Discovery and Fine-Mapping of Adiposity Loci Using High Density Imputation of Genome-Wide

28 Pages·2017·3.92 MB·English

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Epidemiology and Environmental Health Faculty
Epidemiology and Environmental Health
Publications
4-21-2017
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IImmppuuttaattiioonn ooff GGeennoommee--WWiiddee AAssssoocciiaattiioonn SSttuuddiieess iinn IInnddiivviidduuaallss ooff
AAffrriiccaann AAnncceessttrryy:: AAffrriiccaann AAnncceessttrryy AAnntthhrrooppoommeettrryy GGeenneettiiccss
CCoonnssoorrttiiuumm
Maggie C. Y. Ng
Wake Forest University
Mariaelisa Graff
University of North Carolina at Chapel Hill
Yingchang Lu
Icachn School of Medicine at Mount Sinai
Follow this and additional works at: https://uknowledge.uky.edu/epidemiology_facpub
Anne E. Justice
Part of the African Studies Commons, Eastern European Studies Commons, Epidemiology Commons,
University of North Carolina at Chapel Hill
and the Genetics and Genomics Commons
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Wake Forest University
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SNege, Mneaxgtg piea gCe. Yfo.;r G ardadffit, iMonaarli aaeulitshao;r Lsu , Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young,
Kristin; Yanek, Lisa R.; Feitosa, Mary F.; Wojczynski, Mary K.; Rand, Kristin; Brody, Jennifer A.; Cade, Brian
E.; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin;
Tajuddin, Salman M.; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chen,
Wei-Min; Chesi, Alessandra; Irvin, Marguerite R.; Padhukasahasram, Badri; Smith, Jennifer A.; Zheng, Wei;
and Arnett, Donna K., "Discovery and Fine-Mapping of Adiposity Loci Using High Density Imputation of
Genome-Wide Association Studies in Individuals of African Ancestry: African Ancestry Anthropometry
Genetics Consortium" (2017). Epidemiology and Environmental Health Faculty Publications. 20.
https://uknowledge.uky.edu/epidemiology_facpub/20
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DDiissccoovveerryy aanndd FFiinnee--MMaappppiinngg ooff AAddiippoossiittyy LLooccii UUssiinngg HHiigghh DDeennssiittyy IImmppuuttaattiioonn ooff
GGeennoommee--WWiiddee AAssssoocciiaattiioonn SSttuuddiieess iinn IInnddiivviidduuaallss ooff AAffrriiccaann AAnncceessttrryy:: AAffrriiccaann
AAnncceessttrryy AAnntthhrrooppoommeettrryy GGeenneettiiccss CCoonnssoorrttiiuumm
Digital Object Identifier (DOI)
https://doi.org/10.1371/journal.pgen.1006719
NNootteess//CCiittaattiioonn IInnffoorrmmaattiioonn
Published in PLOS Genetics, v. 13, 4, e1006719, p. 1-25.
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted,
modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available
under the Creative Commons CC0 public domain dedication.
Due to the large number of authors, only the first 30 and the authors affiliated with the University of
Kentucky are listed in the author section above. For the complete list of authors, please download this
article.
AAuutthhoorrss
Maggie C. Y. Ng, Mariaelisa Graff, Yingchang Lu, Anne E. Justice, Poorva Mudgal, Ching-Ti Liu, Kristin
Young, Lisa R. Yanek, Mary F. Feitosa, Mary K. Wojczynski, Kristin Rand, Jennifer A. Brody, Brian E. Cade,
Latchezar Dimitrov, Qing Duan, Xiuqing Guo, Leslie A. Lange, Michael A. Nalls, Hayrettin Okut, Salman M.
Tajuddin, Bamidele O. Tayo, Sailaja Vedantam, Jonathan P. Bradfield, Guanjie Chen, Wei-Min Chen,
Alessandra Chesi, Marguerite R. Irvin, Badri Padhukasahasram, Jennifer A. Smith, Wei Zheng, and Donna
K. Arnett
This article is available at UKnowledge: https://uknowledge.uky.edu/epidemiology_facpub/20
RESEARCHARTICLE
Discovery and fine-mapping of adiposity loci
using high density imputation of genome-
wide association studies in individuals of
African ancestry: African Ancestry
Anthropometry Genetics Consortium
MaggieC.Y.Ng1,2☯,MariaelisaGraff3☯,YingchangLu4,AnneE.Justice3,PoorvaMudgal2,
a1111111111 Ching-TiLiu5,KristinYoung3,LisaR.Yanek6,MaryF.Feitosa7,MaryK.Wojczynski7,
a1111111111 KristinRand8,JenniferA.Brody9,BrianE.Cade10,11,LatchezarDimitrov1,QingDuan12,
a1111111111 XiuqingGuo13,LeslieA.Lange12,MichaelA.Nalls14,15,HayrettinOkut2,Salman
a1111111111 M.Tajuddin16,BamideleO.Tayo17,SailajaVedantam18,19,JonathanP.Bradfield20,
a1111111111 GuanjieChen21,Wei-MinChen22,AlessandraChesi23,MargueriteR.Irvin24,
BadriPadhukasahasram25,JenniferA.Smith26,WeiZheng27,MatthewA.Allison28,
ChristineB.Ambrosone29,ElisaV.Bandera30,TraciM.Bartz31,SonjaI.Berndt32,
LeslieBernstein33,WilliamJ.Blot34,ErwinP.Bottinger4,JohnCarpten35,Stephen
J.Chanock32,Yii-DerIdaChen13,DavidV.Conti8,RichardS.Cooper17,MyriamFornage36,
BarryI.Freedman37,MelissaGarcia16,PhyllisJ.Goodman38,Yu-HanH.Hsu18,19,39,
OPENACCESS
JenniferHu40,41,ChadD.Huff42,SueA.Ingles8,43,EstherM.John44,45,RickKittles46,
Citation:NgMCY,GraffM,LuY,JusticeAE, EricKlein47,JinLi48,BarbaraMcKnight49,UmaNayak50,BarbaraNemesure51,
MudgalP,LiuC-T,etal.(2017)Discoveryandfine- AdesolaOgunniyi52,AndrewOlshan3,53,MichaelF.Press54,RebeccaRohde3,Benjamin
mappingofadipositylociusinghighdensity A.Rybicki55,BabatundeSalako52,MaureenSanderson56,YamingShao3,David
imputationofgenome-wideassociationstudiesin S.Siscovick57,JanetL.Stanford58,59,VictoriaL.Stevens60,AlexStram8,SaraS.Strom42,
individualsofAfricanancestry:AfricanAncestry DhananjayVaidya6,61,JohnS.Witte62,63,JieYao13,XiaofengZhu64,ReginaG.Ziegler65,
AnthropometryGeneticsConsortium.PLoSGenet AlanB.Zonderman16,AdebowaleAdeyemo21,StefanAmbs66,MaryCushman67,Jessica
13(4):e1006719.https://doi.org/10.1371/journal. D.Faul68,HakonHakonarson20,69,AlbertM.Levin55,KatherineL.Nathanson70,Erin
pgen.1006719 B.Ware26,68,DavidR.Weir68,WeiZhao26,DeguiZhi71,TheBoneMineralDensityin
ChildhoodStudy(BMDCS)Group¶,DonnaK.Arnett72,StruanF.A.Grant20,23,69,73,Sharon
Editor:GregoryP.Copenhaver,TheUniversityof
L.R.Kardia26,OlufunmilayoI.Oloapde74,D.C.Rao75,CharlesN.Rotimi21,Michele
NorthCarolinaatChapelHill,UNITEDSTATES
M.Sale22,L.KeokiWilliams25,76,BabetteS.Zemel69,77,DianeM.Becker6,Ingrid
Received:December8,2016 B.Borecki7,78,MicheleK.Evans16,TamaraB.Harris16,JoelN.Hirschhorn18,19,79,
YunLi12,80,81,SanjayR.Patel82,BruceM.Psaty83,84,JeromeI.Rotter13,85,James
Accepted:March29,2017 G.Wilson86,DonaldW.Bowden1,2,87,L.AdrienneCupples5,88,Christopher
Published:April21,2017 A.Haiman8,43‡*,RuthJ.F.Loos4,89‡*,KariE.North3‡*
Copyright:Thisisanopenaccessarticle,freeofall 1 CenterforGenomicsandPersonalizedMedicineResearch,WakeForestSchoolofMedicine,Winston-
copyright,andmaybefreelyreproduced, Salem,NC,UnitedStatesofAmerica,2 CenterforDiabetesResearch,WakeForestSchoolofMedicine,
distributed,transmitted,modified,builtupon,or Winston-Salem,NC,UnitedStatesofAmerica,3 DepartmentofEpidemiology,UniversityofNorthCarolina,
otherwiseusedbyanyoneforanylawfulpurpose. ChapelHill,NC,UnitedStatesofAmerica,4 TheCharlesBronfmanInstituteforPersonalizedMedicine,
IcachnSchoolofMedicineatMountSinai,NewYork,NY,UnitedStatesofAmerica,5 Departmentof
TheworkismadeavailableundertheCreative
Biostatistics,BostonUniversitySchoolofPublicHealth,Boston,MA,UnitedStatesofAmerica,6 Department
CommonsCC0publicdomaindedication.
ofMedicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,UnitedStatesofAmerica,
DataAvailabilityStatement:Allrelevantdataare 7 DivisionofStatisticalGenomics,DepartmentofGenetics,WashingtonUniversitySchoolofMedicine,
withinthepaperanditsSupportingInformation St.LouisMO,UnitedStatesofAmerica,8 DepartmentofPreventiveMedicine,KeckSchoolofMedicine,
UniversityofSouthernCalifornia,LosAngeles,CA,UnitedStatesofAmerica,9 CardiovascularHealth
files.Summaryassociationstatisticsfrommeta-
ResearchUnit,DepartmentofMedicine,UniversityofWashington,Seattle,WA,UnitedStatesofAmerica,
analysesareavailablefromdbGAPataccession
10 DivisionofSleepandCircadianDisorders,BrighamandWomen’sHospital,Boston,MA,UnitedStatesof
numberphs000930.
America,11 HarvardMedicalSchool,Boston,MA,UnitedStatesofAmerica,12 DepartmentofGenetics,
Funding:AABC-MEC:TheMECandgenotypingof UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,UnitedStatesofAmerica,13 Institutefor
TranslationalGenomicsandPopulationSciences,LosAngelesBiomedicalResearchInstituteatHarbor-
samplesfortheGWASofbreastandprostate
UCLAMedicalCenter,Torrance,CA,UnitedStatesofAmerica,14 LaboratoryofNeurogenetics,National
cancerwassupportedbyNationalInstitutesof
InstituteonAging,NationalInstitutesofHealth,Bethesda,MD,UnitedStatesofAmerica,15 DataTecnica
HealthgrantsCA63464,CA54281,CA164973,
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 1/25
GWASforadiposityinAfricanancestry
CA1326792,CA148085,HG004726anda International,GlenEcho,MD,UnitedStatesofAmerica,16 NationalInstituteonAging,NationalInstitutesof
DepartmentofDefenseBreastCancerResearch Health,Baltimore,MD,UnitedStatesofAmerica,17 DepartmentofPublicHealthSciences,StritchSchoolof
ProgramEraofHopeScholarAwardtoCAH Medicine,LoyolaUniversityChicago,Maywood,IL,UnitedStatesofAmerica,18 DivisionofEndocrinology
(W81XWH-08-1-0383)andtheNorrisFoundation. andCenterforBasicandTranslationalObesityResearch,BostonChildren’sHospital,Boston,MA,United
StatesofAmerica,19 BroadInstituteofMITandHarvard,Cambridge,MA,UnitedStatesofAmerica,
AABC-CARE:CAREwassupportedbyNational
20 CenterforAppliedGenomics,TheChildren’sHospitalofPhiladelphia,Philadelphia,PA,UnitedStatesof
InstituteforChildHealthandDevelopmentcontract
America,21 CenterforResearchonGenomicsandGlobalHealth,NationalHumanGenomeResearch
NO1-HD-3-3175.AABC-WCHS:WCHSis
Institute,NationalInstitutesofHealth,Bethesda,MD,UnitedStatesofAmerica,22 DepartmentofPublic
supportedbyaU.S.ArmyMedicalResearchand
HealthSciencesandCenterforPublicHealthGenomics,UniversityofVirginiaSchoolofMedicine,
MaterialCommand(USAMRMC)grantDAMD-17- Charlottesville,VA,UnitedStatesofAmerica,23 DivisionofHumanGenetics,TheChildren’sHospitalof
01-0-0334,NationalInstitutesofHealthgrant Philadelphia,Philadelphia,PA,UnitedStatesofAmerica,24 DepartmentofEpidemiology,Universityof
CA100598,andtheBreastCancerResearch AlabamaatBirmingham,Birmingham,AL,UnitedStatesofAmerica,25 CenterforHealthPolicyandHealth
Foundation.AABC-SFBCS:SFBCSwassupported ServicesResearch,HenryFordHealthSystem,Detroit,MI,UnitedStatesofAmerica,26 Departmentof
byNationalInstitutesofHealthgrantCA77305and Epidemiology,UniversityofMichigan,AnnArbor,MI,UnitedStatesofAmerica,27 DivisionofEpidemiology,
UnitedStatesArmyMedicalResearchProgram DepartmentofMedicine,VanderbiltEpidemiologyCenter,VanderbiltUniversitySchoolofMedicine,
Nashville,TN,UnitedStatesofAmerica,28 DivisionofPreventiveMedicine,DepartmentofFamilyMedicine
grantDAMD17-96-6071.AABC-NC-BCFR:The
andPublicHealth,UniversityofCaliforniaSanDiego,LaJolla,CA,UnitedStatesofAmerica,29 Department
BreastCancerFamilyRegistry(BCFR)was
ofCancerPreventionandControl,RoswellParkCancerInstitute,Buffalo,NY,UnitedStatesofAmerica,
supportedbytheNationalCancerInstitute,National
30 DepartmentofPopulationScience,RutgersCancerInstituteofNewJersey,NewBrunswick,NJ,United
InstitutesofHealthunderRFACA-06-503and
StatesofAmerica,31 CardiovascularHealthResearchUnit,DepartmentsofMedicineandBiostatistics,
throughcooperativeagreementswithmembersof UniversityofWashington,Seattle,WA,UnitedStatesofAmerica,32 DivisionofCancerEpidemiologyand
theBreastCancerFamilyRegistryandPrincipal Genetics,NationalCancerInstitute,Rockville,MD,UnitedStatesofAmerica,33 BeckmanResearchInstitute
Investigators,includingtheCancerPrevention oftheCityofHope,Duarte,CA,UnitedStatesofAmerica,34 InternationalEpidemiologyInstitute,Rockville,
InstituteofCalifornia(U01CA69417).Thecontent MD,UnitedStatesofAmerica,35 DepartmentofTranslationalGenomics,KeckSchoolofMedicine,
ofthismanuscriptdoesnotnecessarilyreflectthe UniversityofSouthernCalifornia,LosAngeles,CA,UnitedStatesofAmerica,36 CenterforHuman
viewsorpoliciesoftheNationalCancerInstituteor Genetics,UniversityofTexasHealthScienceCenteratHouston,Houston,TX,UnitedStatesofAmerica,
37 DepartmentofInternalMedicine,WakeForestSchoolofMedicine,Winston-Salem,NC,UnitedStatesof
anyofthecollaboratingcentersintheBCFR,nor
America,38 SWOGStatisticalCenter,FredHutchinsonCancerResearchCenter,Seattle,WA,United
doesmentionoftradenames,commercial
StatesofAmerica,39 PrograminBioinformaticsandIntegrativeGenomics,HarvardMedicalSchool,Boston,
products,ororganizationsimplyendorsementby
MA,UnitedStatesofAmerica,40 SylvesterComprehensiveCancerCenter,UniversityofMiamiLeonard
theU.S.GovernmentortheBCFR.AABC-CBCS:
MillerSchoolofMedicine,Miami,FL,UnitedStatesofAmerica,41 DepartmentofPublicHealthSciences,
CBCSissupportedbyNationalInstitutesofHealth UniversityofMiamiLeonardMillerSchoolofMedicine,Miami,FL,UnitedStatesofAmerica,42 Department
SpecializedProgramofResearchExcellencein ofEpidemiology,UniversityofTexasM.D.AndersonCancerCenter,Houston,TX,UnitedStatesofAmerica,
BreastCancergrantCA58223andCenterfor 43 NorrisComprehensiveCancerCenter,UniversityofSouthernCalifornia,LosAngeles,CA,United
EnvironmentalHealthandSusceptibility,National StatesofAmerica,44 CancerPreventionInstituteofCalifornia,Fremont,CA,UnitedStatesofAmerica,
InstituteofEnvironmentalHealthSciences, 45 DepartmentofHealthResearchandPolicy(Epidemiology)andStanfordCancerInstitute,Stanford
NationalInstitutesofHealth,grantES10126. UniversitySchoolofMedicine,Stanford,CA,UnitedStatesofAmerica,46 DivisionofUrology,Departmentof
Surgery,TheUniversityofArizona,Tucson,AZ,UnitedStatesofAmerica,47 GlickmanUrologicaland
AABC-PLCO:GenotypingofthePLCOsampleswas
KidneyInstitute,ClevelandClinic,Cleveland,OH,UnitedStatesofAmerica,48 DivisionofCardiovascular
fundedbytheIntramuralResearchProgramofthe
Medicine,DepartmentofMedicine,StanfordUniversitySchoolofMedicine,PaloAlto,CA,UnitedStatesof
DivisionofCancerEpidemiologyandGenetics,
America,49 CardiovascularHealthResearchUnit,DepartmentofBiostatistics,UniversityofWashington,
NationalCancerInstitute,theNationalInstitutesof
Seattle,WA,UnitedStatesofAmerica,50 CenterforPublicHealthGenomics,UniversityofVirginiaSchoolof
Health.TheauthorsthankDrs.ChristineBergand Medicine,Charlottesville,VA,UnitedStatesofAmerica,51 DepartmentofPreventiveMedicine,StonyBrook
PhilipProrok,DivisionofCancerPrevention, University,StonyBrook,NY,UnitedStatesofAmerica,52 DepartmentofMedicine,UniversityofIbadan,
NationalCancerInstitute,thescreeningcenter Ibadan,Nigeria,53 LinebergerComprehensiveCancerCenter,UniversityofNorthCarolina,ChapelHill,
investigatorsandstaffofthePLCOCancer ChapelHill,NC,UnitedStatesofAmerica,54 DepartmentofPathologyandNorrisComprehensiveCancer
ScreeningTrial,Mr.ThomasRileyandstaffat Center,UniversityofSouthernCaliforniaKeckSchoolofMedicine,LosAngeles,CA,UnitedStatesof
InformationManagementServices,Inc.,andMs. America,55 DepartmentofPublicHealthSciences,HenryFordHealthSystem,Detroit,MI,UnitedStatesof
America,56 DepartmentofFamilyandCommunityMedicine,MeharryMedicalCollege,Nashville,TN,
BarbaraO’BrienandstaffatWestat,Inc.fortheir
UnitedStatesofAmerica,57 TheNewYorkAcademyofMedicine,NewYork,NY,UnitedStatesofAmerica,
contributionstothePLCOCancerScreeningTrial.
58 DivisionofPublicHealthSciences,FredHutchinsonCancerResearchCenter,Seattle,WA,UnitedStates
AABC-NBHS:NBHSissupportbyNational
ofAmerica,59 DepartmentofEpidemiology,SchoolofPublicHealth,UniversityofWashington,Seattle,WA,
InstitutesofHealthgrantCA100374.NBHSsample
UnitedStatesofAmerica,60 EpidemiologyResearchProgram,AmericanCancerSociety,Atlanta,GA,
preparationwasconductedattheBiospecimen UnitedStatesofAmerica,61 DepartmentofEpidemiology,BloombergSchoolofPublicHealth,Baltimore,
CoreLabthatissupportedinpartbythe MD,UnitedStatesofAmerica,62 DepartmentofEpidemiologyandBiostatistics,UniversityofCalifornia,San
Vanderbilt-IngramCancerCenter(CA68485). Francisco,SanFrancisco,CA,UnitedStatesofAmerica,63 InstituteforHumanGenetics,Universityof
AABC-WFBC:WFBCissupportedbyNational California,SanFrancisco,SanFrancisco,CA,UnitedStatesofAmerica,64 DepartmentofEpidemiologyand
InstitutesofHealthgrantCA73629.AAPC-CPS-II: Biostatistics,CaseWesternReserveUniversity,Cleveland,OH,UnitedStatesofAmerica,65 Divisionof
CPSIIissupportedbytheAmericanCancer CancerEpidemiologyandGenetics,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,MD,
UnitedStatesofAmerica,66 LaboratoryofHumanCarcinogenesis,NationalCancerInstitute,Bethesda,MD,
Society.AAPC-KCPCS:KCPCSwassupportedby
UnitedStatesofAmerica,67 DepartmentofMedicine,UniversityofVermontCollegeofMedicine,Burlington,
NationalInstitutesofHealthgrantsCA056678,
VT,UnitedStatesofAmerica,68 SurveyResearchCenter,InstituteforSocialResearch,Universityof
CA082664andCA092579,withadditionalsupport
Michigan,AnnArbor,MI,UnitedStatesofAmerica,69 DepartmentofPediatrics,PerelmanSchoolof
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 2/25
GWASforadiposityinAfricanancestry
fromtheFredHutchinsonCancerResearchCenter. Medicine,UniversityofPennsylvania,Philadelphia,PA,UnitedStatesofAmerica,70 Departmentof
AAPC-LAAPC:LAAPCwasfundedbygrant99- Medicine,UniversityofPennsylvania,Philadelphia,PA,UnitedStatesofAmerica,71 SchoolofBiomedical
00524V-10258fromtheCancerResearchFund, Informatics,UniversityofTexasHealthScienceCenteratHouston,Houston,TX,UnitedStatesofAmerica,
underInteragencyAgreement#97-12013 72 SchoolofPublicHealth,UniversityofKentucky,Lexington,KY,UnitedStatesofAmerica,73 Division
ofEndocrinology,TheChildren’sHospitalofPhiladelphia,Philadelphia,PA,UnitedStatesofAmerica,
(UniversityofCaliforniacontract#98-00924V)with
74 CenterforClinicalCancerGenetics,DepartmentofMedicineandHumanGenetics,Universityof
theDepartmentofHealthServicesCancer
Chicago,Chicago,IL,UnitedStatesofAmerica,75 DivisionofBiostatistics,WashingtonUniversitySchool
ResearchProgram.AAPC-DCPC:DCPCwas
ofMedicine,St.Louis,MO,UnitedStatesofAmerica,76 DepartmentofInternalMedicine,HenryFord
supportedbyNationalInstitutesofHealthgrant
HealthSystem,Detroit,MI,UnitedStatesofAmerica,77 DivisionofGastroenterology,Hepatologyand
S06GM08016andDepartmentofDefensegrants Nutrition,TheChildren’sHospitalofPhiladelphia,Philadelphia,PA,UnitedStatesofAmerica,78 Regeneron
DAMDW81XWH-07-1-0203andDAMD GeneticsCenter,RegeneronPharmaceuticals,Inc,UnitedStatesofAmerica,79 DepartmentsofGenetics
W81XWH-06-1-0066.AAPC-MEC:TheMECand andPediatrics,HarvardMedicalSchool,Boston,MA,UnitedStatesofAmerica,80 Departmentof
genotypingofsamplesfortheGWASofprostate Biostatistics,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,UnitedStatesofAmerica,
cancerwassupportedbyNationalInstitutesof 81 DepartmentofComputerScience,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC,United
HealthgrantsCA63464,CA54281,CA164973, StatesofAmerica,82 DepartmentofMedicine,UniversityofPittsburgh,Pittsburgh,PA,UnitedStatesof
America,83 CardiovascularHealthResearchUnit,DepartmentsofMedicine,Epidemiology,andHealth
CA1326792,CA148085andHG004726.AAPC-
Services,UniversityofWashington,Seattle,WA,UnitedStatesofAmerica,84 KaiserPermanente
SELECTtrial:TheSELECTtrialissupportedby
WashingtonHealthResearchInstitute,Seattle,WA,UnitedStatesofAmerica,85 DivisionofGenomic
NationalCancerInstitutegrantsU10CA37429and
Outcomes,DepartmentsofPediatricsandMedicine,LosAngelesBiomedicalResearchInstituteatHarbor-
5UM1CA182883.AAPC-PLCO:SeeAABC-PLCO.
UCLAMedicalCenter,LosAngeles,CA,UnitedStatesofAmerica,86 DepartmentofPhysiologyand
AAPC-GECAP:GECAPwassupportedbyNational Biophysics,UniversityofMississippiMedicalCenter,Jackson,MS,UnitedStatesofAmerica,87 Department
InstitutesofHealthgrantES011126.AAPC-SCCS: ofBiochemistry,WakeForestSchoolofMedicine,Winston-Salem,NC,UnitedStatesofAmerica,88 NHLBI
SCCSisfundedbyNationalInstitutesofHealth FraminghamHeartStudy,Framingham,MA,UnitedStatesofAmerica,89 TheMindichChildHealthand
grantCA092447.SCCSsamplepreparationwas DevelopmentInstitute,IchanSchoolofMedicineatMountSinai,NewYork,NY,UnitedStatesofAmerica
conductedattheBiospecimenCoreLabthatis
supportedinpartbytheVanderbilt-IngramCancer ☯Theseauthorscontributedequallytothiswork.
‡Theseauthorsjointlysupervisedthiswork.
Center(CA68485).AAPC-MDA:MDAwassupport
¶FullmembershipoftheBoneMineralDensityinChildhoodStudy(BMDCS)GroupisprovidedinS2Text.
bygrantsCA68578,ES007784,DAMDW81XWH-
*[email protected](CAH);[email protected](RJFL);[email protected](KEN)
07-1-0645,andCA140388.AAPC-CaPGenes:CaP
GeneswassupportedbyCA88164andCA127298.
ARIC:TheAtherosclerosisRiskinCommunities
Abstract
Studyiscarriedoutasacollaborativestudy
supportedbyNationalHeart,Lung,andBlood
Institutecontracts(HHSN268201100005C, Genome-wideassociationstudies(GWAS)haveidentified>300lociassociatedwithmea-
HHSN268201100006C,HHSN268201100007C,
suresofadiposityincludingbodymassindex(BMI)andwaist-to-hipratio(adjustedforBMI,
HHSN268201100008C,HHSN268201100009C,
WHR ),butfewhavebeenidentifiedthroughscreeningoftheAfricanancestry
HHSN268201100010C,HHSN268201100011C, adjBMI
andHHSN268201100012C),R01HL087641, genomes.Weperformedlargescalemeta-analysesandreplicationsinupto52,895individ-
R01HL59367andR01HL086694;NationalHuman ualsforBMIandupto23,095individualsforWHR fromtheAfricanAncestryAnthro-
adjBMI
GenomeResearchInstitutecontract
pometryGeneticsConsortium(AAAGC)using1000Genomesphase1imputedGWASto
U01HG004402;andNationalInstitutesofHealth
improvecoverageofbothcommonandlowfrequencyvariantsinthelowlinkagedisequilib-
contractHHSN268200625226C.Theauthorsthank
thestaffandparticipantsoftheARICstudyfortheir riumAfricanancestrygenomes.Inthesex-combinedanalyses,weidentifiedonenovel
importantcontributions.Infrastructurewaspartly locus(TCF7L2/HABP2)forWHR andeightpreviouslyestablishedlociatP<5×10−8:
adjBMI
supportedbyGrantNumberUL1RR025005,a
sevenforBMI,andoneforWHR inAfricanancestryindividuals.Anadditionalnovel
componentoftheNationalInstitutesofHealthand adjBMI
NIHRoadmapforMedicalResearch.BioMe:NIH/ locus(SPRYD7/DLEU2)wasidentifiedforWHRadjBMIwhencombinedwithEuropean
NHGRIU01HG007417.BMDCS:Wethankthe GWAS.Inthesex-stratifiedanalyses,weidentifiedthreenovellociforBMI(INTS10/LPL
investigatorsHeidiKalkwarf,JoanLappe,Sharon
andMLC1inmen,IRX4/IRX2inwomen)andfourforWHR (SSX2IP,CASC8,PDE3B
adjBMI
Oberfield,VicenteGilsanz,JohnShepherdand
andZDHHC1/HSD11B2inwomen)inindividualsofAfricanancestryorbothAfricanand
AndreaKellyfortheircontribution.BMDCSis
supportedbyNIH:R01HD58886,HD076321, Europeanancestry.Forfourofthenovelvariants,theminorallelefrequencywaslow(<5%).
DK094723-01,DK102659-01;NICHDN01-HD-1- Inthetrans-ethnicfinemappingof47BMIlociand27WHR locithatwerelocus-wide
adjBMI
3228,-3329,-3330,-3331,-3332,-3333;CTSA
significant(P<0.05adjustedforeffectivenumberofvariantsperlocus)fromtheAfrican
programGrant8UL1TR000077.CARDIA:The
ancestrysex-combinedandsex-stratifiedanalyses,26BMIlociand17WHR locicon-
CoronaryArteryRiskDevelopmentinYoungAdults adjBMI
(CARDIA)studyissupportedbytheNHLBI tained(cid:20)20variantsinthecrediblesetsthatjointlyaccountfor99%posteriorprobabilityof
(contractsHHSN268201300025C, drivingtheassociations.Theleadvariantsin13oftheselocihadahighprobabilityofbeing
HHSN268201300026C,HHSN268201300027C,
causal.AscomparedtoourpreviousHapMapimputedGWASforBMIandWHR
adjBMI
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 3/25
GWASforadiposityinAfricanancestry
HHSN268201300028C,HHSN268201300029C, includingupto71,412and27,350Africanancestryindividuals,respectively,ourresultssug-
andHHSN268200900041C);theIntramural gestthat1000GenomesimputationshowedmodestimprovementinidentifyingGWASloci
ResearchProgramoftheNationalInstituteon
includinglowfrequencyvariants.Trans-ethnicmeta-analysesfurtherimprovedfinemapping
Aging(NIA);andanintra-agencyagreement
betweentheNIAandtheNHLBI(grantAG0005). ofputativecausalvariantsinlocisharedbetweentheAfricanandEuropeanancestry
CFS:TheClevelandFamilyStudy(CFS)is populations.
supportedbytheNationalInstitutesofHealth:
HL046380,HL113338,RR000080.Dr.Cadehas
beensupportedbyHL007901.CHOP:This
researchwasfinanciallysupportedbyanInstitute
DevelopmentAwardfromtheChildren’sHospitalof Authorsummary
Philadelphia,aResearchDevelopmentAwardfrom
theCotswoldFoundation,NIHgrantR01 Genome-wideassociationstudies(GWAS)haveidentified>300geneticregionsthat
HD056465andtheDanielB.BurkeEndowedChair influencebodysizeandshapeasmeasuredbybodymassindex(BMI)andwaist-to-hip
forDiabetesResearch(SFAG).CHS:ThisCHS ratio(WHR),respectively,butfewhavebeenidentifiedinpopulationsofAfricanancestry.
researchwassupportedbyNHLBIcontracts
WeconductedlargescalehighcoverageGWASandreplicationofthesetraitsin52,895
HHSN268201200036C,HHSN268200800007C,
and23,095individualsofAfricanancestry,respectively,followedbyadditionalreplication
N01HC55222,N01HC85079,N01HC85080,
inEuropeanpopulations.Weidentified10genome-widesignificantlociinallindividuals,
N01HC85081,N01HC85082,N01HC85083,
N01HC85086;andNHLBIgrantsU01HL080295, andanadditionalsevenlocibyanalyzingmenandwomenseparately.WecombinedAfri-
R01HL085251,R01HL087652,R01HL105756, canandEuropeanancestryGWASandwereabletonarrowdown43outof74African
R01HL103612,R01HL120393andHL130114with ancestryassociatedgeneticregionstocontainsmallnumberofputativecausalvariants.
additionalcontributionfromtheNationalInstitute
Ourresultshighlighttheimprovementofapplyinghighdensitygenomecoverageand
ofNeurologicalDisordersandStroke(NINDS).
combiningmultipleancestriesintheidentificationandrefinementoflocationofgenetic
Additionalsupportwasprovidedthrough
R01AG023629fromtheNationalInstituteonAging regionsassociatedwithadipositytraits.
(NIA).AfulllistofprincipalCHSinvestigatorsand
institutionscanbefoundatCHS-NHLBI.org.The
provisionofgenotypingdatawassupportedinpart
bytheNationalCenterforAdvancingTranslational Introduction
Sciences,CTSIgrantUL1TR000124,andthe
NationalInstituteofDiabetesandDigestiveand Obesityisaworldwidepublichealthepidemic,withcurrentUSestimatesof37.9%obeseand
KidneyDiseaseDiabetesResearchCenter(DRC) 7.7%morbidlyobeseadults[1].Disparitiesinobesityrates,aswellasratesofcomorbidities
grantDK063491totheSouthernCalifornia andmortality,areevidentacrosssexandracial/ethnicgroups.EstimatesfromNHANESfor
DiabetesEndocrinologyResearchCenter.
2013–2014[1]showthatobesityismoreprevalentamongAfricanAmericans(48.5%)than
Participantsprovidedinformedconsentfor
amongnon-HispanicWhites(37.1%).Inaddition,obesityratesarehigheramongAfrican
participationinDNAstudies.Thecontentissolely
Americanwomen(57.2%)thanamongAfricanAmericanmen(38.2%).Forcomparison,the
theresponsibilityoftheauthorsanddoesnot
necessarilyrepresenttheofficialviewsofthe obesityratesinnon-HispanicWhiteswere38.7%and35.4%,respectively,forwomenand
NationalInstitutesofHealth.FamHS:NIH/NIDDK men.
R01DK089256,andNIH/NHLBIR01HL117078. Genome-wideassociationstudies(GWAS)indiversepopulationshaveidentified>300
GeneSTAR:NIH/NHLBIU01HL72518;NIH/NHLBI
lociassociatedwithmeasuresofadiposityincludingbodymassindex(BMI)andwaist-to-hip
HL087698;NIH/NHLBI58625-01A1;NIH/NHLBI
ratio(adjustedforBMI,WHR )inpopulationsofEuropean[2–9],African[10–12],and
HL071025-01A1;NIH/NINRNR0224103;NIH/ adjBMI
NCRRM01-RR000052.HANDLS:HealthyAgingin EastAsianancestry[13–15].Themajorityofassociatedvariantsarecommon(MAF>5%)
NeighborhoodsofDiversityacrosstheLifeSpan withsmalleffectsize,andjointlyexplainonlyafractionofthephenotypicvariances[7–8].It
Study(HANDLS)wassupportedbytheIntramural haslongbeenhypothesizedthatlowfrequency(MAF=0.5–5%)andrare(MAF<0.5%)vari-
ResearchProgramoftheNIH,NationalInstituteon
antsmayalsocontributetovariabilityincomplextraits.However,thesevariantsarenotwell
AgingandtheNationalCenteronMinorityHealth
capturedinpreviousGWASimputedtotheHapMapreferencepanel[16–17].Theavailability
andHealthDisparities(project#Z01-AG000513
ofhigherdensityreferencepanelssuchasthe1000GenomesProject(38Mvariantsin1092
andhumansubjectsprotocol#2009-149).
HealthABC:Health,Aging,andBodyComposition individualsfromphase1)[18]hasdemonstratedimprovedimputationqualityinEuropean
Study(HealthABCStudy)wassupportedbyNIA populationsparticularlyforlowfrequencyvariants(aggregateR2~0.6forMAF=0.5%).How-
contractsN01AG62101,N01AG62103,and everitsimpactislessclearfornon-Europeanpopulations[19].Wetookthisopportunityto
N01AG62106.Thegenome-wideassociationstudy
usehigherdensityimputationtoreevaluateourpreviousGWASforassociationswithanthro-
wasfundedbyNIAgrant1R01AG032098-01A1to
pometrictraitsinindividualsofAfricanancestry(AA)includingAfricanAmericansand
WakeForestUniversityHealthSciencesand
Africans.
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 4/25
GWASforadiposityinAfricanancestry
genotypingserviceswereprovidedbytheCenter TheAfricanAncestryAnthropometryGeneticsConsortium(AAAGC)previouslyidenti-
forInheritedDiseaseResearch(CIDR).CIDRis fiedsevengenome-widesignificantlociforBMIinupto71,412AAindividuals,andanaddi-
fullyfundedthroughafederalcontractfromthe
tionallocuswhencombinedwithEuropeanancestry(EA)datafromtheGeneticInvestigation
NationalInstitutesofHealthtoTheJohns
ofANthropometricTraits(GIANT)consortiumusingGWASimputedtotheHapMapPhase
HopkinsUniversity,contractnumber
2referencepanel[11].Nogenome-widesignificantlociwereidentifiedforWHR ina
HHSN268200782096C.Thisresearchwas adjBMI
supportedinpartbytheIntramuralResearch GWASofupto27,350AAindividuals[12].ThelowyieldofdiscoveryinAAstudiesislikely
ProgramoftheNIH,NationalInstituteonAging. duetotheirrelativelysmallersamplesizesincomparisontoEAstudies[7–8],aswellastheir
HRS:HRSissupportedbytheNationalInstituteon lowerdegreeoflinkagedisequilibrium(LD)andthuspoorerimputationquality.Here,we
Aging(NIAU01AG009740).Thegenotypingwas
extendedourpreviousworkintheAAAGCtoperformmeta-analysesandreplicationof
fundedseparatelybytheNationalInstituteon
GWASimputedtothe1000Genomesreferencepanelinupto52,895AAindividualsforBMI
Aging(RC2AG036495,RC4AG039029),andthe
analysiswasfundedinpartbyR03AG046389.Our andupto23,095AAindividualsforWHRadjBMI.Weaimedto1)discovernovelvariants,2)
genotypingwasconductedbytheNIHCenterfor finemapestablishedloci,and3)evaluatethecoverageandcontributionoflowfrequencyvari-
InheritedDiseaseResearch(CIDR)atJohns antsingeneticassociationsinAApopulations.
HopkinsUniversity.Genotypingqualitycontroland
finalpreparationofthedatawereperformedbythe
Results
GeneticsCoordinatingCenterattheUniversityof
Washington.HUFS:TheHUFS(HowardUniversity Studyoverview
FamilyStudy)wassupportedbygrants
Weconductedsex-combinedandsex-stratifiedmeta-analysesofGWASsummarystatistics
S06GM008016-380111toAAandS06GM008016-
320107toCR,bothfromtheNIGMS/MBRS/ across17studiesforBMI(N=42,752)and10studiesforWHR (N=20,384)inAAindi-
adjBMI
SCOREProgram.Participantenrollmentforthe vidualsinstage1discovery(S1andS2Tables,S1Fig).Missinggenotypesinindividualstudies
HUFSwascarriedoutattheHowardUniversity wereimputedtothe1000GenomesProjectcosmopolitanreferencepanel(PhaseIIntegrated
GeneralClinicalResearchCenter(GCRC),which
ReleaseVersion3,March2012)[18]usingMaCH/minimac[20]orSHAPEIT2/IMPUTEv2
wassupportedbygrant2M01RR010284fromthe
[21–22](S3Table).AmongallvariantswithMAF(cid:21)0.1%inthelargestWomen’sHealthIni-
NationalCenterforResearchResources(NCRR),a
componentoftheNationalInstitutesofHealth tiative(WHI)study,theaverageinfoscorewas0.81and90.5%hadimputationinfoscore(cid:21)
(NIH).Thisresearchwassupportedinpartbythe 0.3(S4Table).Genomiccontrolcorrectionswereappliedtoeachstudyandaftermeta-analysis
NIHIntramuralResearchProgramintheCenterfor (λ=1.07forBMI,1.01forWHR )(S3Table,S2–S5Figs).Associationresultsfor~18M
adjBMI
ResearchonGenomicsandGlobalHealth
variantsforBMIand~21MvariantsforWHR weresubsequentlyinterrogatedfurther.
(CRGGH)withsupportfromtheNationalHuman adjBMI
Fromstage1meta-analyses,variantsassociatedwithBMI(3,241inall,1,498inmen,2,922
GenomeResearchInstitute,theNationalInstitute
ofDiabetesandDigestiveandKidneyDiseases,the inwomen)andWHRadjBMI(2,496inall,1,408inmen,2,827inwomen)atP<1×10−4were
CenterforInformationTechnology,andtheOffice carriedforwardforreplicationinAAandEA.Stage2included10,143AA(2,458menand
oftheDirectorattheNationalInstitutesofHealth 7,685women)forBMIand2,711AA(981menand1,730women)forWHR analyses.
adjBMI
(Z01HG200362).HyperGEN:TheHyperGEN Stage3included322,154EA(152,893menand171,977women)forBMIand210,086EA
networkisfundedbycooperativeagreements
(104,079menand116,742women)forWHR analysesbyimputingHapMapsummary
(U10)withNHLBI:HL54471,HL54472,HL54473, adjBMI
statisticsresults[7–8]to1000Genomes[23](S1Fig).Meta-analyseswereperformedtocom-
HL54495,HL54496,HL54497,HL54509,
HL54515,andR01HL55673fromtheNational bineeithersex-combinedorsex-specificresultsfromAA(stages1+2,N(cid:20)57,895forBMI,(cid:20)
Heart,Lung,andBloodInstitute.Thestudy 23,095forWHR insex-combinedanalyses)andbothAAandEA(stages1+2+3,N(cid:20)
adjBMI
involves:UniversityofUtah:(NetworkCoordinating 380,049forBMI,(cid:20)233,181forWHR insex-combinedanalyses,S6–S9Figs).Variants
adjBMI
Center,FieldCenter,andMolecularGeneticsLab); thatreachedgenome-widestatisticalsignificance(P<5×10−8)wereassessedforgeneralization
Univ.ofAlabamaatBirmingham:(FieldCenterand
ofassociationswithBMItochildrenintwoadditionalAAcohorts(N=7,222).
EchoCoordinatingandAnalysisCenter);Medical
CollegeofWisconsin:(EchoGenotypingLab);
BostonUniversity:(FieldCenter);Universityof Genome-widesignificantlociinmeta-analyses
Minnesota:(FieldCenterandBiochemistryLab);
Sex-combinedanalyses. Inthesex-combinedmeta-analysisofBMIinAA,sevenprevi-
UniversityofNorthCarolina:(FieldCenter);
WashingtonUniversity:(DataCoordinatingCenter); ouslyestablishedEuropeanorAfricanancestry-derivedlociin/nearSEC16B,TMEM18,
WeilCornellMedicalCollege:(EchoReading GNPDA2,GALNT10,KLHL32,FTOandMC4Rreachedgenome-widesignificance(P<
Center);NationalHeart,Lung,&BloodInstitute. 5×10−8)(Table1,S6andS10AFigs).Thers7708584variantatGALNT10hadthelowest
ForacompletelistofHyperGENInvestigators: P-value(P=4.2×10−14)andwasthesameleadvariantasreportedinourpreviousAAstudy
http://www.biostat.wustl.edu/hypergen/
(S5Table)[11].TheassociationatKLHL32wasspecifictotheAApopulationastheleadvari-
Acknowledge.html.JHS:TheJacksonHeartStudy
antwasnotstatisticallysignificantinEA(P>0.05),consistentwithourpreviousfinding(S5
issupportedbycontractsHHSN268201300046C,
Table)[11].NoadditionalnovelBMIlociwereidentifiedaftermeta-analysisofAAandEA
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 5/25
GWASforadiposityinAfricanancestry
HHSN268201300047C,HHSN268201300048C, data.TwopreviouslyreportedlociinAA,ADCY3andMIR148A-NFE2L3[11],didnotreach
HHSN268201300049C,HHSN268201300050C genome-widesignificanceinthepresentstudy.Thepreviouslyreportedleadvariantat
fromtheNationalHeart,Lung,andBloodInstitute ADCY3,rs7586879,showedweakereffectandassociationinAA(effect=0.047,P=3.60×10−8
andtheNationalInstituteonMinorityHealthand
[11]vs.effect=0.032,P=1.05×10−4,thisstudy).Ontheotherhand,amoderatelycorrelated
HealthDisparities.JGWissupportedby
U54GM115428fromtheNationalInstituteof (r2=0.52inAFR)variant,rs10203482,showstrongerassociationatP=3.35×10−7(S5Table).
GeneralMedicalSciences.Maywood:NIH:R37- AtMIR148A/NFE2L3,thepreviouslyreportedleadvariantidentifiedbymeta-analysisofAA
HL045508,R01-HL074166,R01-HL086718,R01- andEA,rs10261878,alsoshowedweakerassociationinthecurrentstudyprimarilydueto
HG003054;analysisalsofundedthroughR01- weakassociationinEA(P=4.10×10−5inAA,4.69×10−3inEAand2.10×10−5inAA+EA)(S5
DK075787.MESA:TheMulti-EthnicStudyof
Table).ForWHR ,anestablishedlocus(ADAMTS9-AS2)(S10BFig)andanovellocus
Atherosclerosisstudy(MESA)wassupportedby adjBMI
(TCF7L2/HABP2)(Fig1A)showedsignificantassociations,thelatterleadvariantrs116718588
theMulti-EthnicStudyofAtherosclerosis(MESA)
contractsN01-HC-95159,N01-HC-95160,N01- waslowfrequency(MAF=0.045,Table1).Meta-analysesincludingbothAAandEAindivid-
HC-95161,N01-HC-95162,N01-HC-95163,N01- ualsrevealedanadditionalnovellocusatSPRYD7/DLEU2forWHR (Table1,Fig1Aand
adjBMI
HC-95164,N01-HC-95165,N01-HC-95166,N01- S7Fig).Overall,alltheBMIassociatedleadvariantswerepresentinHapMapandwereinhigh
HC-95167,N01-HC-95168,N01-HC-95169andby LD(r2>0.5in1000GenomesAFRpopulation)withtheleadvariantsinourpreviousHap-
grantsUL1-TR-000040andUL1-RR-025005from
Mapimputeddata,exceptforTMEM18rs62105306(r2=0.17)whichisabsentinHapMap.In
NCRR.FundingforMESASHARegenotypingwas
contrast,allthreeWHR leadvariantswereabsentinHapMapandtheleadvariantsat
providedbyNHLBIContractN02-HL-6-4278.The adjBMI
provisionofgenotypingdatawassupportedinpart ADAMTS9-AS2andTCF7L2-HABP2wereinlowLD(r2<0.5)withtheleadvariantsinour
bytheNationalCenterforAdvancingTranslational previousHapMapimputeddata[11–12].Weusedconditionalandjointassociationanalyses
Sciences,CTSIgrantUL1TR001881,andthe toexaminethegenome-widesignificantlocusforsecondarysignals,butnoadditionalinde-
NationalInstituteofDiabetesandDigestiveand
pendentsignalswerefound.
KidneyDiseaseDiabetesResearchCenter(DRC)
Sex-stratifiedanalyses. Inthesex-stratifiedmeta-analysisinAA,fourestablishedBMI
grantDK063491totheSouthernCalifornia
DiabetesEndocrinologyResearchCenter.Nigeria: loci(SEC16B,GALNT10,FTOandMC4R)andoneestablishedWHRadjBMIlocus(ADAMT-
NIH:R37-HL045508,R01-HL053353,R01- S9-AS2)weregenome-widesignificantamongwomen(S6Table,S8andS9Figs).ADAMT-
DK075787andU01-HL054512;analysisalso S9-AS2showedastrongerassociationwithWHR amongwomenthanamongmen
adjBMI
fundedthroughR01-DK075787.ROOT:NIH:R01-
(P =0.02)(S6Table),consistentwithfindingsamongEA[9].Ontheotherhand,although
CA142996,P50-CA125183,R01-CA89085,and het
ourobservedSEC16Brs543874effectsizedifferences(0.064vs.0.038,P =0.08)forBMIin
U01-CA161032.AmericanCancerSociety:MRSG- het
womencomparedtomenweresimilartothosepreviouslyobservedamongEA(0.060vs.
13-063-01-TBGandCRP-10-119-01-CCE.
SAPPHIRE:NIH/NHLBIR01HL118267;NIH/NIAID 0.034,P =5.23×10−5)[7],wedidnotobservestatisticallysignificantdifferencesineffectsize,
het
R01AI079139;NIH/NIDDKR01DK064695andR01 likelyduetoamuchsmallersamplesizeandthuslowerstatisticalpowerinourstudy.Allthese
DK113003;AmericanAsthmaFoundation. fivelociwerealsogenome-widesignificantinthesex-combinedmeta-analyses.Theywerenot
SIGNET-REGARDS:TheSeaIslandsGenetics
furtherexaminedinsubsequentsex-stratifiedanalysesgiventheirsmallersamplesizescom-
Network(SIGNET)wassupportedbyR01
paredtothesex-combinedanalyses.InAA,additionalnovellociwereobservedforassociation
DK084350(MMSale).Theauthorsthanktheother
investigators,thestaff,andtheparticipantsofthe withBMI;thesewerevariantsinIRX4/IRX2amongwomen,variantsinINTS10/LPLand
REGARDSstudyfortheirvaluablecontributions.A MLC1amongmen(Fig2),andforWHR ,variantsinSSX2IPandPDE3Bamongwomen
adjBMI
fulllistofparticipatingREGARDSinvestigatorsand (Fig1B,Table2).Inmeta-analysesincludingbothAAandEA,twoadditionalnovellociat
institutionscanbefoundathttp://www.
CASC8andZDHHC1/HSD11B2wereidentifiedforWHR inwomen(Table2,Fig1B).
regardsstudy.org.Thisstudy(REGARDS)was adjBMI
Amongallloci,theeffectsizesofsixvariants(IRX4/IRX2,INTS10/LPL,MLC1,ADAMT-
supportedbyacooperativeagreementU01
NS041588fromtheNationalInstituteof S9-AS2,PDE3BandCASC8)werenominallysignificantdifferentbetweenmenandwomenin
NeurologicalDisordersandStroke(NINDS). AA(P <0.05)(S6Table).
het
WFSM:Genotypingserviceswereprovidedbythe Replicationinchildren. Weevaluatedthesevensex-combinedandthreesex-specific
CenterforInheritedDiseaseResearch(CIDR). genome-widesignificantBMIlociforassociationsin7,222AAchildren(3,552boysand3,670
CIDRisfullyfundedthroughafederalcontract
girls).Allleadvariantsdisplayeddirectionalconsistency,andfiveoftheseincludingSEC16B,
fromtheNationalInstitutesofHealthtoTheJohns
TMEM18,GNPDA2,GALNT10andMC4RshowednominalassociationswithBMI(P<0.05,
HopkinsUniversity,contractnumber
HHSC268200782096C.Thisworkwassupported Pbinomial=4.70×10−8)(S7Table),supportingtheroleoftheselociinmodulatingadiposityin
byNationalInstitutesofHealthgrantsR01 AAchildren.WHR datawerenotavailableinthecohortsofchildren.
adjBMI
DK087914,R01DK066358,R01DK053591,R01 Functionalcharacterizationofnovelloci. Weusedmultiplecomplementaryapproaches
HL56266,R01DK070941andbytheWakeForest
toelucidatetheputativecausalgenesand/orvariantsassociatedwiththeninenovelBMIand
SchoolofMedicinegrantM01RR07122and
WHR locifromthesex-combinedandsex-stratifiedanalyses,includingannotating
VentureFund20543.WHI:Fundingsupportforthe adjBMI
nearbycodingvariants,cis-expressionquantitativetraitloci(cis-eQTL)analyses,and
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 6/25
GWASforadiposityinAfricanancestry
“Epidemiologyofputativegeneticvariants:The functionalregulatorygenomicelementanalyses.OnemissensevariantinPLEKHG4,
Women’sHealthInitiative”studyisprovided rs8044843,wasinhighLD(r2=0.75inAFR)withrs6499129associatedwithWHR in
adjBMI
throughtheNHGRIPAGEprogram(U01HG004790 women(S8Table).WedidnotidentifyanycodingvariantsinhighLD(r2>0.7)withother
anditsNHGRIARRAsupplement).TheWHI
leadvariantswithintheflanking1Mb-regions.RegulatoryelementanalysesusingRegulo-
programisfundedbytheNationalHeart,Lung,and
meDB[24]andHaploReg[25]revealedthatproxies(r2=0.73–0.84)toleadvariantsatthree
BloodInstitute;NIH;andU.S.DepartmentofHealth
andHumanServicesthroughcontracts WHR loci(SPRYD7/DLEU2,PDE3B,andZDHHC1/HSD11B2)wereassociatedwith
adjBMI
N01WH22110,24152,32100-2,32105-6,32108- transcriptionfactorbinding,DNasepeak,promoterorenhancerhistonemarks(S8Table).In
9,32111-13,32115,32118-32119,32122,42107- addition,theleadvariantrs2472591atSPRYD7/DLEU2wasinhighLD(r2=0.85)with
26,42129-32,and44221.Theauthorsthankthe
rs790943,acis-eQTLassociatedwithexpressionofthenearbygene,TRIM13,inbloodden-
WHIinvestigatorsandstafffortheirdedication,
driticcellsintuberculosispatients[26](S9Table),suggestingtheassociationsattheSPRYD7/
andthestudyparticipantsformakingtheprogram
possible.AfulllistingofWHIinvestigatorscanbe DLEU2locusmaybeinvolvedintheregulationofnearbygeneexpressionatTRIM13.
foundat:http://www.whiscience.org/publications/ Cross-traitassociationsofnovelloci. WesearchedtheNHGRI-EBIGWAS[27]and
WHI_investigators_shortlist.pdf.CAH:R01 Genome-WideRepositoryofAssociationsBetweenSNPsandPhenotypes(GRASP)[28]cata-
DK101855-01.CL:R01DK089256.KEN:R01
logstoassessifanyoftheninenovelleadvariantswereinhighLDwithvariantsthatwere
DK089256,R01DK101855-01,
genome-widesignificantly(P<5×10−8)ornominally(P<0.05)associatedwithrelated
15GRNT25880008.KLY:KL2TR001109.LAC:R01
anthropometricandcardiometabolictraitsorgeneexpressioninpriorstudies.Althougha
DK089256.RJFL:R01DK101855-01.YLi:
R01HG006292andR01HL129132.Thefunders fewleadvariantswerephysicallyclose(<500kb)toGWASlociforrelatedtraitsinthe
hadnoroleinstudydesign,datacollectionand NHGRI-EBIGWASCatalog(Figs1and2),noneofourleadvariantswereinhighLDwiththe
analysis,decisiontopublish,orpreparationofthe previouslyassociatedleadvariants.Additionally,therewerenonearbyassociationsfornovel
manuscript.
BMIlociintheGRASPCatalog.OfthenovelvariantsassociatedwithWHR ,rs2472591
adjBMI
Competinginterests:Ihavereadthejournal’s atSPRYD7/DLEU2,rs378854nearMYC,andrs6499129nearZDHHC1/HSD11B2wereinhigh
policyandtheauthorsofthismanuscripthavethe LD(r2>0.7)withpreviously-reportedWHR variants,buttheydidnotreachgenome-
adjBMI
followingcompetinginterests:BMPservesonthe widesignificance(P>2×10−5)[3](S9Table).Othernearbyassociationswithrelatedcardio-
DSMBofaclinicaltrialfundedbythemanufacturer
metabolictraitsincludechronickidneydisease(CKD),highdensitylipoproteincholesterol
andontheSteeringCommitteefortheYaleOpen
DataAccessProjectfundedbyJohnson& (HDL-C),anthropometrictraits(BMI,height,andbirthweight),bloodpressure(systolic
Johnson.IBworksinRegeneronPharmaceuticals, bloodpressureandhypertension),diabetes-relatedtraits(bloodglucoseandHOMA-IR),and
Inc.MAN’sparticipationissupportedbya geneexpressionofseveralgenes(e.g.ATP6V0D1,ZDHHC1,DUS2L,AGRP,GFOD2and
consultingcontractbetweenDataTecnica
LRRC29).
InternationalandtheNationalInstituteonAging,
NIH,Bethesda,MD,USA.Asapossibleconflictof
interest,MANalsoconsultsforIlluminaInc,the
EvaluationofestablishedEuropeanlociinAfricanancestrypopulations
MichaelJ.FoxFoundationandUniversityof
CaliforniaHealthcare. ConditionalanalysisinGWASloci. AmongthesixBMI(SEC16B,TMEM18,GNPDA2,
GALNT10,FTOandMC4R)andoneWHR (ADAMTS9-AS2)genome-widesignificant
adjBMI
lociinAAthatwerepreviouslyreportedinEA[7–8],wetestedwhethertheAfricanderived
leadvariantswereindependentofthereportedEuropeansignalsbyconditioningontheEuro-
peanleadvariantsortheirsurrogates.ForthreeoftheBMIloci(SEC16B,GNPDA2and
MC4R),ourleadvariantsarethesameasthosereportedinthepreviousliterature[7].Forall
otherloci,theleadvariantsdemonstratedsubstantiallylowersignificanceuponconditional
analysis,suggestingthattheAfricanancestryresultsrepresentedthesameassociationsignals
aspreviouslyreportedinGWASperformedpredominantlyinEApopulations(S10Table).
SNPtransferability. Wefurtherexaminedallsex-combinedandsex-stratifiedBMIand
WHR lociidentifiedfrompreviousEAstudies[7–9]inourAAdata.Among176EA
adjBMI
leadvariantsfrom170BMIloci,119variantsdisplayeddirectionallyconsistentassociations
withBMIinourdata,31ofthesewerenominallysignificantatP<0.05(P =2.2×10−18
binomial
among176variants).Among84EAleadvariantsfrom65WHR loci,69variantsdis-
adjBMI
playeddirectionallyconsistentassociationswithWHR ,and23ofthesewerenominally
adjBMI
significant(P =5.3×10−19among84variants)(S11Table).EAleadvariantsin11BMI
binomial
and3WHR locishoweddirectionalconsistencyandsignificantassociationsaftercorrec-
adjBMI
tionformultiplecomparisons(P<1.92×10−4).Amongthe54nominallytransferablelead
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 7/25
GWASforadiposityinAfricanancestry
ation AA+EA P 86.35E-46 63.04E-28 55.60E-46 54.35E-15 75.43E-03 21.13E-146 82.09E-64 79.13E-27 NA 13.53E-08 dard
replic EA N 322,00 244,17 320,95 234,01 233,99 321,60 321,95 145,25 NA 140,43 E:stan
cestry P 4.36E-35 6.10E-21 1.87E-38 3.80E-07 7.44E-01 2.40E-139 8.23E-54 5.17E-19 NA 1.69E-05 are;S
n u
dEuropeana AADiscovery+Replication EffectP(SE) 0.0551.76E-(0.008)13 0.0532.17E-(0.009)09 0.0443.95E-(0.008)09 0.0544.21E-(0.007)14 0.046.08E-(0.007)09 0.0692.72E-(0.01)11 0.0592.29E-(0.008)12 0.0642.46E-(0.01)11 0.1343.22E-(0.024)08 0.054.36E-(0.012)05 asuredbyI-sq
andreplicationsamples,an AAReplication EffectPHetISqN(SE) 0.0576.59E-28.910,143(0.017)04 0.044.40E-49.410,143(0.02)02 0.0115.40E-5410,143(0.017)01 0.0343.93E-6.210,143(0.016)02 0.0259.97E-35.210,143(0.015)02 0.081.19E-49.210,143(0.025)03 0.0441.99E-33.510,143(0.019)02 0.0058.75E-42.12,711(0.033)01 0.3483.82E-45.62,711(0.084)05 0.062.21E-02,160(0.049)01 ncy;HetISq:heterogeneityme
covery N 42,681 41,492 42,752 42,750 42,751 42,750 42,750 20,383 20,384 20,371 freque
s q e
ncestrydi ADiscovery PHetIS 75E-011 55E-008 76E-3.610 05E-4.613 75E-008 48E-009 74E-35.311 90E-012 88E-006 72E-005 effectallel
a A 5. 1. 3. 1. 1. 5. 2. 3. 5. 9. F:
n A
Africa Effect(SE) 0.055(0.008) 0.056(0.01) 0.053(0.008) 0.059(0.008) 0.043(0.008) 0.067(0.011) 0.062(0.009) 0.07(0.01) 0.114(0.025) 0.05(0.013) stry;E
8−0in EAF 0.248 0.751 0.243 0.307 0.659 0.117 0.197 0.457 0.955 0.206 ance
1 n
P5<× Effect/Otheralleles G/A T/C G/A A/G T/C T/C C/T G/T A/G T/A uropea
at E
RlociadjBMI Locus SEC16B TMEM18 GNPDA2 GALNT10 KLHL32 FTO MC4R ADAMTS9-AS2 TCF7L2/HABP2 SPRYD7/DLEU2 osome;EA:
H m
reviouslyidentifiedBMIandW Leadvariantbylocus ChrPositionKnownLocus(if(b37/hg19)Yes,leadpublishedvariant) 1177,889,480Yesrs543874 2633,660Yesrs13021737 445,182,527Yesrs10938397 5153,543,466Yesrs7715256;ars7708584 a697,410,536Yesrs974417 1653,828,066Yesrs1558902 1857,829,135Yesrs6567160 364,703,394Yesrs2371767 10115,189,239No 1350,536,360No BMI:bodymassindex;Chr:chro st-to-hipratioadjustedforBMI ntsreportedinAfricanancestry urnal.pgen.1006719.t001
Table1.Novelandpsamples. TraitLeadSNP BMIrs543874 BMIrs62105306 BMIrs10938397 BMIrs7708584 BMIrs17057164 BMIrs17817964 BMIrs6567160 WHRrs66815886adjBMI WHRrs116718588adjBMI WHRrs2472591adjBMI AA:Africanancestry; error;WHR:waiadjBMIaleadpublishedvaria https://doi.org/10.1371/jo
PLOSGenetics|https://doi.org/10.1371/journal.pgen.1006719 April21,2017 8/25