight.Thegeneticestimateispresentedtwice:in
thesecondcaseitwasadjustedforfetalgenotypeusingasubsetofavailablestudies.Theerrorbars
representthe95%confidenceintervalsaroundtheeffectsizeestimates.Formaternalpre-
pregnancyBMIandfastingglucose,the95%confidenceintervalsforboththeobservationaland
geneticapproachesexcludethenull,suggestingpositivepossiblecausalrelationshipsbetween
maternalBMIandfastingglucoseandbirthweight.FormaternalSBP,theobservationalanalysis
suggestedaweakpositiveassociationwithbirthweight,whereasthegeneticanalysisshowed
evidenceofanegativepossiblecausalrelationship.Observationalanalysessuggestedthathigher
maternaltriglyceridelevels,lowermaternaladiponectinandlowermaternalHDL-cholesterollevels
wereassociatedwithhigherbirthweight,whilelowermaternalvitaminDstatuswasassociatedwith
lowerbirthweight,butnoneoftheseweresupportedbythegeneticanalyses.
28Table1.Keycharacteristicsofparticipantsbystudy(forfulldetails,seeeTable1)
Abbreviatedstudyname*
Country(samplesource)
Offspringyearsofbirth
Nwomenwithbirthweightofonechild
Noffspringwith
genotype
Meanmaternalageat
deliveryinyears(SD)
Meanmaternal
pre-pregnancyBMI(SD)in
kg/m2
Meanoffspring
birthweight(SD)ingrams
ALSPACmothers33 UK 1991-1992 7304 4913 28.5(4.8) 22.93(3.73) 3481(475)
BBCmothers34 Germany 2000-2004 1357 1357 30.1(5.4) 22.78(3.93) 3472(511)
B58C-WTCCC35 UK 1972-2000 855 NA 26.2(5.2) NA 3325(483)
B58C-T1DGC35 UK 1972-2000 836 NA 26.1(5.4) NA 3379(469)
CHOPmothers36 USA 1987-
present 312 NA NA NA 3440(562)
COPSAC-2000mothers37 Denmark 1998-2001 282 282 30.4(4.3) NA 3560(505)
DNBC-GOYA38 Denmark 1996-2002 1805 NA 29.2(4.2) 23.57(4.27) 3643(495)
DNBC-PTB-CONTROL39 Denmark 1987-2009 1649 975 29.9(4.2) 23.57(4.27) 3595(497)
EFSOCHmothers40 UK 2000-2004 746 332‡ 30.5(5.3) 24.07(4.42) 3512(480)
GEN-3Gmothers41 Canada 2010-2013 676 NA 28.4(4.4) 24.83(5.63) 3448(433)
GenerationRmothers42 TheNetherlands 2002-2006 3810 2196 31.2(4.5)† 23.12(3.92) 3528(494)
HAPOmothers(GWAS)5
UK,Canada,Australia 2000-2006 1380 1300 31.5(5.3)† 24.5(5.0) 3557(517)
HAPOmothers(non-
GWAS)5
USA,UK,Canada,Australia
2000-2006 3590 2318 30.4(5.4)† 24.63(5.33) 3526(463)
MoBamothers43 Norway 1999-2008 650 350 28.5(3.3) 23.93(3.94) 3679(430)
NFBC196644 Finland 1987-2001 2035 NA 26.5(3.7) NA 3525(461)
NTR45 TheNetherlands 1946-2003 706 NA 27.1(3.7) NA 3469(529)
QIMR46 Australia 1929-1990 892 NA Q24.5(4.0)R 22.79(5.13) 3344(532)
TwinsUK47,48 UK NA 1602 NA NA NA 3365(581)
*Expandedstudynames:ALSPAC,AvonLongitudinalStudyofParentsandChildren;BBC,BerlinBirthCohort;B58C-WTCCC,1958BritishBirthCohort-WellcomeTrustCaseControlConsortium;B58C-T1DGC,1958BritishBirthCohort-Type1DiabetesGeneticsConsortium;CHOP,Children’sHospitalOfPhiladelphia;DNBC-GOYA,DanishNationalBirthCohort-GeneticsofObesityinYoungAdultsstudy;DNBC-PTB-CONTROLS,DanishNationalBirthCohortPretermBirthstudyControls;EFSOCH,ExeterFamilyStudyOfChildhoodHealth;GEN-3G,GeneticsofGlycemicregulationinGestationandGrowth;HAPO,HyperglycemiaandAdversePregnancyOutcomestudy(GWAS,Genome-WideAssociationStudy);MoBa,theNorwegianMotherandBabyCohort;NFBC1966,theNorthernFinland1966BirthCohort;NTR,NetherlandsTwinRegistry;QIMR,QueenslandInstituteofMedicalResearch.†InGenerationR,maternalagewasrecorded,onaverage,at14.4weeksofgestation;inHAPO,maternalagewasrecorded,onaverage,at28weeksofgestation.‡FetalgenotypeinEFSOCHavailableonlyforthefastingglucosegeneticscore.NA,notavailable.
29Table2.Associationsbetweenmaternalgeneticscoresandmaternalobesity-relatedtraits
Maternalobesity-relatedtrait
NumberofSNPsusedtoconstructgeneticscore
ReferenceforprimaryGWAS
paperforeachsetofSNPs*
Estimateof%variancein
maternaltraitexplainedby
geneticscoreinpregnantwomen†
TotalNwomenwithtraitmeasured
duringpregnancy(exceptBMI,for
whichtheappropriate
measurementispre-pregnancy)
Nstudies
Estimatedchangeinmaternaltraitperaverageweighted
trait-raising/lowering‡allele(95%CI)
Pvalue
HeterogeneityPvalue;I2%,
whereresultsfrom>1studyweremeta-analysed
Higherpre-pregnancyBodyMassIndex
(BMI)30
Speliotesetal.,2010,NatGenet49
1.8%inALSPAC11,822 5 0.145(0.126,0.164)
kg/m2 <2x10-16 0.18;35.8
Higherfastingglucose§ 13
Dupuisetal.2010,NatGenet50
5%inEFSOCH5,402 3 0.029(0.025,0.032)
mmol/L <2x10-16 0.70;0
Higheroddsofgestationaldiabetesandexistingdiabetes(SNPsassociatedwith
type2diabetes)
55
Morrisetal.2012,NatGenet51
1.4%inALSPAC6,606
(54Cases,6,552controls)
1 Oddsratio:1.08(1.03,1.14) 0.003 -
Highertriglycerides 17 Teslovichetal.2010,Nature52
3%inEFSOCH 663 1 0.055(0.032,0.078)mmol/L 3x10-6 -
LowerHDL-cholesterol 4 Teslovichetal.2010,Nature52
3%inEFSOCH 733 1 -0.050(-0.072,-0.027)mmol/L 1x10-5 -
Highersystolicbloodpressure 33 Ehretetal.2010,
Nature531%inALSPAC 8,450 2 0.186(0.140,0.231)
mmHg <2x10-16 0.04;76.0
LowervitaminDstatus,ln[25(OH)D] 2(“Synthesis”score)¶
Vimaleswaranetal.2013,PloSMed6
0.2%inALSPAC4,767 1 -0.024(-0.039,-
0.009)onlogscale 0.002 -
Loweradiponectin,ln[adiponectin] 3
Yaghootkaretal.2013,Diabetes54
2%inHAPO1,376 1 -0.17(-0.23,-0.11)
onlogscale 1x10-8 -
*Thereferencesincolumn3indicatethepublishedgenome-wideassociationstudiesthatoriginallyidentifiedtheSNPsusedinthegeneticscores(studiesofnon-pregnantindividuals).†Toestimatethevarianceineachtraitexplainedbyitsrespectivegeneticscoreinpregnantwomen(column4),thelargestavailablestudywasused.Abbreviations:ALSPAC,AvonLongitudinalStudyofParentsandChildren33.EFSOCH,ExeterFamilyStudyOfChildhoodHealth40.HAPO,HyperglycemiaandAdversePregnancyOutcomestudy5.FurtherdetailsabouttheincludedstudiescanbefoundineTable4.‡Thedecisiontomodeltheassociationinrelationtothetrait-raisingortrait-loweringalleledependedontheknowndirectionofassociationofeachtraitwithhigherBMI(seeBox1).Column1specifieseachofthesedirectionsofassociation.§Removingtheonestudyinwhichthers10830963SNPwaspoorlyimputed(r2<0.8),weobtainedverysimilarresults(n=4026;effectsize=0.028(95%CI:0.024,0.032);P<2x10-16;Phet=0.46;I2=0%).
30¶ThetwoSNPsselectedforthevitaminDgeneticscorehaveahypothesizedroleinthesynthesisofvitaminD(asopposedtoitsmetabolism)andarerecommendedforuseinMendelianrandomizationstudies.16,17Levelsof25(OH)Dandadiponectinlevelswerelog-transformedtoachievenormalitybeforeanalyses.
31Table3.Associationsbetweenmaternalgeneticscoresandbirthweightofoffspring
Maternaltraitforwhichgeneticscorewas
constructedNstudies TotalN
women
Estimatedchangeinoffspringbirthweight(grams)permaternaltrait-
raising/lowering*allele(95%CI),tothenearest1
gram†
Pvalue
HeterogeneityPValue;I2%frommeta-analysis
Nstudieswithfetalgenotypes
TotalNoffspringwith
genotypesavailable
Estimatedchangeinbirthweight(grams)permaternaltrait-raising/loweringallele*(95%CI),tothenearest1gram†,adjustedforfetal
genotypes
Pvalue(adjustedforfetal
genotypes)
HeterogeneityPValue;I2%frommeta-analysis
(adjustedforfetal
genotypes)
Higherpre-pregnancyBMI 16 25,265 2(0,3) 0.008 0.84;0 7 10,964 4(1,6) 0.004 0.20;30.5
Higherfastingglucose 15 23,902 8(6,10) 7x10-14 0.11;33.3 8 11,493 11(7,14) 7x10-9 0.26;21.6
Higheroddsoftype2Diabetes 12 18,670 2(0,2) 0.06 0.22;23.1 5 7,769 4(2,6) 0.0004 0.81;0
Higheroddsoftype2Diabetes(excludingpre-existingandgestational
diabetes)
6 13,029 2(1,3) 0.02 0.92;0 4 6,210 4(1,6) 0.006 0.93;0
Highertriglycerides 15 24,985 -2(-4,0) 0.12 0.83;0 6 11,031 -2(-7,1) 0.21 0.86;0
LowerHDL-cholesterol 15 22,167 0(-3,3) 1 0.52;0 6 9,176 0(-5,5) 0.98 0.85;0
Highersystolicbloodpressure 13 20,062 -4(-6,-2) 1x10-5 0.14;30.4 5 7,790 -3(-6,0) 0.09 0.50;0
Highersystolicbloodpressure(excludingpre-
eclampsiaandhypertension)
7 13,271 -5(-7,-3) 6x10-6 0.18;32 4 5,488 -4(-8,0) 0.04 0.16;41.2
LowervitaminDstatus 18 30,340 -6(-12,0) 0.03 0.13;37.1 3 9,510 -14(-25,3) 0.01 0.77;0
Loweradiponectin 9 14,920 -2(-16,12) 0.76 0.90;0 5 7,820 7(-16,30) 0.55 0.71;0
*Thedecisiontomodeltheassociationinrelationtothetrait-raisingortrait-loweringalleledependedontheknowndirectionofassociationofeachtraitwithhigherBMI(seeBox1).Column1specifieseachofthesedirectionsofassociation.Resultsareperaverageweightedallele,adjustedforsexandgestationalage.†StandarddeviationofbirthweightaveragedoveranumberofEuropeanstudies(=484g)55wasusedtogeneratetheseestimatesfromz-scores.Weconsidereda2-tailedPvalueof<0.05toprovideevidenceagainstthenullhypothesis.
32
33Table4.Acomparisonoftheobservationalwiththegeneticassociationbetweeneachmaternaltraitandoffspringbirthweight
Maternaltrait Valueofa1SDchangeinthetraitwithunits
Study/ies*usedforobservationalestimates
[TotalNwomen]
Nwomenforobservationalestimates
Observationalestimateofthechangeinbirth
weight(g)per1SD(or10%†)changein
maternaltrait,adjustedforsexand
gestationalage(95%CI)
Geneticestimateofthechangeinbirthweight(g),adjusted
forsexandgestationalage,per1SD(or10%†)changeinmaternaltrait,unadjustedfor
fetalgenotype(95%CI)[NwomenasinTables
1and2]
Pvalue‡comparing
observationalwithgeneticbirth
weightassociations(unadjustedforfetalgenotype)
Geneticestimateofthechangeinbirthweight(g),adjusted
forsex,gestationalageandfetalgenotype,per1SD(or10%†)changeinmaternaltrait(95%CI)[N
offspringasinTables1and2]
Pvalue‡comparing
observationalwithgeneticbirth
weightassociations(adjustedfor
fetalgenotype)
Higherpre-pregnancyBMI 4kg/m2
ALSPACMothers,EFSOCHMothers,HAPO
Mothers11,969 62(56,70) 55(17,93) 0.70 104(32,176) 0.28
Higherfastingglucose 0.4mmol/L EFSOCHMothers,HAPO
Mothers 6,008 92(80,104) 114(80,147) 0.28 145(91,199) 0.09
Highertriglycerides 0.7mmol/L EFSOCHMothers 930 32(7,56) -24(-55,8) 0.007 -33(-86,20) 0.03
LowerHDL-cholesterol 0.5mmol/L EFSOCHMothers 927 30(3,58) 0(-33,34) 0.17 -1(-55,54) 0.32
Highersystolicbloodpressure 10mmHg ALSPACMothers,HAPO
Mothers 12,077 24(15,34) -208(-394,-21) 0.01 -151(-390,89) 0.14
LowervitaminDstatus 10%† ALSPACMothers 4,710 -4(-7,-2) -26(-54,2) 0.13 -56(-112,1) 0.07
Loweradiponectin 10%† HAPOMothers(GWASonly) 1,376 14(9,18) -1(-9,7) 0.002 4(-9,17) 0.19
*Heterogeneitystatisticsfromthemeta-analysesofobservationalassociationswere:Phet=0.03andI2=67.7%forBMI;Phet=0.09andI2=59.1%forfastingglucose;Phet=0.54andI2=0%forSBP.† For25[OH]Dandadiponectin,wepresenttheestimatedchangeinbirthweightper10%reductioninmaternaltraitlevelbecausethesevariableswereloggedforanalysis.‡P-values<0.05areconsideredtoindicateevidencethatthegeneticeffectsizeestimateisdifferentfromtheobservationalestimate,suggestingthattheobservationalestimateissubjecttoconfoundingorbias.ALSPAC:AvonLongitudinalStudyofParentsAndChildren33;EFSOCH:ExeterFamilyStudyofChildhoodHealth40;HAPO:HyperglycaemiaandAdversePregnancyOutcomes5;SDstandarddeviation