a principalcomponent meta-analysison multiple...
TRANSCRIPT
P age1 of34
A principalcom ponent m eta-analysison m ultiple anthropom etric traitsidentifiesnovel1
lociforbody shape2
Janina S R ied*1,Janina Jeff*2,Audrey Y Chu3, Jennifer L Bragg-Gresham 4,Jenny van3
Dongen5,JenniferE Huffm an6,T arunveerS Ahluw alia7,8,9,Gem m aCadby10,N iinaEklund11,4
JoelEriksson12,T õnu Esko13,14,15,16,M ary F Feitosa17,AnujGoel18,19,M athiasGorski20,21,5
Caroline Hayw ard6,N ancy L Heard-Costa22,23,Anne U Jackson24,Eero Jokinen25,S tavroula6
Kanoni26,27,KatiKristiansson11,28,Zoltán Kutalik29,30,31,JariL ahti32,33,Jian'an L uan34,R eedik7
M ägi15,19,Anubha M ahajan19,M assim o M angino35,Carolina M edina-Gom ez36,37,Keri L8
M onda38,39,IljaM N olte40,L ouisP érusse41,42,IngaP rokopenko19,43,44,L u Q i45,46,L yndaM9
R ose3,ErikaS alvi47,48,M eganT S m ith49,Harold S nieder40, Alena S tančáková 50,YunJu S ung51,10
Ioanna T achm azidou26, Alexander T eum er52,53, Gudm ar T horleifsson54, P im van der11
Harst55,56,57,R yan W W alker2,58,S ophie R W ang16,59,60,61,S arah H W ild62,S araM W illem s63,12
Andrew W ong64,W eihuaZhang65,66,EvaAlbrecht1,AlexessanderCouto Alves67,S tephan JL13
Bakker68,Cristina Barlassina47,48,T raci M Bartz49,69,70,John Beilby71,72,Claire Bellis73,74,14
R ichard N Bergm an75,S ven Bergm ann29,30,John Blangero76,M atthias Blüher77,78,Eric15
Boerw inkle79,L ori L Bonnycastle80,S tefan R Bornstein81,M arcel Bruinenberg82,Harry16
Cam pbell62,Yii-DerIdaChen83,Charleston W K Chiang84,P eterS Chines80,FrancisS Collins80,17
Fracensco Cucca85,L Adrienne Cupples22,FrancescaD’Avila47,48,Eco JC de Geus5,86,George18
Dedoussis87,M aria Dim itriou26,87,Angela Döring88,89,Johan G Eriksson32,90,91,Aliki-Eleni19
Farm aki87,M artin Farrall18,19,T eresaFerreira19, KristaFischer15,N itaG Forouhi34,N ele20
Friedrich92,AnetteP riorGjesing7,N icolaGlorioso93,M ariaelisaGraff38,Harald Grallert89,94,95,21
N ielsGrarup7,Jürgen Gräßler96,JagvirGrew al65,66,AndersHam sten97,98,99,M arie N eergaard22
Harder7, Catharina A Hartm an100, M aija Hassinen101, N icholas Hastie6, Andrew T ym23
Hattersley102,AkiS Havulinna11,M arkku Heliövaara11,HansHillege57,Albert Hofm an36,24
O ddgeir Holm en103,Georg Hom uth53,Jouke-Jan Hottenga5,Jennie Hui71,72,104 L ise L otte25
Husem oen105,P irro G Hysi35,Aaron Isaacs63,T illItterm ann52,S hapourJalilzadeh18,19,Alan L26
Jam es106, T orben Jørgensen107,108,109, P ekka Jousilahti11, Antti Jula11, Johanne M arie27
Justesen7,Anne E Justice38,M ikaKähönen110,111,M ariaKaraleftheri112,Kay T ee Khaw 113,28
S irkka M Keinanen-Kiukaanniem i114,115, L eena Kinnunen116, P aul B Knekt11, Heikki A29
Koistinen116,117,118,IvanaKolcic119,Ishm inderK Kooner66,S eppo Koskinen11,P eterKovacs77,30
T heodosiosKyriakou18,19,T om iL aitinen120,121,ClaudiaL angenberg34,122,AlexandraM L ew in67,31
P eter L ichtner123,CeciliaM L indgren13,19,124,JaanaL indström 11,Allan L inneberg105,107,125,32
R oberto L orbeer52,M attias L orentzon12, R obert L uben126, Valeriya L yssenko8,127, S atu33
M ännistö11, P aolo M anunta128, Irene M ateo L each57, W endy L M cArdle129, Barbara34
M cknight49,70,130,Karen L M ohlke131,Evelin M ihailov15,L iliM ilani15,R ebeccaM ills66,M ay E35
M ontasser132,Andrew P M orris19,133,Gabriele M üller134,ArthurW M usk135,N arisu N arisu80,36
Ken K O ng34,64,136,Ben A O ostra63,Clive O sm ond137,Aarno P alotie28,138,Jam esS P ankow 139,37
L avinia P aternoster140,Brenda W P enninx141,Irene P ichler142,M aria G P ilia143,O zren38
P olašek62,119,P eter P P ram staller142,144,145,O lliT R aitakari146,147,T uom o R ankinen148,DC39
P age2 of34
R ao51,149, N igel W R ayner19,44,150, R asm us R ibel-M adsen7, T reva K R ice51,149, M arcus40
R ichards44,64, P aul M R idker3,151, Fernando R ivadeneira36,37, Kathy A R yan132, S erena41
S anna143,M arkA S arzynski148,S alom e S choltens40,R obert A S cott34,S ylvain S ebert43,152,153,42
L orraine S outham 19,26,T hom asHem pel S parsø7,Valgerdur S teinthorsdottir54,Kathleen43
S tirrups26,27,R onald P S tolk40,Konstantin S trauch1,154,Heather M S tringham 24,M orrisA44
S w ertz56, Am y JS w ift80,Anke T önjes78,Em m anouilT safantakis155,P eterJvan derM ost40,45
Jana V Van Vliet-O staptchouk156, L iesbeth Vandenput12,Erkki Vartiainen11, Cristina46
Venturini35,157, N iek Verw eij57, Jorm a S Viikari158,159, Veronique Vitart6, M arie-Claude47
Vohl42,160, Judith M Vonk40,Gérard W aeber161,Elisabeth W idén28,Gonneke W illem sen5,48
T om W ilsgaard162,T hom asW W inkler21,Alan FW right6,L auraM Yerges-Arm strong132,Jing49
Hua Zhao34, M Carola Zillikens37, Dorret I Boom sm a5, Claude Bouchard148, John C50
Cham bers65,66,163,DanielIChasm an3,151,DanieleCusi47,48,T heL ifelinesCohortS tudy82,R on T51
Gansevoort68,Christian Gieger1,89,95,T orben Hansen7,164,Andrew A Hicks142,Frank Hu45,46,52
Kristian Hveem 103, M arjo-R iitta Jarvelin152,165,166,167, Eero Kajantie11,90,168,169, Jaspal S53
Kooner66,163,170,DianaKuh64,JohannaKuusisto50,M arkku L aakso50,T im oA L akka101,171,T erho54
L ehtim äki172,173, Andres M etspalu15, Inger N jølstad162,174, Claes O hlsson12, Albertine J55
O ldehinkel100, L yle J P alm er175,176, O luf P edersen7, M arkus P erola11,15,28, Annette56
P eters89,95,177,Bruce M P saty70,178,179,180,Hannu P uolijoki181,R ainer R auram aa101,182,Igor57
R udan62,Veikko S alom aa11,P eter EH S chw arz81,183,Alan R S hudiner132,184,Jan H S m it141,58
T horkild I A S ørensen7,185,186, T im othy D S pector35, Kari S tefansson54,187, M ichael59
S tum voll77,78,Angelo T rem blay41,Jaakko T uom ilehto188,189,190,André G U itterlinden36,37,60
M attiU usitupa191,192,U w e Völker53,193,P eterVollenw eider161,N icholasJW areham 34,Hugh61
W atkins18,19, Jam es F W ilson6,62, Eleftheria Zeggini26, Goncalo R Abecasis24, M ichael62
Boehnke24,Ingrid B Borecki17,P anosDeloukas27,150,194,CorneliaM van Duijn63,195,Caroline63
Fox22,151,L eifC Groop127,196,IrisM Heid21,197,David JHunter13,45,46,198,R obert C Kaplan199,64
M arkIM cCarthy19,44,200,KariEN orth201,Jeffrey R O 'Connell132,David S chlessinger202,U nnur65
T horsteinsdottir54,187, David P S trachan203, T im othy Frayling204, Joel N66
Hirschhorn13,14,16,59,60,61,205,M artinaM üller-N urasyid**1,154,177,206,R uthJFL oos**2,34,58,207,20867
68
A ffiliations69
1. Institute ofGenetic Epidem iology,Helm holtz Zentrum M ünchen -Germ an R esearch70
CenterforEnvironm entalHealth,N euherberg,85764,Germ any71
2. T he CharlesBronfm an Institute for P ersonalized M edicine,T he Icahn S chool of72
M edicineatM ountS inai,N ew York,N Y,10029,U S A73
3. Division ofP reventive M edicine,Brigham and W om en'sHospital,Boston,M A,02215,74
U S A75
4. Kidney Epidem iology and Cost Center,InternalM edicine-N ephrology,U niversity of76
M ichigan,AnnArbor,M I,48109,U S A77
5. Departm ent of Biological P sychology, VU U niversity, Am sterdam , 1081BT , T he78
N etherlands79
6. M R C Hum anGeneticsU nit,InstituteofGeneticsand M olecularM edicine,U niversity of80
Edinburgh,Edinburgh,EH4 2X U ,S cotland81
P age3 of34
7. N ovo N ordisk Foundation CenterforBasic M etabolic R esearch,S ection ofM etabolic82
Genetics, Faculty of Health and M edical S ciences, U niversity of Copenhagen,83
Copenhagen,2100,Denm ark84
8. S tenoDiabetesCenterA/S ,Gentofte,DK-2820,Denm ark85
9. CO P S AC,Copenhagen P rospective S tudies on Asthm a in Childhood,Herlev and86
GentofteHospital,U niversity ofCopenhagen,L edreborgAllé34,DK-2820 Copenhagen,87
Denm ark88
10. Centre for Genetic O riginsofHealth and Disease,U niversity ofW estern Australia,89
Craw ley,W A,6009,Australia90
11. N ationalInstitute forHealth and W elfare (T HL ),Departm ent ofHealth,Helsinki,FI-91
00271,Finland92
12. Centre forBone and ArthritisR esearch,Departm ent ofInternalM edicine and Clinical93
N utrition,Institute of M edicine,S ahlgrenska Academ y,U niversity of Gothenburg,94
Gothenburg,413 45,S w eden95
13. Broad Institute ofthe M assachusettsInstitute ofT echnology and Harvard U niversity,96
Cam bridge,2142,U S A97
14. DivisionsofEndocrinology and Geneticsand CenterforBasicand T ranslationalO besity98
R esearch,BostonChildren'sHospital,Boston,M A,02115,U S A99
15. EstonianGenom eCenter,U niversity ofT artu,T artu,51010,Estonia100
16. Departm entofGenetics,HarvardM edicalS chool,Boston,M A,02115,U S A101
17. Division of S tatistical Genom ics,Departm ent of Genetics,W ashington U niversity102
S choolofM edicine,S t.L ouis,M O ,63108,U S A103
18. Division ofCardiovacularM edicine,R adcliffe Departm ent ofM edicine,U niversity of104
O xford,O xford,O X 3 9DU ,U K105
19. W ellcom e T rust Centre forHum an Genetics,U niversity ofO xford,O xford,O X 3 7BN ,106
U K107
20. Departm ent of N ephrology,U niversity Hospital R egensburg,R egensburg,93042,108
Germ any109
21. Departm ent of Genetic Epidem iology, Institute of Epidem iology and P reventive110
M edicine,U niversity ofR egensburg,R egensburg,93053,Germ any111
22. N ationalHeart,L ung,and Blood Institute,the Fram ingham Heart S tudy,Fram ingham112
M A,01702,U S A113
23. Departm entofN eurology,BostonU niversity S choolofM edicine,Boston,M A 02118114
24. CenterforS tatisticalGenetics,Departm entofBiostatistics,U niversity ofM ichigan,Ann115
Arbor,M I,48109,U S A116
25. Hospital for Children and Adolescents,U niversity of Helsinki,Helsinki,FI-00290,117
Finland118
26. W ellcom eT rustS angerInstitute,Hum anGenetics,Hinxton,Cam bridge,CB10 1S A,U K119
27. W illiam Harvey R esearch Institute,Bartsand T he L ondon S choolofM edicine and120
Dentistry,Q ueenM ary U niversity ofL ondon,L ondon,EC1M 6BQ ,U K121
28. Institute for M olecular M edicine Finland,U niversity ofHelsinki,Helsinki,FI-00290,122
Finland123
29. S w issInstituteofBioinform atics,L ausanne,1015,S w itzerland124
30. Departm entofM edicalGenetics,U niversity ofL ausanne,L ausanne,1005,S w itzerland125
31. Institute of S ocialand P reventive M edicine,U niversity HospitalL ausanne (CHU V),126
L ausanne,1010,S w itzerland127
32. FolkhälsanR esearchCentre,Helsinki,FI-00290,Finland128
P age4 of34
33. InstituteofBehaviouralS ciences,U niversity ofHelsinki,Helsinki,FI-00014,Finland129
34. M R C Epidem iology U nit,U niversity ofCam bridge S choolofClinicalM edicine,Institute130
of M etabolic S cience, U niversity of Cam bridge, Cam bridge Biom edical Cam pus,131
Cam bridge,CB2 0Q Q ,U K132
35. Departm ent of T w in R esearch and Genetic Epidem iology,King'sCollege L ondon,133
L ondon,S E1 7EH,U K134
36. Departm ent of Epidem iology,Erasm usM edical Center,R otterdam ,3015GE,T he135
N etherlands136
37. Departm ent ofInternalM edicine,Erasm usM edicalCenter,R otterdam ,3015GE,T he137
N etherlands138
38. Departm ent ofEpidem iology,U niversity ofN orth Carolinaat ChapelHill,ChapelHill,139
N C,27599,U S A140
39. T he CenterforO bservationalR esearch,Am gen Inc.,T housand O aks,CA,91320-1799,141
U S A142
40. U niversity of Groningen, U niversity M edical Center Groningen, Departm ent of143
Epidem iology,Groningen,9700 R B,T heN etherlands144
41. Departm entofKinesiology,L avalU niversity,Q uébec,Q C,G1V 0A6,Canada145
42. Institute ofN utrition and FunctionalFoods,L avalU niversity,Q uébec,Q C,G1V 0A6,146
Canada147
43. Departm ent of Genom icsof Com m on Disease,S choolof P ublic Health,Im perial148
CollegeL ondon,L ondon,W 12 0N N ,U K149
44. O xford Centre for Diabetes,Endocrinology and M etabolism ,U niversity of O xford,150
ChurchillHospital,O xford,O X 3 7L J,U K151
45. Channing Division of N etw ork M edicine,Departm ent of M edicine,Brigham and152
W om en’sHospitaland HarvardM edicalS chool,Boston,M A,02115,U S A153
46. Departm entofN utrition,Harvard S choolofP ublicHealth,Boston,M A,02115,U S A154
47. Departm ent ofHealth S ciences,U niversity ofM ilano at S an P aolo Hospital,M ilano,155
20139,Italy156
48. FilareteFoundation,Genom icand Bioinform aticsU nit,M ilano,Italy157
49. Departm entofBiostatistics,U niversity ofW ashington,S eattle,W A,98195,U S A158
50. Departm entofM edicine,U niversity ofEasternFinland and Kuopio U niversity Hospital,159
Kuopio,70210,Finland160
51. Division of Biostatistics,W ashington U niversity S choolof M edicine,S t. L ouis,M O ,161
63110,U S A162
52. Institute forCom m unity M edicine,U niversity M edicine Greifsw ald,Greifsw ald,17475,163
Germ any164
53. Interfaculty Institute for Geneticsand Functional Genom ics,U niversity M edicine165
Greifsw ald,Greifsw ald,17475,Germ any166
54. deCO DEGenetics,Am geninc.,R eykjavik,101,Iceland167
55. Durrer Center for Cardiogenetic R esearch, Interuniversity Cardiology Institute168
N etherlands-N etherlandsHeartInstitute,U trecht,3501 DG,T heN etherlands169
56. U niversity of Groningen, U niversity M edical Center Groningen, Departm ent of170
Genetics,Groningen,9700 R B,T heN etherlands171
57. U niversity of Groningen, U niversity M edical Center Groningen, Departm ent of172
Cardiology,Groningen,9700 R B,N etherlands173
58. T heDepartm entofP reventiveM edicine,T heIcahnS choolofM edicineatM ountS inai,174
N ew York,N Y,10029,U S A175
P age5 of34
59. P rogram in M edical and P opulation Genetics, Broad Institute of Harvard and176
M assachusettsInstituteofT echnology,Cam bridge,M A,02142,U S A177
60. DivisionofEndocrinology,BostonChildren'sHospital,Boston,M A,02115,U S A178
61. DivisionsofGeneticsand Endocrinology and P rogram in Genom ics,Boston'sChildren's179
Hospital,Boston,M A,02115,U S A180
62. Centre forGlobalHealth R esearch,U sherInstitute ofP opulation Health S ciencesand181
Inform atics,U niversity ofEdinburgh,T eviotP lace,Edinburgh,EH8 9AG,S cotland182
63. GeneticEpidem iology U nit,Departm ent ofEpidem iology,Erasm usU niversity M edical183
Center,R otterdam ,3015GE,T heN etherlands184
64. M R C U nitforL ifelongHealth& AgeingatU CL ,L ondon,W C1B 5JU ,U K185
65. Departm ent ofEpidem iology and Biostatistics,Im perialCollege L ondon,L ondon ,W 2186
1P G,U K187
66. EalingHospitalN HS T rust,M iddlesex,U B1 3HW ,U K188
67. Departm ent ofEpidem iology and Biostatistics,M R C Health P rotection Agency (HP A)189
Centre forEnvironm entand Health,S choolofP ublicHealth,Im perialCollege,L ondon,190
U K191
68. U niversity of Groningen, U niversity M edical Center Groningen, Departm ent of192
M edicine,Groningen,9700 R B,N etherlands193
69. Departm entofM edicine,U niversity ofW ashington,S eattle,W A,U S A194
70. CardiovascularHealth R esearch U nit,U niversity ofW ashington,S eattle,W A,98101,195
U S A196
71. P athw estL aboratory M edicineofW esternAustralia,N edlands,W A,6009,Australia197
72. S chool of P athology and L aboratory M edicine,U niversity of W estern Australia,198
N edlands,W A,6009,Australia199
73. Genom icsR esearchCentre,InstituteofHealthand Biom edicalInnovation,Q ueensland200
U niversity ofT echnology,Brisbane,Q ueensland4001,Australia201
74. Hum an Genetics,Genom e Institute ofS ingapore,Agency forS cience,T echnology and202
R esearchofS ingapore,138672,S ingapore203
75. Diabetesand O besity R esearchInstitute,Cedars-S inaiM edicalCenter,L osAngeles,CA,204
90048,U S A205
76. S outh T exasDiabetesand O besity Institute,U niversity ofT exasR io Grande Valley,206
Brow nsville,T X ,78520207
77. U niversity ofL eipzig,IFB Adiposity Diseases,L eipzig,04103,Germ any208
78. U niversity ofL eipzig,Departm entofM edicine,L eipzig,04103,Germ any209
79. Hum an GeneticsCenter and Institute of M olecular M edicine,U niversity of T exas210
HealthS cienceCenter,Houston,T exas,77030,U S A211
80. M edicalGenom icsand M etabolicGeneticsBranch,N ationalHum an Genom eR esearch212
Institute,N IH,Bethesda,M D,20892,U S A213
81. Departm entofM edicine III,U niversity ofDresden,M edicalFaculty CarlGustavCarus,214
Dresden,01307,Germ any215
82. U niversity ofGroningen,U niversity M edicalCenterGroningen,T he L ifeL inesCohort216
S tudy,Groningen,9700 R B,T heN etherlands217
83. L osAngelesBioM edicalR esesarch Institute atHarbor-U CL A M edicalCenter,T orrance,218
CA ,90502,U S A219
84. Departm entofP sychiatry,U niversity ofCalifornia,L osAngeles,CA,90095,U S A220
85. U niversity ofS assari,S assari,07100,Italy221
P age6 of34
86. EM GO Institute for Health and Care R esearch, VU U niversity M edical Center,222
Am sterdam ,1081 BT ,T heN etherlands223
87. Departm ent of N utrition and Dietetics,S choolof Health S cience and Education,224
HarokopioU niversity,Athens,17671,Greece225
88. Institute ofEpidem iology I,Helm holtz Zentrum M ünchen -Germ an R esearch Center226
forEnvironm entalHealth,N euherberg,85764,Germ any227
89. Institute ofEpidem iology II,Helm holtz Zentrum M ünchen -Germ an R esearch Center228
forEnvironm entalHealth,N euherberg,85764,Germ any229
90. Departm entofChronicDisease P revention,N ationalInstitute forHealth and W elfare,230
Helsinki,FI-00271,Finland231
91. Departm ent of GeneralP ractice and P rim ary Health Care,U niversity of Helsinki,232
Helsinki,FI-00014,Finland233
92. Institute of Clinical Chem istry and L aboratory M edicine, U niversity M edicine234
Greifsw ald,Greifsw ald,17475,Germ any235
93. Hypertension and R elated Disease Centre,AO U -U niversity ofS assari,S assari,7100,236
Italy237
94. Germ anCenterforDiabetesR esearch(DZD),N euherberg,85764,Germ any238
95. R esearch U nit of M olecular Epidem iology,Helm holtz Zentrum M ünchen -Germ an239
R esearchCenterforEnvironm entalHealth,N euherberg,85764,Germ any240
96. Departm ent of M edicine III,P athobiochem istry,T echnische U niversitaet,Dresden,241
01307,Germ any242
97. Departm entofM edicine,KarolinskaInstitutet,S tockholm ,S w eden243
98. AtherosclerosisR esearch U nit,Departm ent ofM edicine S olna,KarolinskaInstitutet,244
S tockholm ,17176,S w eden245
99. Center for M olecular M edicine,Karolinska U niversity Hospital,S tockholm ,17176,246
S w eden247
100. U niversity ofGroningen,U niversity M edicalCenterGroningen,Interdisciplinary Center248
P sychopathology and Em otionR egulation,Groningen,9700 R B,T heN etherlands249
101. KuopioR esearchInstituteofExerciseM edicine,Kuopio,70100,Finland250
102. Institue ofBiom edical& ClinicalS cience,U niversity ofExeter,Barrack R oad,Exeter,251
EX 2 5DW252
103. Departm ent ofP ublic Health and GeneralP ractice,N orw egian U niversity ofS cience253
andT echnology,T rondheim ,7489,N orw ay254
104. S choolofP opulation Health,U niversity ofW estern Australia,N edlands,W A,6009,255
Australia256
105. R esearch Centre for P revention and Health,Glostrup Hospital, Glostrup, 2600,257
Denm ark258
106. Departm ent of P ulm onary P hysiology and S leep M edicine,S ir Charles Gairdner259
Hospital,N edlands,W A,6009,Australia260
107. Departm entofClinicalM edicine,Faculty ofHealth and M edicalS ciences,U niversity of261
Copenhagen,Copenhagen,2200,Denm ark262
108. Faculty ofM edicine,U niversity ofAalborg,Aalborg,9220,Denm ark263
109. R esearch Centre for P revention and Health,CapitalR egion of Denm ark,DK2600,264
Denm ark265
110. Departm ent ofClinicalP hysiology,T am pere U niversity Hospital,T am pere,FI-33521,266
Finland267
P age7of34
111. Departm ent of Clinical P hysiology, U niversity of T am pere S chool of M edicine,268
T am pere,FI-33014,Finland269
112. EchinosM edicalCentre,Echinos,67300,Greece270
113. ClinicalGerontology U nit,Box 251,Addenbrooke'sHospital,HillsR oad,Cam bridge,271
CB2 2Q Q ,U K272
114. Faculty ofM edicine,InstituteofHealthS ciences,U niversity ofO ulu,O ulu,Finland273
115. U nitofGeneralP ractice,O ulu U niversity Hospital,O ulu,Finland274
116. N ationalInstituteforHealthand W elfare,Helsinki,FI-00271,Finland275
117. U niversity ofHelsinkiand HelsinkiU niversity CentralHospital,Departm entofM edicine276
andAbdom inalCenter:Endocrinology,Helsinki,00029,Finland277
118. M inervaFoundationInstituteforM edicalR esearch,Helsinki,00290 Finland278
119. Departm ent ofP ublic Health,Faculty ofM edicine,U niversity ofS plit,S plit,21000,279
Croatia280
120. KuopioU niversity Hospital,Kuopio,70029,Finland281
121. Departm entofClinicalP hysiology and N uclearM edicine,U niversity ofEastern Finland282
,Kuopio,FI-70211,Finland283
122. Departm entofEpidem iology andP ublicHealth,U CL ,L ondon,W C1E6BT ,U K284
123. Institute ofHum an Genetics,Helm holtz Zentrum M ünchen -Germ an R esearch Center285
forEnvironm entalHealth,N euherberg,85764,Germ any286
124. T heBigDataInstitute,U niversity ofO xford,O xford,O X 3 7L J,U K287
125. Departm ent of Clinical Experim ental R esearch, R igshospitalet, Glostrup, 2600,288
Denm ark289
126. S trangew aysR esearchL aboratory W ort'sCausew ay,Cam bridge,CB1 8R N ,U K290
127. L und U niversity DiabetesCentre and Departm ent of ClinicalS cience,Diabetes&291
Endocrinology U nit,L undU niversity,M alm ö,221 00,S w eden292
128. Chair of N ephrology,U niversità Vita S alute S an R affaele and Genom icsof R enal293
DiseasesandHypertensionU nit,IR CCS S anR affaeleS cientificInstitute,M ilan,Italy294
129. S choolofS ocialand Com m unity M edicine,U niversity ofBristol,Bristol,BS 8 2BN ,U K295
130. P rogram in Biostatisticsand Biom athem atics,Divison ofP ublic Health S ciences,Fred296
HutchinsonCancerR esearchCenter,S eattle,W A,98109,U S A297
131. Departm entofGenetics,U niversity ofN orthCarolina,ChapelHill,N C,27599,U S A298
132. P rogram forP ersonalized and Genom icM edicine,Division ofEndocrinology,Diabetes299
& N utrition,DeptofM edicine,U niversity ofM aryland S choolofM edicine,Baltim ore,300
M D,21201,U S A301
133. Departm entofBiostatistics,U niversity ofL iverpool,L iverpool,L 69 3GA,U K302
134. Center for Evidence Based Healthcare,U niversity ofDresden,M edicalFaculty Carl303
GustavCarus,Dresden,01307,Germ any304
135. Departm ent ofR espiratory M edicine,S irCharlesGairdner Hospital,N edlands,W A,305
6009,Australia306
136. Departm entofP aediatrics,U niversity ofCam bridge,Cam bridge,CB2 0Q Q ,U K307
137. M R C L ifecourse Epidem iology U nit,U niversity ofS outham pton,S outham pton General308
Hospital,S outham pton,S O 16 6YD,U K309
138. M assachusettsGeneralHospital,CenterforHum an GeneticR esearch,P sychiatricand310
N eurodevelopm entalGeneticsU nit,Boston,M A,02114,U S A311
139. Division ofEpidem iology and Com m unity Health,S choolofP ublicHealth,U niversity of312
M innesota,M inneapolis,M N ,55455-0381,U S A313
P age8of34
140. M R C Integrative Epidem iology U nit,S chool of S ocial and Com m unity M edicine,314
U niversity ofBristol,Bristol,BS 81T H,U K315
141. Departm ent of P sychiatry and EM GO Institute for Health and Care R esearch,VU316
U niversity M edicalCenter,AJErnstraat1887,1081 HL Am sterdam ,theN etherlands317
142. CenterforBiom edicine,European Academ y Bozen/Bolzano (EU R AC),Bolzano,39100,318
Italy -Affiliated InstituteoftheU niversity ofL übeck,L übeck,23562,Germ any319
143. IstitutodiR icercaGeneticaeBiom edica,CN R ,M onserrato,9042,Italy320
144. Departm entofN eurology,U niversity ofL übeck,L übeck,23562,Germ any321
145. Departm entofN eurology,GeneralCentralHospital,Bolzano,39100,Italy322
146. Departm ent ofClinicalP hysiology and N uclearM edicine,T urku U niversity Hospital,323
T urku,FI-20521,Finland324
147. R esearch Centre of Applied and P reventive Cardiovascular M edicine,U niversity of325
T urku,T urku,FI-20520,Finland326
148. Hum an Genom icsL aboratory,P ennington Biom edicalR esearch Center,Baton R ouge,327
L A,70808,U S A328
149. Departm ent ofP sychiatry,W ashington U niversity S choolofM edicine,S t.L ouis,M O ,329
63110,U S A330
150. W ellcom e T rust S anger Institute,Hum an Genetics,Hinxton,Cam bridgeshire,CB10331
1HH,U K332
151. Harvard M edicalS chool,Boston,M A,02115,U S A333
152. BiocenterO ulu,U niversity ofO ulu,O ulu,Finland334
153. CenterForL ife-CourseHealthR esearch,U niversity ofO ulu,FI-90014 O ulu,Finland335
154. Institute of M edical Inform atics, Biom etry and Epidem iology, Chair of Genetic336
Epidem iology,L udw ig-M axim ilians-U niversität,M unich,81377,Germ any337
155. AnogiaM edicalCentre,Anogia,74051,Greece338
156. U niversity of Groningen, U niversity M edical Center Groningen, Departm ent of339
Endocrinology,Groningen,9700 R B,T heN etherlands340
157. InstituteofO phthalm ology,U niversity CollegeL ondon,L ondon,EC1V 9EL ,U K341
158. Departm entofM edicine,U niversity ofT urku,T urku,FI-20521,Finland342
159. DivisionofM edicine,T urku U niversity Hospital,T urku,Finland343
160. S choolofN utrition,L avalU niversity,Q uébec,Q C,G1V 0A6,Canada344
161. Departm entofInternalM edicine,U niversity HospitalL ausanne(CHU V) and U niversity345
ofL ausanne,L ausanne,1011,S w itzerland346
162. Departm entofCom m unity M edicine,Faculty ofHealthS ciences,U niversity ofT rom sø,347
T rom sø,9037,N orw ay348
163. Im perialCollegeHealthcareN HS T rust,L ondon,W 12 0HS ,U K349
164. Faculty ofHealthS ciences,U niversity ofS outhernDenm ark,O dense,5000,Denm ark350
165. U nitofP rim ary Care,O ulu U niversity Hospital,O ulu,90029 O YS ,Finland351
166. Departm ent ofEpidem iology and Biostatistics,M R C– P HE Centre forEnvironm ent &352
Health,S choolofP ublicHealth,Im perialCollegeL ondon,U K353
167. Center for L ife Course Epidem iology,Faculty of M edicine,P .O .Box 5000,FI-90014354
U niversity ofO ulu,Finland355
168. Children'sHospital,HelsinkiU niversity Hospitaland U niversity ofHelsinki,Helsinki,FI-356
00029,Finland357
169. Departm ent ofO bstetricsand Gynecology,M R C O ulu,O ulu U niversity Hospitaland358
U niversity ofO ulu,FI-90029,O ulu,Finland359
170. N ationalHeartandL ungInstitute,Im perialCollegeL ondon,L ondon,W 12 0N N ,U K360
P age9 of34
171. Departm ent of P hysiology,Institute of Biom edicine,U niversity of Eastern Finland,361
KuopioCam pus,Kuopio,70210,Finland362
172. Departm entofClinicalChem istry,U niversity ofT am pereS choolofM edicine,T am pere,363
FI-33014,Finland364
173. Departm ent of Clinical Chem istry,Fim lab L aboratories and S chool of M edicine,365
U niversity ofT am pere,T am pere,FI-33520,Finland366
174. Departm ent ofClinicalM edicine,Faculty ofHealth S ciences,U niversity ofT rom sø,367
T rom sø,9037,N orw ay368
175. S choolofP ublicHealth,U niversity ofAdelaide,Adelaide,S A 5005,Australia369
176. R obinsonR esearchInstitute,U niversity ofAdelaide,Adelaide,S A 5005,Australia370
177. DZHK(Germ anCentreforCardiovascularR esearch),partnersiteM unichHeartAlliance,371
M unich,80802,Germ any372
178. Departm entofM edicine,U niversity ofW ashington,S eattle,W A,98101,U S A373
179. Departm entsofEpidem iology and Health S ervices,U niversity ofW ashington,S eattle,374
W A,98101,U S A375
180. GroupHealthR esearchInstitute,GroupHealthCooperative,S eatte,W A,98101,U S A376
181. S outhO strobothniaCentralHospital,S einäjoki,Finland377
182. Departm ent ofClinicalP hysiology and N uclearM edicine,Kuopio U niversity Hospital,378
Kuopio,70211,Finland379
183. P aulL angerhansInstitute Dresden,Germ an Center for DiabetesR esearch (DZD),380
Dresden,Germ any381
184. Geriatric R esearch and Education ClinicalCenter,VetransAdm inistration M edical382
Center,Baltim ore,M D,21042,U S A383
185. M R C Integrative Epidem iology U nit,S chool of S ocial and Com m unity M edicine,384
U niversity ofBristol,Bristol,BS 82BN ,U nited Kingdom385
186. Institute ofP reventive M edicine,Bispebjerg and Frederiksberg Hospital,T he Capital386
R egion,Frederiksberg,2000,Denm ark387
187. Faculty ofM edicine,U niversity ofIceland,R eykjavik,101,Iceland388
188. DiabetesP reventionU nit,N ationalInstituteforHealthand W elfare,Helsinki,FI-00271,389
Finland390
189. CentreforVascularP revention,Danube-U niversity Krem s,Krem s,3500,Austria391
190. DiabetesR esearchGroup,KingAbdulazizU niversity,Jeddah,21589,S audiArabia392
191. Departm ent of P ublic Health and ClinicalN utrition,U niversity of Eastern Finland,393
70211,Finland394
192. R esearchU nit,KuopioU niversity Hospital,Kuopio,70029,Finland395
193. DZHK (Germ an Centre for Cardiovascular R esearch), partner site Greifsw ald,396
Greifsw ald,17475,Germ any397
194. P rincess Al-Jaw hara Al-Brahim Centre of Excellence in R esearch of Hereditary398
Disorders(P ACER -HD),KingAbdulazizU niversity,Jeddah,21589,S audiArabia399
195. CenterforM edicalS ystem sBiology,L eiden,2300,T heN etherlands400
196. Finnish Institute forM olecularM edicine (FIM M ),HelsinkiU niversity,Helsinki,00014,401
Finland402
197. Institute of Genetic Epidem iology, Helm holtz Zentrum M ünchen, N euherberg,403
Germ any404
198. Departm ent ofEpidem iology,Harvard S choolofP ublic Health,Boston,M A,02115,405
U S A406
P age10 of34
199. Departm ent of Epidem iology and P opualtion Health,Albert Einstein College of407
M edicine,Bronx,N Y,10461,U S A408
200. O xfordN IHR Biom edicalR esearchCentre,O xford,O X 3 7L J,U K409
201. CarolinaCenterforGenom e S ciencesand Departm ent ofEpidem iology,U niversity of410
N orthCarolinaatChapelHill,ChapelHill,N C,27599‑7400,U S A411
202. N ationalInstituteonAging,N ationalInstitutesofHealth,Bethesda,M D,20892,U S A412
203. P opulationHealthR esearchInstitute,S tGeorge's,U niversity ofL ondon,L ondon,S W 17413
0R E,U K414
204. GeneticsofCom plex T raits,U niversity ofExeterM edicalS chool,U niversity ofExeter,415
ExeterEX 1 2L U ,U K416
205. M etabolism Initiative,Broad Institute,Cam bridge,M A,02142,U S A417
206. Departm ent of M edicine I,U niversity Hospital Grosshadern,L udw ig-M axim ilians-418
U niversität,M unich,81377,Germ any419
207. T he GeneticsofO besity and R elated M etabolic T raitsP rogram ,T he Icahn S choolof420
M edicineatM ountS inai,N ew York,N Y,10029,U S A421
208. T he M indich Child Health and Developm entInstitute,T he Icahn S choolofM edicine at422
M ountS inai,N ew York,N Y,10029,U S A423
424
* T hese authorscontributed equally to thisw ork.** T hese authorsjointly supervised this425
w ork.426
Correspondence should be addressed to R uth L oos(em ail: ruth.loos@ m ssm .edu) or to427
M artinaM üller-N urasyid(em ail:m artina.m ueller@ helm holtz-m uenchen.de)428
P age11 of34
A bstract429
L arge consortiahave revealed hundredsof genetic lociassociated w ith anthropom etric430
traits,one trait at atim e.W e exam ined w hethergenetic variantsaffect body shape asa431
com posite phenotype that isrepresented by acom bination ofanthropom etric traits.W e432
developed an approach that calculatesaveraged P Cs(AvP Cs) representing body shape433
derived from six anthropom etric traits(body m assindex,height,w eight,w aist and hip434
circum ference,w aist-to-hip ratio).T he first fourAvP Csexplain >99% ofthe variability,are435
heritable,and associate w ith cardiom etabolic outcom es. W e perform ed genom e-w ide436
association analysesforeach body shapecom positephenotypeacross65 studiesand m eta-437
analyzed sum m ary statistics. W e identify six novelloci: L EM D2 and CD47 for AvP C1,438
R P S 6KA5/C14orf159 and GAN AB forAvP C3,and AR L 15 and AN P 32 forAvP C4.O urfindings439
highlight the value ofusing m ultiple traitsto define com plex phenotypesfordiscovery,440
w hicharenotcapturedby single-traitanalyses,and m ay shedlightontonew pathw ays.441
P age12 of34
IN T R O DU CT IO N442
L arge-scale m eta-analysesof genom e-w ide association studies(GW AS ) have identified443
num erouslociforanthropom etrictraits,includingm ore than 600 lociforheight1-3 and over444
160 lociforobesity-related outcom es,predom inantly forcom m only available traitssuch as445
body m assindex (BM I)2 and w aist-to-hip ratio (W HR )4,5,butalso forbody fatpercentage6 ,446
childhood obesity7 and extrem eand early onsetobesity7-9.W hileGW AS -m eta-analyseshave447
successfully revealed new loci,so far,all these studieshave focused on one single448
anthropom etrictrait at atim e and m ay not adequately capture differencesin body shape449
betw een individualsw ho are sim ilarin one trait but different in others. Forexam ple,tw o450
individualsm ay havethesam eBM I,buttheirW HR and/orheightcandiffersubstantially,so451
that each hasadifferent body shape,w hich m ay translate into differencesin disease452
risk10,11. S everallociidentified from previoussingle-traitGW AS on BM I,BM I-adjusted W HR453
(W HR adjBM I)and height are associated w ith m ore than one anthropom etric trait1,2,4,12.For454
exam ple,the locinear M C4R and near P O M C/ADCY3 are each associated w ith BM Iand455
height. How ever,the BM I-increasing allele of the near-M C4R locusisassociated w ith456
increased height,w hereasthe BM I-increasing allele of the near-P O M C/ADCY3 locusis457
associated w ith reduced height1,2.T hus,these lociare likely each associated w ith am ore458
com prehensive body shape phenotype that isnot captured by current GW AS that only459
consideranthropom etrictraitsindividually.460
In recentyears,severalapproacheshave been developed to exam ine w hetherS N P s461
influence m ultiple correlated traitsassociated w ith disease13,14.How ever,m ostapproaches462
testphenotypesseparately and arethussubjecttom ultipletestingpenaltiesthatultim ately463
reduce the statisticalpow erto detectgenotype-phenotype relationshipsam ong correlated464
traits.O ne w ay forw ard isto apply adim ension reduction m ethod to the traitsofinterest,465
P age13 of34
such asprincipalcom ponent analysis(P CA)that com binesm ultiple correlated traitsinto a466
set of uncorrelated outcom es(P Cs)15,16. T hism ethod isvery appealing to capture a467
com posite phenotype,such asbody shape.T o date,no large-scale GW AS m eta-analyses468
have been reported that aim to identify geneticlociassociated w ith body shape based on469
sim ultaneousanalysisofm ultipleanthropom etrictraitsusingP CA m ethods.470
T herefore,the purpose ofourstudy w astw ofold.First,w e aim ed to capture body471
shape in itsm ulti-dim ensionalstructure using principalcom ponents(P Cs) from several472
com m only available anthropom etrictraits.T o allow the m eta-analysisofsum m ary statistics473
acrossalarge num berofcohorts,w e developed an approach that calculatesaveraged P Cs474
(AvP Cs)that robustly represent body shape acrossaw ide range ofstudies.S econd,using475
thisapproach,w e aim ed to identify geneticlociassociated w ith body shape based on the476
AvP Csin65 studiesoftheGIAN T Consortium ,including>170,000 individuals.477
478
R ES U L T S479
DefiningCom positeP henotypesofBody S hapeinaM eta-A nalysisS etting480
Asbasisforouranalysisofbody shapew eused six anthropom etrictraits:BM I,W HR ,height,481
w eight,hip and w aist circum ference.First,w e perform ed separate P CA in asubset of20482
large population-based studies (up to 82,355 individuals, S upplem ent T able 1) and483
com pared the loadingsofthe anthropom etric traitsin each P C betw een studies. Visual484
inspection ofP CA loadingsshow ed high concordance acrossstudies(S upplem entary Fig.1)485
and betw een m en and w om en.Betw een-study variation in variance explained by the P Cs486
w assm all(S upplem entary Fig.1,S upplem entary T able 2).O n average,the first fourP Cs487
explained m ore than 99% percent ofthe variance (Figure 1,S upplem entary T able 2),and488
w ere therefore pursued asbody shape outcom esforourgene-discovery effort.Given the489
P age14 of34
across-study stability ofP Cs,w e derived averageloadingsthatw ere calculated asw eighted490
m eansofloadingsfrom all20 population-based studiesthatw ere analyzed in thisstep.W e491
used theseaverageloadingsto calculateaverageprincipalcom ponents(AvP Cs)astargetsin492
each ofthe GW AS included in the first and second stage.In otherw ords,the phenotypes493
used forgenom e-w ideassociationw ereconstructed inaconsistentw ay acrossstudies,such494
thatthesum m ary statisticscouldbem eta-analyzed.495
Each AvP C representsaspecific com position ofthe six anthropom etric traitsand496
thuscapturesaspecificaspect ofbody shape (Figure 1).T he first AvP C,w hich explainson497
average 64.4% ofthe variation in alltraits,show shigh loadingsforalltraits,except for498
height. T he loadingsare in the sam e direction; m eaning that the AvP C capturesinter-499
individualvariation in either increased or decreased BM I,w eight,W HR ,hip and w aist500
circum ference. T herefore,variation in thisP C seem sto predom inantly capture overall501
adiposity. T he second AvP C,w hich explains18.5% of the variation,ischaracterized by502
particularly high butopposite loadingson heightand W HR .In otherw ords,AvP C2 captures503
variationinacom positephenotypethatrepresentstallindividualsw ithasm allW HR ,orvice504
versa,shortindividualsw ith alarge W HR .T he third AvP C,explaining13.8% ofthe variation,505
also show spredom inantly high loadingson heightand W HR butin the sam e direction,w ith506
an opposite loading ofnearly the sam e size on hip circum ference.Given these loadings,507
AvP C3 discrim inatesm ainly betw een tallindividualsw ith ahigh W HR resulting from a508
sm allerhip circum ferenceon oneextrem eand shortindividualsw ith low W HR ,and alarger509
hip circum ference on the otherextrem e.T he fourth AvP C explainson average 3% and is510
harderto interpret.Itdisplayshigh loadingsonBM Iand body w eight,and oppositeloadings511
ofasim ilarsize on hip and w aistcircum ference.T hese could be interpreted asaphenotype512
rangingbetw een high BM Iand w eight,w ith relatively sm allhip and w aistcircum ference on513
P age15 of34
the one hand and low BM Iand w eight but large w aist and hip circum ference on the other514
hand.515
Consistent w ith the individualanthropom etric traits,the fourAvP Csthat describe516
body shape are also heritable.U sing datafrom fourisolate populations(n = 4,000),w e517
estim ated that AvP C2 hasthe highest heritability (75-80% ),consistent w ith the fact that518
height isthe m ain contributing trait to thisAvP C w ith astrong genetic com ponent 1.T he519
heritability ofAvP C1 (35-50% ),AvP C3 (50-75% )and AvP C4 (25-50% )w ere m oderately high520
and sim ilarto the heritability forindividualanthropom etrictraits17 (S upplem entary Fig.2).521
From aclinicalperspective,each ofthe fourAvP Csexhibit know n correlationsw ith cardio-522
m etabolic traits(S upplem ent Fig. 3),including diastolic blood pressure,systolic blood523
pressure,totalcholesterol,low -density lipoprotein cholesterol,high-density lipoprotein524
cholesterol,andtotaltriglycerideslevels.525
526
Genom icDiscovery ofBody S hapeCom positeP henotypes527
W e perform ed atw o-staged m eta-analysisto identify geneticlocithat are associated w ith528
the fourAvP Cs(S upplem entary T able 3,S upplem entary T able 4).In the firststage,am eta-529
analysisof43 studiesw ith im puted genom e-w ide S N P dataincluding m ore than 133,000530
individualsidentified S N P sin 385 lociacrossthe fourAvP Cs(56 lociforAvP C1,205 for531
AvP C2,89 forAvP C3,and 35 forAvP C4)thatshow ed prom isingassociation (p-value < 5x10-532
6)foratleastoneofthefourAvP Cs(Figure2,S upplem entary Fig.4).L eadS N P s(and proxies;533
see M ethods)ofeach locusw ere taken forw ard forvalidation in asecond stage,including534
datafrom m ore than 39,900 individualsfrom 22 studiesofw hich 12 studieshad genotypes535
from theIllum inaCardioM etabochip and 10 studieshad im puted genom e-w ideS N P data.In536
the com bined analyses,consisting ofthe first and second stage studies,the association of537
P age16 of34
207 ofthe 385 locireached genom e-w ide significance (p-value <5x10-8)(31 forAvP C1,124538
for AvP C2,45 for AvP C3,and 7 for AvP C4) (Figure 2,Figure 3,S upplem entary Fig. 4,539
S upplem entary T able 6),ofw hich 16 lociw ere identified fortw o AvP Csand one show ed540
significant association w ith three AvP Cs(S upplem entary Fig. 7,S upplem entary T able 5)541
resulting in atotalof189 lociw ith association to atleastone AvP C.T o determ ine w hether542
the lociw e identified w ere independent ofthe locipreviously found forBM I,W HR adjBM I543
and height,w e perform ed conditionalanalyseson S N P sreported in previousGIAN T -GW AS544
publicationson BM I,W HR adjBM I,and height1,2,4,5,18,19.A locusw asconsidered independent545
ofreported findingsifthe p-value in the analysesconditioned on allpreviously identified546
locirem ained suggestive (p-value <5x10-6).In total,183 locihad already been established547
forBM I,W HR adjBM Iorheight (Figure 3,S upplem entary Fig.7),w hereassix locihad not548
previously been identified forassociation w ith conventionalanthropom etrictraits;tw o for549
AvP C1,tw o for AvP C3 and tw o for AvP C4 (T able 1,local association plotsgiven in550
S upplem entary Fig.5).Forthese six novelloci,the resultsofthe lead S N P sw ere checked in551
previously perform ed GW AS m eta-analyseson anthropom etricand cardio-m etabolictraits552
(S upplem entary T able7).553
554
R esultsforA vP C1555
For AvP C1,w e identified 31 genom e-w ide significant loci,of w hich tw o w ere novel556
(upstream of L EM D2 and CD47). O f the 29 previously established loci,24 have been557
associated w ith BM Ionly18,3 w ith height only1,3,w hile tw o locihave been reported for558
associationsw ith both BM Iand height3,18 (Figure 3A).W hile both novellocishow ed som e559
evidence ofassociation w ith BM Iin the latest GIAN T -GW AS (n >339,000;p<7.2x10-3;T able560
1),they did notreach genom e-w ide significance.T he lead S N P (rs943466)7kb upstream of561
P age17of34
to L EM D2 hasbeen reported tobeassociated w ith expression ofL EM D2 in liver(p=1.66x10-562
9)20,21.Anothervariant in L EM D2 (rs2296743 at 8kb from ourlead S N P rs943466; r2=0.2,563
D’=1.0)w aspreviously reported foritsprom ising association (p-value = 8x10-6)w ith energy564
intake at dinnerin asm allGW AS of815 Hispanicchildren22.T he lead S N P (rs7640424)for565
thesecondnovellocusw aslocated inanenhancerregion10kbupstream ofCD4723,24,w hich566
encodesam em brane protein thatm ightbe involved in signaltransduction and m em brane567
transport25.N o genom e-w ide significant associationshave been reported forthe lead S N P568
orotherS N P sin the CD47 gene before23-25.How ever,arecentstudy revealed alinkto diet-569
induced obesity inm iceand suggestsCD47 asapotentialdrug-targettocom batobesity and570
m etaboliccom plications26,27.571
572
R esultsforA vP C2573
ForAvP C2,w e identified no novelloci.Alm ost all(n=122)ofthe 124 lociassociated w ith574
AvP C2 had previously been identified for height1 (Figure 3B),w hich isconsistent w ith575
AvP C2’shigh loadingsonheightand oppositeloadingson W HR .O fthese122 loci,103 w ere576
reported for association to height only,w hereasof the 19 rem aining loci,four w ere577
previously associated w ith height,BM Iand W HR adjBM I,tw o lociw ere reported forheight578
and BM I,and 13 locioverlapped w ith height and W HR .T he tw o AvP C2 locithat did not579
associatew ithheightw erepreviously identifiedforW HR adjBM I19.580
581
R esultsforA vP C3582
W e identified 45 locithatreached genom e-w ide significance forAvP C3,ofw hich tw o w ere583
novel.Consistent w ith the loadingsofAvP C3,43 ofthe associated locihad been reported584
before forheight1 orW HR 4,19 (Figure 3C).T he lead S N P ofthe firstnovellocusrs7492628,585
P age18of34
upstream ofthe genesR P S 6KA5 (> 20kb)and C14orf159 (>30kb),failed to reach genom e-586
w ide significance in previousW HR adjBM I GW AS (p-value =9.3x10-8) and w asnom inally587
associated w ith extrem e obesity risk(p-value=7.26x10-5)28.T he lead S N P ofthe othernovel588
locus,GAN AB,rs7949030,show ed som eevidenceofassociation w ithW HR adjBM Iin thelatest589
GIAN T GW AS (p-value=3.3x10-6)and w asreported to be an eQ T L forseveralothergenes21:590
Inm onocytes,regulationofM IR 3654,EEF1G,EM L 3,BS CL 2,HN R N P U L 2-BS CL 2,L R R N 4CL w as591
found29-31. BS CL 2 isof interest,asit isa know n candidate gene for the m ost severe592
lipodystrophy phenotype32.In blood rs7949030 w asfound to be an eQ T L ofHN R N P U L 2-593
BS CL 2,AHN AK,L R R N 4CL and IN T S 533,34,w hileinskinand adipocytesitw asfound asaneQ T L594
forEM L 330,31,35.595
596
R esultsforA vP C4597
S even lociw ere identified forAvP C4,ofw hich five had been previously reported;one for598
BM Iand height,one forW HR and height,one forheight only and tw o forW HR only1,3,4,36599
(Figure 3).T he lead S N P softhe tw o novellociidentified w ith AvP C4 w ere both intronic,in600
AR L 15 and AN P 32.T he allele associated w ith increased AvP C4 ofthe lead S N P (rs4865796)601
in AR L 15 w as m oderately associated w ith higher BM I (p-value=1.6x10-4), increased602
adiponectin levels (p-value=4.2x10-6 ADIP O GEN 37) and decreased risk of diabetes (p-603
value=1.8x10-5,DIAGR AM 38). T hisS N P w asassociated w ith fasting insulin (rs4865796,604
p=2.1x10-8 and 2.2x10-12 afteradjustm ent forBM I39).O thernearby S N P sin high L D,have605
previously been reported for associations w ith BM I-adjusted adiponectin levels606
(rs6450176/rs4311394,r2=0.087,D’=0.8737,40),HDL -C levels(rs645017641,42)and riskoftype607
2 diabetes(rs702634,r2=1.0 ,D’=1.038). A duplication in AR L 15,tagged by rs16992296)w as608
previously found to be associated w ith increased riskofchildhood obesity in European and609
P age19 of34
African Am ericans43.How ever,thisduplication isindependent ofthe association w e found610
forrs4865796-AR L 15 and AvP C4,w hich isin low L D (r2EU R = 0.065)w ith the duplication611
(represented by rs16992296),located 168kb upstream .T he lead S N P (rs7855432) ofthe612
second locus,AN P 32B,w asm oderately associated w ith height(p-value=5.5x10-6)1.A S N P in613
high L D (rs4743150 r2= 0.95,D'= 1.0) w asreported to be prom isingly associated w ith614
coronary heartdiseaserisk(p-value=5x10-6)44.615
616
DIS CU S S IO N617
W e developed a P CA-based approach to capture variation across m ultiple traits618
sim ultaneously inauniform w ay acrossm ultiplestudies.R esultingAvP Csarearobustcross-619
phenotype representation allow ingtheiruse in large-scale m eta-analyses.W e assessed this620
approachtocapturebody shapebased onsix individualanthropom etrictraitsand identified621
six novellocithat w ere not identified before in m uch largerGW AS -m eta-analysesforBM I,622
W HR adjBM I and height1,2,4.O urfindingssuggest that the body shape com posite phenotype,623
assessed by AvP Cs, represents inform ation that is not fully captured by individual624
(anthropom etric)traits.Application ofthism ethod to otherrelated traits,e.g.in im m une625
disease,different typesofcancer,cardiom etabolic traits,orothercorrelated traitsm ight626
com parably revealnew loci,and potentially new pathw ays,thathavenotbeen identified in627
single-traitGW AS .628
629
T heAvP Csarecom binationsofdifferentanthropom etrictraitsandthereforecapture630
m ore com plex body shape phenotypesthan the single traits.AvP C1,representing overall631
adiposity,and AvP C2,representing height w ith respect to W HR ,are the m ost im portant632
contributorsto body shape,explaining on average m ore than 80% ofthe variation.M ore633
P age20 of34
specificbody shape typesw ere captured by AvP C3 and AvP C4 and w ere defined by im pact634
ofheightand W HR (AvP C3)orBM I,w aistandhip(AvP C4).O urinitialanalysesdem onstrated635
that the loadingsare stable acrossstudies,study designs,and betw een m en and w om en.636
M oreover,w e have show n that the AvP Cs are heritable traits and correlated w ith637
cardiom etabolictraitsand riskfactors.638
639
T o furtherdem onstrate the strength ofthisapproach,w e com pared totalvariance640
explained ofsingle traitsand AvP Csby S N P spreviously identified in single-trait GW AS (for641
BM I,W HR adjBM I,height1,2,4. For exam ple,the 97 loci that have been reported for642
associationinthelatestBM Isingle-traitGW AS (N ~ 340,000)explain8.7% ofthevariationin643
AvP C1,w hereasthey explained only 2.68% ofthevariationinBM I2.T hesedataindicatethat644
our P C-defined phenotype for overall body size (AvP C1) capturesa m ore com posite645
phenotypecom pared toBM Iasasingle-trait.Explainingm oreofthevariancew iththesam e646
geneticvariantsasprevioussingle-traitstudiesin ourcom posite phenotype show sprom ise647
toupdateand inform existingm ethods.648
649
S o far, typical GW AS have tested for association of genetic variants w ith650
anthropom etrictraits,onetraitatatim e.W edefine‘body shape’ asacom positeofm ultiple651
traitsdefined by P Cs.W e first perform ed P C-analysesin representative population-based652
studiesand averaged P C loadingsacrossthese studies(AvP Cs).W e subsequently use these653
AvP Csto calculate P Csin allparticipating studies. T hisapproach ensuresthat P Csare654
calculated in a uniform m anner acrossallstudies,thusfacilitating subsequent m eta-655
analyses.T hisapproach could be applied to capture geneticvariation acrossrelated traits656
P age21 of34
that iscurrently not captured by single-traitsGW AS (e.g.in the context ofautoim m une657
disease,bloodtraits,lipid levels,differentcancers,etc.).658
Consistent w ith published anthropom etric traits10,11,17, the derived AvP Cs are659
heritable and correlated w ith clinically relevant outcom es. W e identified additionalloci,660
despite am uch sm allersam ple size com pared to the latest single-trait GW AS analysesfor661
BM I,height and W HR adjBM I1,2,4. T hissuggeststhat the AvP C m ethod capturesphenotype662
inform ation that isnot captured by single-trait analysesand associated locim ay highlight663
biologicalpathw aysthatarenotrevealed w ithsingle-traitassociatedlocionly.664
Even though ourapproach hasseveraladvantages,it isnot m eant to replace single665
trait GW AS analyses.A num beroflocithat w ere identified in the latest single-trait GW AS666
w erenotidentified inourbody shapeGW AS ;i.e.w eidentified 124 loci(or14.2% )ofthe837667
locirecently reported intheGIAN T single-traitm eta-analyses(S upplem entary Figure6).T his668
m ay be due to the fact that these recent single-trait GW AS m eta-analysesw ere at least669
tw ice aslarge asthe current body shape GW AS . How ever,even w hen w e com pare the670
num berofidentified lociin earlierGW AS m eta-analyses,w hich are ofsim ilarsize asthe671
current body shape GW AS ,w e do not identify allpreviously reported lociforsingle traits.672
P erhapsthisism ost obviousw ith height (largely representative ofAvP C2),w here w e only673
identified 91 (13.1% )of697 lociidentified forheight. T hisisin part due to the fact that a674
conservativedefinitionforlinkagedisequilibrium w asapplied (r2 > 0.8),lackofpow erdueto675
sam ple size forS N P sofm odest effects,orperhapsthe AvP Csintroducesnoise to purely676
single traitssuch asheight. Consistent w ith thisfinding,w e also observe that som e single677
traitsalso explain m ore ofthe variance ofbody shape com pared to AvP Cs.O urcom parison678
ofthevarianceexplained betw eenprevioussingletraitsm eta-GW AS and ourAvP Cssupport679
thisevidence foroverlapping associated variants.S ince AvP C2 representslargely asingle680
P age22 of34
trait,height,w ith large heightloadingsw e w ere unable to explain m ore ofthe variance.In681
fact w e explained lessofthe variance,w hich islikely due to noise introduced using this682
com posite AvP Csphenotype.T hisobservation isalso evident forvariance in body shape683
explained by heightcom paredtoAvP C3 andAvP C4,butisincontrasttoBM I,acom plex trait684
com prised ofm ultiple anthropom etricm easurem ents,w hich explainslessvariance in body685
shape com pared to AvP C3 and AvP C4.It isim portant to em phasize ourapproach ism ost686
inform ativeforcom plex traitssuch asBM Ithatarederived from aseriesofothertraits.W e687
believe that using P C space to define com plex traitsisusefulfor the detection ofloci688
involvedinm ultiplepathw aysthatm ightgoundetected inasingletraitsetting.689
690
W e have developed anew strategy that appliesaP CA approach in am eta-analysis691
settingto com bine com posite phenotypesin aharm onized w ay acrossm ultiple studies.W e692
successfully applied thisapproach to anthropom etric traitsto capture body shape. T he693
derived com bined anthropom etrictraits(AvP Cs)w ere show n to beheritable and correlated694
to cardio-m etabolictraits.L arge-scale GW AS m eta-analysesofthe AvP Csidentified six new695
locithat w ere not identified by previoussingle-trait GW AS that w ere tw ice aslarge in696
sam plessize. T hisP CA approach could m axim ize gene discovery forothercorrelated traits,697
such ascancers,im m une disease,hem atologictraits,etc.and m ay identify genesthatpoint698
tow ardsshared physiologicalpathw ays.699
700
701
P age23 of34
M ET HO DS702
S tudy description703
In the firststage analyses,43 studiesparticipated (133,376 individuals)thathad HapM ap 2704
im puted genom e-w ide dataavailable.A subsetof20 studiesw ith unrelated individualsw as705
used for calculation of average loadings. S econd stage analysesw ere perform ed in 10706
studies(7,734 individuals) w ith genom e-w ide datathat becam e available after the first707
stage and 12 studies(32,170 individuals) w ith Cardio-M etaboChip (by Illum ina© ) data708
(num berofincluded studiesand individualsgiven in S upplem entary T able 3).Detailson709
study phenotypes,genotyping and im putation ofeach study are given in the S upplem ent710
T ables8 and9,respectively.711
Ethicsstatem ent712
Allstudy participantsgave w ritten inform ed consent and ethic com m itteesapproved all713
studies.T heethicstatem entofeachstudy isgiveninthestudy specificacknow ledgem ents.714
CalculationofaverageL oadings715
In 20 independent studies(S upplem entary T able 1) w ith unrelated participantsprincipal716
com ponentanalyses(P CAs)w ere perform ed on six anthropom etrictraits(BM I,height,hip,717
w aist,w eight and W HR ).Each study perform ed aP CA on the standardized residualsofthe718
anthropom etrictraitsadjusted forage and gender.T he sam e analysesw ere done form en719
and w om en separately w ith residualsadjusted forage only.T he result ofthe P CA in each720
study isaset ofsix principalcom ponents(P Cs)that are orthogonallinearcom binationsof721
the six anthropom etric traits. In other w ordseach P C isa w eighted sum of the six722
transform ed anthropom etrictraitsand independent ofthe otherP Cs.T he w eightsofeach723
trait perP C are called loadings.Each study also calculated the explained variance perP C.724
P age24 of34
T he loadingsand explained variancesw ere com parableforallstudies(S upplem entary Fig.1725
(1)).726
W ith the intention to create phenotypesthat are identically constructed in all727
studies,the resultsofsingle study P CAsw ere used to deduce the average loadings.T his728
approach isreasonable asthe loadingsofthe study specific P CAsw ere com parable.W ith729
the use ofthe single study correlation m atricesacom bined average correlation m atrix w as730
derived (w eighted sum divided by num berofindividuals).T hisaverage correlation m atrix is731
then used asbasisforaP CA.T he loadingsthat result from thisP CA are called average732
loadings(Figure1(1)and S upplem entary T able2).T hisw asperform ed form en,w om en and733
allindividualscom bined,how everultim ately w eused com bined loadingsforprim ary results734
reported in them anuscript.S ex specificresultsare reported in the supplem entary m aterial.735
T heaverageloadingsand explained variancew erecom parabletothestudy specificloadings736
andexplainedvariances(S upplem entary Fig.1).737
Heritability analyses738
Heritability of the avP Csw ascalculated w ithin four population isolates,CR O AT IA-Vis739
(n=909),CR O AT IA-Korcula(n=842),CR O AT IA-S plit (n=499)and O R CADES (n=866)using the740
“ polygenic” functionoftheGenABEL packageforR 45.741
A verageprincipalcom ponentsasbody shapephenotype742
T he average loadingsw ere used in each study to calculate the AvP Csin astandardized w ay.743
T herefore,the average loadingsw ere distributed togetherw ith an R -script (http://w w w .r-744
project.org/) that calculated the AvP Csaslinear com bination of residualsof the study745
phenotypesw ith the use ofthe average loadings. T hisw asdone for m en and w om en746
separately and additionally forcom bined in studiesw ith relatednessstructure.Asthe first747
P age25 of34
fourP Csexplainon averagem orethan 99% ofthevariance(Figure1(2))w edecided to lim it748
allanalysestothesefourP Cs.749
S tage1 A nalyses750
GW AS on the firstfourAvP Csw ere calculated form en and w om en separately in studiesof751
unrelated sam plesand com bined forstudiesw ith related sam plesw ith an adjustm ent for752
study site w hen necessary.Allstudiesofthe first stage analysesused HapM ap 2 im puted753
genom e-w ide data. GW AS resultsunderw ent extensive quality controland study-w ise754
filtering (callrate >95% ,p-value (HW E)> 10-6,im putation quality,m inorallele count(M AC)755
>3).T he m etaanalysesofGW AS resultsforthe firstfourAvP Csw e com bined sex-stratified756
resultsforstudiesw ith unrelated individualsand unstratified GW AS resultsforstudiesw ith757
relatednessindividuals.M etaanalysesw ere perform ed w ith M ET AL 46 using fixed effects758
inverse variance-w eighted m ethod. S ingle study and the m eta analysisp-valuesw ere759
corrected by the genom ic control inflation factor λ (m eta analysis λ before correction: 760
λ(P C1)=1.29, λ(P C2)= 1.407, λ(P C3)= 1.236, λ(P C4)= 1.136). R esults w ere lim ited to S N P s that 761
are in HapM ap 2 and had resultsform ore than 30,000 individuals.Heterogeneity analysis762
w asperform ed w ith M ET AL .Each AvP C allS N P sw ith aprom isingp-value (p-value < 5x10-6)763
w ere identified in com bined analyses. T o identify prom ising lociclustering (L D > 0.01,764
distance <1000kb)w ith P L IN K47 based on HapM ap 2 genotypesw asperform ed.Allleading765
S N P sperclum p forAvP Csw ere taken forw ard to 2nd stage analysesand nam ed prom ising766
S N P sinthism anuscript.767
T w o S N P sthat w ere prom ising for the first principalcom ponent had very low768
heterogeneity p-values(rs10847678 (p-value(het)= 8.8x10-152),rs13296358 (p-value(het)=769
5.4x10-67)).Forboth S N P sthe effectw asdriven only by asingle study and no otherS N P in770
P age26 of34
high L D had aprom ising p-value.T herefore,these tw o S N P sw ere rem oved from further771
analyses.772
S tage2 A nalyses773
Asm entioned above for2nd stage analysesam ixture ofstudiesw ith genom e-w ide S N P774
dataand M etaboChip genotypesw asavailable.S om e ofthe leading S N P softhe 1st stage775
analysesw ere not genotyped on the M etaboChip.T o increase the pow erforallprom ising776
S N P sof each AvP C proxiesw ere defined that w ere allS N P sclose to prom ising S N P s777
(distance <500kb),in high L D (L D > 0.9)and available in m orethan 70% ofthe individualsof778
the 2nd stage.R esultsofthe 2nd stage analysesunderw entthe sam e quality controlas1st779
stageresults.780
Com binedA nalyses781
T hecom bined analysesofall1stand 2nd stageGW AS w asperform ed w ith M ET AL [35] w ith782
inverse variance based m ethod.R esultsform en and w om en w ere com bined asdescribed783
for the 1st stage m eta-analyses. Allprom ising locifor w hich at least one proxy had a784
genom e-w ide significant p-value in the com bined analysisw ere nam ed genom e-w ide785
significant lociand the best S N P ofthe com bined analyses(largest absolute beta) w as786
reportedastopS N P ofthislocus.787
N ovelloci-ConditionalA nalysesandL ook-upsinpreviousGIA N T analyses788
T w o analysesw ere perform ed to distinguish betw een genom e-w ide significantbody shape789
locithat are know n from previousGW AS on BM I,height and W HR and novelbody shape790
loci.Firstly,conditionalanalysesw ere perform ed.W e used the 226 reported topS N P s(32791
BM I,180 height,14 W HR ) ofpublished GIAN T analyseson BM I,height and W HR 1,2,4 to792
perform conditionalanalysesofthe 1ststage m eta-analysesusing GCT A15,48 .T he resultsof793
P age27of34
thisanalysisw ere then analyzed conditioned on 843 topS N P s(97 BM I,697 height,49 W HR )794
ofthepublished GIAN T analyses1,2,4.T oidentify theoverlapoftheresultsforAvP Csw iththe795
single anthropom etrictraits,the sam e conditionalanalysesw ereperform ed forBM I,height796
and W HR separately.Forcalculation ofthe L D-structure genotype datafrom KO R A F4 w as797
used.T w o topS N P softhe unpublished GIAN T resultshad to be rem oved before analysesas798
they w ere in high correlation w ith tw o othertopS N P s. Ifthe body shape topS N P sw ere799
independent lociidentified by previousGIAN T analyses,the p-value should stay prom ising800
(p-value < 5x10-6)in both conditionalanalyses.S econdly,w e checked by look-upsifthose801
genom e-w ide significant S N P sthat are independent from the previously reported topS N P s802
w erenotgenom e-w idesignificant(p-value> 5x10-8)inGIAN T analyses1,2,4.803
Genom e-w idesignificantS N P sarenam ed novelS N P sifthey fulfillthefollow ingconditions:804
(1)P -value ofconditioned analyseson topS N P sreported by previousGIAN T analyses(on805
BM I,height,W HR )rem ainedprom ising(p-value< 5x10-6).806
(2) P -value in previousGIAN T analyses(on BM I,height,W HR ) w asnot genom e-w ide807
significant(p-value> 5x10-8).808
P leiotropiceffects809
For identification of potentialpleiotropic effectsseverallook-upsin variouslarge-scale810
consortiaon differentphenotypesw ereperform ed,includingGIAN T ,DIAGR AM and M AGIC,811
allreferencesare given in the resultstable ofthe look-ups(S upplem entary T able 7).For812
com parison of effect directionsthe loadingsof each AvP C have to be considered. For813
exam ple AvP C2 includesheight w ith apositive loading and BM Iw ith anegative loading.814
T hat m eansan increasing effect on AvP C2 m eansan increasing effect on height but a815
decreasingeffectonBM I.816
P age28of34
FurtherAnalyses817
P CA,furtheranalysesand plotsw ere generated w ith R (http://w w w .r-project.org/)ifnot818
stated otherw ise.Apartfrom the GCT A analyses,w hich usesL D structureofKO R A F4,allL D819
analysesw ere perform ed in P L IN K based on HapM ap 2 (CEU )genotypes.Forcom parison of820
findingsbetw een locifrom different AvP Cstw o lociare assum ed to be identicalifthe821
topS N P sareinhighL D (L D > 0.8).822
823
Dataavailability824
S um m ary statisticsofallanalysescanbedow nloadedfrom :825
https://w w w .broadinstitute.org/collaboration/giant/826
827
A U T HO R CO N T R IBU T IO N S828
A detailed listofauthorcontributionisdescribed inS upplem entary N otes.829
830
A cknow ledgem ents831
A com pletelistofacknow ledgem entisdescribedinS upplem entary N otes.832
833
Com petingFinancialInterest834
Kari S tefansson, Valgerdur S teinthorsdottir, Gudm ar T horleifsson, and U nnur835
T horsteinsdottirare em ployed by deCO DE Genetics/Am gen inc.Gérard W aeberand P eter836
Vollenw eiderreceived an unrestricted grant from GS K to build the CoL ausstudy.Bruce M .837
P saty serveson aDS M B foraclinicaltrialofadevice funded by the m anufacturer(Zoll838
L ifeCor).839
P age29 of34
840
841
R EFER EN CES842
843
1. W ood,A.R . et al. Defining the role of com m on variation in the genom ic and844
biologicalarchitectureofadulthum anheight.N atGenet46,1173-86 (2014).845
2. L ocke,A.E.et al.Geneticstudiesofbody m assindex yield new insightsforobesity846
biology.N ature518,197-206 (2015).847
3. L ango Allen,H.et al.Hundredsofvariantsclustered in genom iclociand biological848
pathw aysaffecthum anheight.N ature467,832-8 (2010).849
4. S hungin,D. et al. N ew genetic locilink adipose and insulin biology to body fat850
distribution.N ature518,187-96 (2015).851
5. L iu,C.T .et al.Genom e-w ide association ofbody fat distribution in African ancestry852
populationssuggestsnew loci.P L oS Genet9,e1003681 (2013).853
6. Kilpelainen,T .O .etal.Geneticvariation nearIR S 1 associatesw ith reduced adiposity854
and anim paired m etabolicprofile.N atGenet43,753-60 (2011).855
7. Bradfield, J.P . et al. A genom e-w ide association m eta-analysis identifies new856
childhoodobesity loci.N atGenet44,526-31 (2012).857
8. W heeler,E.et al.Genom e-w ide S N P and CN V analysisidentifiescom m on and low -858
frequency variantsassociated w ith severe early-onset obesity.N at Genet 45,513-7859
(2013).860
9. M eyre,D.et al.Genom e-w ide association study forearly-onset and m orbid adult861
obesity identifiesthree new risklociin European populations.N at Genet 41,157-9862
(2009).863
10. M yint, P .K., Kw ok, C.S ., L uben, R .N ., W areham , N .J. & Khaw , K.T . Body fat864
percentage,body m assindex and w aist-to-hip ratio aspredictorsofm ortality and865
cardiovasculardisease.Heart100,1613-9 (2014).866
11. InterAct,C.etal.L ong-term riskofincidenttype 2 diabetesand m easuresofoverall867
and regionalobesity: the EP IC-InterAct case-cohort study. P L oS M ed 9,e1001230868
(2012).869
12. He,M .et al. M eta-analysisofgenom e-w ide association studiesofadult height in870
EastAsiansidentifies17novelloci.Hum M olGenet24,1791-800 (2015).871
13. P endergrass,S .A.et al.P henom e-w ide association study (P heW AS )fordetection of872
pleiotropy w ithin the P opulation Architecture using Genom icsand Epidem iology873
(P AGE)N etw ork.P L oS Genet9,e1003087(2013).874
14. Denny,J.C.etal.P heW AS :dem onstrating the feasibility ofaphenom e-w ide scan to875
discovergene-diseaseassociations.Bioinform atics26,1205-10 (2010).876
15. Yang,J.etal.Conditionaland jointm ultiple-S N P analysisofGW AS sum m ary statistics877
identifiesadditionalvariantsinfluencing com plex traits.N at Genet 44,369-75,S 1-3878
(2012).879
16. Aschard, H. et al. M axim izing the pow er of principal-com ponent analysis of880
correlated phenotypesin genom e-w ide association studies. Am J Hum Genet 94,881
662-76 (2014).882
17. P olderm an,T .J.etal.M eta-analysisofthe heritability ofhum an traitsbased on fifty883
yearsoftw instudies.N atGenet47,702-9 (2015).884
18. S peliotes,E.K.et al.Association analysesof249,796 individualsreveal18 new loci885
associatedw ithbody m assindex.N atGenet42,937-48 (2010).886
P age30 of34
19. Heid,I.M .et al.M eta-analysisidentifies13 new lociassociated w ith w aist-hip ratio887
and revealssexualdim orphism in the geneticbasisoffatdistribution.N atGenet42,888
949-60 (2010).889
20. Innocenti, F. et al. Identification, replication, and functional fine-m apping of890
expression quantitative trait lociin prim ary hum an liver tissue. P L oS Genet 7,891
e1002078(2011).892
21. Arnold,M .,R affler,J.,P feufer,A.,S uhre,K.& Kastenm uller,G.S N iP A:an interactive,893
geneticvariant-centeredannotationbrow ser.Bioinform atics31,1334-6 (2015).894
22. Com uzzie,A.G. et al. N ovel genetic loci identified for the pathophysiology of895
childhoodobesity intheHispanicpopulation.P L oS O ne7,e51954 (2012).896
23. W elter,D. et al. T he N HGR I GW AS Catalog,a curated resource of S N P -trait897
associations.N ucleicAcidsR es42,D1001-6 (2014).898
24. Beck,T .,Hastings,R .K.,Gollapudi,S .,Free,R .C. & Brookes,A.J. GW AS Central: a899
com prehensive resource for the com parison and interrogation of genom e-w ide900
associationstudies.EurJHum Genet22,949-52 (2014).901
25. L i,M .J.etal.GW AS db:adatabase forhum an geneticvariantsidentified by genom e-902
w ideassociationstudies.N ucleicAcidsR es40,D1047-54 (2012).903
26. S oto-P antoja,D.R .,Kaur,S . & R oberts,D.D. CD47 signaling pathw ayscontrolling904
cellular differentiation and responsesto stress. Crit R ev Biochem M olBiol,1-19905
(2015).906
27. M aim aitiyim ing,H.,N orm an,H.,Zhou,Q .& W ang,S .CD47 Deficiency P rotectsM ice907
From Diet-induced O besity and Im provesW holeBody Glucose T olerance and Insulin908
S ensitivity.S ciR ep5,8846 (2015).909
28. P aternoster,L .etal.Genom e-w ide population-based association study ofextrem ely910
overw eightyoungadults--theGO YA study.P L oS O ne6,e24303 (2011).911
29. Zeller,T .et al.Geneticsand beyond--the transcriptom e ofhum an m onocytesand912
diseasesusceptibility.P L oS O ne5,e10693 (2010).913
30. W ang,H.D.et al.DN A m ethylation study offetusgenom e through agenom e-w ide914
analysis.BM C M edGenom ics7,18(2014).915
31. T egha-Dunghu,J.et al.EM L 3 isanuclearm icrotubule-binding protein required for916
thecorrectalignm entofchrom osom esinm etaphase.JCellS ci121,1718-26 (2008).917
32. W ee,K.,Yang,W .,S ugii,S . & Han,W . T ow ardsam echanistic understanding of918
lipodystrophy and seipinfunctions.BiosciR ep34(2014).919
33. W estra,H.J. et al. S ystem atic identification oftranseQ T L sasputative driversof920
know ndiseaseassociations.N atGenet45,1238-43 (2013).921
34. R am das,M .,Harel,C.,Arm oni,M .& Karnieli,E.AHN AK KO M ice are P rotected from922
Diet-InducedO besity butareGlucoseIntolerant.Horm M etabR es47,265-72 (2015).923
35. Grundberg,E.etal.M appingcis-and trans-regulatory effectsacrossm ultiple tissues924
intw ins.N atGenet44,1084-9 (2012).925
36. Cham bers,J.C. et al. Genetic lociinfluencing kidney function and chronic kidney926
disease.N atGenet42,373-5 (2010).927
37. Dastani,Z. et al. N ovellocifor adiponectin levelsand their influence on type 2928
diabetesand m etabolic traits: am ulti-ethnic m eta-analysisof45,891 individuals.929
P L oS Genet8,e1002607(2012).930
38. R eplication,D.I.G.et al.Genom e-w ide trans-ancestry m eta-analysisprovidesinsight931
into the geneticarchitecture oftype 2 diabetessusceptibility.N atGenet46,234-44932
(2014).933
P age31 of34
39. S cott,R .A. et al. L arge-scale association analysesidentify new loci influencing934
glycem ic traitsand provide insight into the underlying biologicalpathw ays. N at935
Genet44,991-1005 (2012).936
40. R ichards,J.B.et al.A genom e-w ide association study revealsvariantsin AR L 15 that937
influenceadiponectinlevels.P L oS Genet5,e1000768 (2009).938
41. T eslovich,T .M .etal.Biological,clinicaland population relevance of95 lociforblood939
lipids.N ature466,707-13 (2010).940
42. GlobalL ipidsGenetics,C.etal.Discovery and refinem entoflociassociated w ithlipid941
levels.N atGenet45,1274-83 (2013).942
43. Glessner,J.T .etal.A genom e-w ide study revealscopy num bervariantsexclusive to943
childhoodobesity cases.Am JHum Genet87,661-6 (2010).944
44. Coronary Artery Disease Genetics,C.A genom e-w ide association study in Europeans945
and S outh Asiansidentifiesfive new lociforcoronary artery disease.N at Genet 43,946
339-44 (2011).947
45. Aulchenko,Y.S .,R ipke,S .,Isaacs,A. & van Duijn,C.M . GenABEL : an R library for948
genom e-w ideassociationanalysis.Bioinform atics23,1294-6 (2007).949
46. W iller,C.J.,L i,Y. & Abecasis,G.R . M ET AL : fast and efficient m eta-analysisof950
genom ew ideassociationscans.Bioinform atics26,2190-1 (2010).951
47. P urcell,S . et al. P L IN K: atoolset forw hole-genom e association and population-952
basedlinkageanalyses.Am JHum Genet81,559-75 (2007).953
48. Yang,J.,L ee,S .H.,Goddard,M .E.& Visscher,P .M .GCT A: atoolforgenom e-w ide954
com plex traitanalysis.Am JHum Genet88,76-82 (2011).955
956
957
P age32 of34
FigureL egends958
Figure 1: L oadingsand explained variance ofA vP Csforbody shape. (1a) L oadingsof959
AcP Cs,and(1b)explained varianceofAvP Csforbody shape.960
Figure2:M anhattan and Q Q -plotsofassociation resultson A vP Csofbody shape.P -values961
ofthe firststage m eta-analysisare given in the M anhattan and Q Q -plots.Allgenom e-w ide962
significantlociarehighlighted.963
Figure3:N um beroflociassociated w ith A vP Csand know n from previousGIA N T analyses964
on BM I,W HR orheight.T he Venn diagram sspecify foreach AvP C how m any significantly965
associated loci(prom isingp-valueinthefirststagem etaanalysis(<5x10-6)and genom ew ide966
significant in first and second stage com bined analysis(<5x10-8))are know n from previous967
GIAN T analysisonBM I,heightorW HR .In theupperrightcornerofeachplotthenum berof968
lociisgiventhatarenotknow nfrom previousGIAN T analyses.969
970
Figure1:LoadingsandexplainedvarianceofAvPCsforbodyshape.
(1a)loadingsofAvPCs
(1b)Explainedvariance
Figure2:ManhattanandQQ-plotsofassociationresultsonAvPCsofbodyshape.
P-valuesofthefirststagemeta-analysisaregivenintheManhattanandQQ-plots.Allgenome-
widesignificantlociarehighlighted.
Figure3:NumberoflociassociatedwithAvPCsandknownfrompreviousGIANTanalyseson
BMI, WHR or height. The Venn diagrams specify for each AvPC how many significantly
associated loci (promisingp-value in the first stagemetaanalysis (<5x10-6)andgenomewide
significant in first and second stage combined analysis (<5x10-8)) are known from previous
GIANTanalysisonBMI,heightorWHR.Intheupperrightcornerofeachplotthenumberofloci
isgiventhatarenotknownfrompreviousGIANTanalyses.
A" B"
C" D"
P age33 of34
971
T able1:Associationresultsfornovellociw ithavP C ofbody shape.T heassociationresultsforthe1ststage,2nd stageand 1stand2nd stagecom bined analysisisgivenforallsix locithatw eregenom ew idesignificantly associated(prom isingp-valueinthefirststagem etaanalysis(<5x10-6)andgenom ew idesignificantinfirstandsecond stagecom binedanalysise(<5x10-8))w ithoneoftheavP Csandnovel.M oreover,thep-valuesoftheanalysisconditionedonalltophitsfrom therecentGIAN T publicationsonBM I,heightandW HR .
effect/
other
allele
1ststageupto
133,376sam ples
2ndstageupto
39,904sam ples
1st+ 2ndstagecom bined
upto173,278sam ples
conditionedanalysisonallGIA N T tophits
p-valueofS N P sinGIA N T analysis**
p-valueofS N P sinGIA N T analysis***
trait S N P (leadS N P )
nextgene
EAF* p-value p-value
beta(sebeta)
p-value N
beta(sebeta)
p-value BM I
height W HR BM I
height W HR
avPC1 rs7640424 CD47
C/T
69%
5.40E-07 0.0015
0.05(0.008)
3.18E-09
171544
0.05(0.01)
5.80E-07
0.0072
0.74 0.25
2.28E-06 0.28 0.85
avPC1
rs943466(rs2281819)
L EMD2
G/A
76%
6.39E-07 0.016
0.049(0.009)
3.47E-08
172174
0.049(0.01)
7.28E-07
2.7E-04
0.045 0.54
9.34E-06 0.75 0.25
avPC3 rs7949030
GANAB
G/A
38%
2.74E-08 0.11
0.024(0.004)
5.58E-09
139195
0.025(0.004)
6.36E-09
0.082
0.80
1.4E-04 0.54
0.041
3.3E-06
avPC3 rs7492628
R P S 6KA5
G/C
30%
8.75E-08 0.13
0.024(0.004)
1.90E-08
139874
0.024(0.004)
7.93E-08
0.064
0.62
4.9E-05
0.0050 0.58
9.3E-08
avPC4
rs4865796(rs1664781)
AR L 15
G/A
32%
5.59E-07 0.011
0.008(0.001)
2.25E-08
172517
0.008(0.002)
7.25E-07
5.1E-05
0.034 0.40
1.6E-04
0.020 0.84
avPC4 rs7855432
AN P 32B
G/T
80%
1.40E-07 0.17
0.01(0.002)
4.06E-08
140805
0.01(0.002)
1.78E-07 0.33
0.046 0.49 0.32
5.5E-06 0.91
* EAFism eanofEAFofallstudiesinthe1ststagem etaanalysis** alltophitsoftheGIAN T analysispublishedbefore2014 3,6
*** alltophitsoftheGIAN T analysisunpublishedand/orpublishedafter2014 1,2,4
P age34 of34
972