Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults

RESEARCH ARTICLE Genome-wide physical ac i i y in e ac ions in adiposi y ―A me a-analysis o 200,452 adul s Ma iaelisa G a 1☯ *, Robe A. Sco 2☯ , Anne E. Jus ice 1☯ , K is in L. Young 1,3☯ , Ma y F. Fei osa 4 , Llilda Ba a a 4 , Thomas W. Winkle 5 , Aud ey Y. Chu 6,7 , Anubha Mahajan 8 , Da id Hadley 9 , Lu ing Xue 6,10 , Tsegaselassie Wo kalemahu 11 , Nancy L. Hea d-Cos a 6,12 , Ma cel den Hoed 2,13 , Ta un ee S. Ahluwalia 14,15 , Qibin Qi 16 , Julius S. Ngwa 17 , F ida Rens o ¨m 18,19 , Lydia Quaye 20 , John D. Eiche 21 , James E. Hayes 22,23 , Ma ilyn Co nelis 11,24,25 , Zol an Ku alik 26,27 , Elise Lim 10 , Jian’an Luan 2 , Jenni e E. Hu man 6,28 , Weihua Zhang 29,30 , Wei Zhao 31 , Paula J. G i in 10 , Toomas Halle 32 , Sha qa Ahmad 18 , Ped o M. Ma ques-Vidal 33 , S ephanie Bien 34 , Loic Yengo 35 , Alexande Teume 36,37 , Albe Ve non Smi h 38,39 , Meena Kuma i 40 , Ma ie Nee gaa d Ha de 14 , Johanne Ma ie Jus esen 14 , Ma cus E. Klebe 41,42 , Me e Hollens ed 14 , Ku Lohman 43 , Na alia V. Ri e a 44 , John B. Whi ield 45 , Jing Hua Zhao 2 , Hea he M. S ingham 46 , Leo-Pekka Lyy ika ¨inen 47,48 , Cha lo e Huppe z 49,50,51 , Gonneke Willemsen 49,50 , Wou e J. Pey o 52 , Ying Wu 53 , Ka i K is iansson 54,55 , Ayse Demi kan 56,57 , My iam Fo nage 58,59 , Maija Hassinen 60 , Law ence F. Bielak 31 , Gemma Cadby 61 , Toshiko Tanaka 62 , Reedik Ma ¨gi 32 , Pe e J. an de Mos 63 , Anne U. Jackson 46 , Jenni e L. B agg-G esham 46 , Ve onique Vi a 28 , Jona han Ma en 28 , Pau Na a o 28 , Clai e Bellis 64,65 , Do o a Pasko 66 ,Åsa Johansson 67 , Sø en Sni ke 68 , Yu- Ching Cheng 68,69 , Joel E iksson 70 , Unhee Lim 71 , Me e Aadahl 72,73 , Linda S. Adai 74 , Naja Amin 56 , Be e ley Balkau 75 , Juha Au inen 76,77 , John Beilby 78,79,80 , Richa d N. Be gman 81 , S en Be gmann 27,82 , Alain G. Be oni 83,84 , John Blange o 85 , Ame ´lie Bonne ond 35 , Lo i L. Bonnycas le 86 , Judi h B. Bo ja 87,88 , Sø en B age 2 , Fabio Busone o 89 , S e e Buyske 90,91 , Ha y Campbell 92 , Pe e S. Chines 86 , F ancis S. Collins 86 , Tanguy Co e 27,82 , Geo ge Da ey Smi h 93 , G aciela E. Delgado 41 , Nicole Dueke 94 , Ma cus Do ¨ 37,95 , Tapani Ebeling 96,97 , Gudny Ei iksdo i 38 , Tõnu Esko 32,98,99,100 , Jessica D. Faul 101 , Mao Fu 68 , K is ine Fæ ch 15 , Ch is ian Giege 102,103,104 , S en Gla ¨se 95 , Jian Gong 34 , Penny Go don-La sen 3,74 , Ha ald G alle 102,104,105 , Tanja B. G amme 41 , Niels G a up 14 , Ge a d an G oo hees 52 , Kenne Ha ald 54 , Nicholas D. Has ie 28 , Aki S. Ha ulinna 54 , Dena He nandez 106 , Lucia Hindo 107 , Lynne J. Hocking 108,109 , Oddgei L. Holmens 110 , Ch is ina Holzap el 102,111 , Jouke Jan Ho enga 49,112 , Jie Huang 113 , Tao Huang 11 , Jennie Hui 78,79,114 , Co nelia Hu h 104,105 , Nina Hu i-Ka ¨ho ¨nen 115,116 , Alan L. James 78,117,118 , John-Olo Jansson 119 , Min A. Jhun 31 , Ma kus Juonala 120,121 , Leena Kinnunen 122 , Heikki A. Kois inen 122,123,124 , I ana Kolcic 125 , Pi jo Komulainen 60 , Johanna Kuusis o 126 , Ki s i K aløy 127 , Mika Ka ¨ho ¨nen 128,129 , Timo A. Lakka 60,130 , Leno e J. Laune 131 , Benjamin Lehne 29 , Cecilia M. Lindg en 8,132,133 , Ma ias Lo en zon 70,134 , Robe Luben 135 , Michel Ma e 136,137 , Yu i Milaneschi 52 , Ke i L. Monda 1,138 , G an W. Mon gome y 45 , Ma leen H. M. De Moo 50,139 , An onella Mulas 89,140 , Ma ina Mu ¨lle -Nu asyid 103,141,142 , A. W. Musk 78,114,143 , Reija Ma ¨nnikko ¨ 60 , Sa u Ma ¨nnis o ¨ 54 , Na isu Na isu 86 , Ma hias Nauck 37,144 , Jenni e A. Ne le on 59 , Ilja M. Nol e 63 , Albe ine J. Oldehinkel 145 , Ma hias Olden 5 , Ken K. Ong 2 , Sandosh Padmanabhan 109,146 , La inia Pa e nos e 93 , Je emiah Pe ez 10 , Ma kus Pe ola 54,55,147 , Anne e Pe e s 104,105,142 , Ul ike Pe e s 34 , Pa icia A. Peyse 31 , Inga P okopenko 148 , Hannu Puolijoki 149 , Olli T. Rai aka i 150,151 , Tuomo Rankinen 152 , Lau a J. Rasmussen-To ik 24 , Rajesh Rawal 102,103,104 , Paul M. Ridke 7,153 , Lynda M. Rose 7 , Igo Rudan 92 , Cinzia Sa i 154 , Ma k A. Sa zynski 152 , Kai Sa onen 60 , William R. Sco 29 , Se ena Sanna 89 , Alan R. Shuldine 68,69 , S e e Sidney 155 , Gu ¨n he Silbe nagel 156 , Blai H. Smi h 109,157 , Jenni e A. Smi h 31 , Ha old Sniede 63 , Alena S anča ´ko a ´ 126 , Ba ba a S e n eld 155 , Amy J. Swi 86 , Tuija Tammelin 158 , Sian-Tsung Tan 159 , Ba ba a Tho and 104,105 , Do o he ´e Thuillie 35 , Liesbe h Vandenpu 70 , Hen ik Ves e gaa d 14,15 , Jana V. an Vlie -Os ap chouk 160 , PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 1 / 26 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Ci a ion: G a M, Sco RA, Jus ice AE, Young KL, Fei osa MF, Ba a a L, e al. (2017) Genome-wide physical ac i i y in e ac ions in adiposi y ―A me a- analysis o 200,452 adul s. PLoS Gene 13(4): e1006528. h ps://doi.o g/10.1371/jou nal. pgen.1006528 Edi o : Todd L. Edwa ds, Vande bil Uni e si y, UNITED STATES Recei ed: Augus 17, 2016 Accep ed: Decembe 7, 2016 Published: Ap il 27, 2017 Copy igh : This is an open access a icle, ee o all copy igh , and may be eely ep oduced, dis ibu ed, ansmi ed, modi ied, buil upon, o o he wise used by anyone o any law ul pu pose. The wo k is made a ailable unde he C ea i e Commons CC0 public domain dedica ion. Da a A ailabili y S a emen : All genome-wide associa ion me a-analysis esul s iles a e a ailable a he GIANT Conso ium websi e: www. b oadins i u e.o g/collabo a ion/gian . Funding: The iews exp essed in his manusc ip a e hose o he au ho s and do no necessa ily ep esen he iews o he Na ional Hea , Lung, and Blood Ins i u e; he Na ional Ins i u es o Heal h; o he U.S. Depa men o Heal h and Human Se ices. Funding o his s udy was p o ided by he Aase and Ejne Danielsens Ma ie-Claude Vohl 161,162 , Uwe Vo ¨lke 37,163 , Ge ´ a d Waebe 33 , Ma k Walke 164 , Sa ah Wild 165 , And ew Wong 166 , Alan F. W igh 28 , M. Ca ola Zillikens 167 , Niha Zubai 34 , Ch is ophe A. Haiman 168 , Loic Lema chand 71 , Ul Gyllens en 67 , Claes Ohlsson 70 , Albe Ho man 169,170 , Fe nando Ri adenei a 167,169,170 , And e ´G. Ui e linden 167,169 , Louis Pe ´ usse 161,171 , James F. Wilson 28,92 , Ca oline Haywa d 28 , Oz en Polasek 92,125 , F ancesco Cucca 89,140 , K is ian H eem 127 , Ca ha ina A. Ha man 172 , Anke To ¨njes 173 , S e ania Bandinelli 174 , Lyle J. Palme 175 , Sha on L. R. Ka dia 31 , Raine Rau amaa 60,176 , Tho kild I. A. Sø ensen 14,73,93,177 , Jaakko Tuomileh o 122,178,179 , Veikko Salomaa 54 , B enda W. J. H. Penninx 52 , Eco J. C. de Geus 49,50 , Do e I. Boomsma 49,112 , Te ho Leh ima ¨ki 47,48 , Massimo Mangino 20,180 , Ma kku Laakso 126 , Claude Boucha d 152 , Nicholas G. Ma in 45 , Diana Kuh 166 , Yongmei Liu 83 , Allan Linnebe g 72,181,182 , Win ied Ma ¨ z 41,183,184 , Kons an in S auch 103,185 , Mika Ki ima ¨ki 186 , Tama a B. Ha is 187 , Vilmundu Gudnason 38,39 , Hen y Vo ¨lzke 36,37 , Lu Qi 11 , Ma jo-Rii a Ja ¨ elin 29,76,77,188,189 , John C. Chambe s 29,30,190 , Jaspal S. Koone 30,159,190 , Philippe F oguel 35,191 , Cha les Koope be g 34 , Pe e Vollenweide 33 , Go ¨ an Hallmans 19 , To ben Hansen 14 , Olu Pede sen 14 , And es Me spalu 32 , Nicholas J. Wa eham 2 , Claudia Langenbe g 2 , Da id R. Wei 101 , Da id J. Po eous 109,192 , E ic Boe winkle 59 , Daniel I. Chasman 7,100,153 , CHARGE Conso ium, EPIC-In e Ac Conso ium, PAGE Conso ium ¶ , Gonc¸alo R. Abecasis 46 , Inês Ba oso 193,194,195 , Ma k I. McCa hy 8,196,197 , Timo hy M. F ayling 66 , Je ey R. O’Connell 68 , Co nelia M. an Duijn 56,170,198 , Michael Boehnke 46 , I is M. Heid 5 , Ka en L. Mohlke 53 , Da id P. S achan 199 , Ca oline S. Fox 21 , Ching-Ti Liu 10 , Joel N. Hi schho n 99,100,200 , Robe J. Klein 23 , And ew D. Johnson 6,21 , Ing id B. Bo ecki 4 , Paul W. F anks 11,18,201 , Ka i E. No h 202 , L. Ad ienne Cupples 6,10 , Ru h J. F. Loos 2,203,204,205‡ *, Tuomas O. Kilpela ¨inen 2,14,205‡ * 1Depa men o Epidemiology, Gillings School o Global Public Heal h, Uni e si y o No h Ca olina a Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 2MRC Epidemiology Uni , Ins i u e o Me abolic Science, Uni e si y o Camb idge, Camb idge, Uni ed Kingdom, 3Ca olina Popula ion Cen e , Uni e si y o No h Ca olina a Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 4Depa men o Gene ics, Washing on Uni e si y School o Medicine, S . Louis, Missou i, Uni ed S a es o Ame ica, 5Depa men o Gene ic Epidemiology, Uni e si y o Regensbu g, Regensbu g, Ge many, 6Na ional Hea , Lung, and Blood Ins i u e, F amingham Hea S udy, F amingham, Massachuse s, Uni ed S a es o Ame ica, 7Di ision o P e en i e Medicine, B igham and Women’s Hospi al, Bos on, Massachuse s, Uni ed S a es o Ame ica, 8Wellcome T us Cen e o Human Gene ics, Uni e si y o Ox o d, Ox o d, Uni ed Kingdom, 9Di ision o Popula ion Heal h Sciences and Educa ion, S . Geo ge’s, Uni e si y o London, London, Uni ed Kingdom, 10 Depa men o Bios a is ics, Bos on Uni e si y School o Public Heal h, Bos on, Massachuse s, Uni ed S a es o Ame ica, 11 Depa men o Nu i ion, Ha a d T.H. Chan School o Public Heal h, Bos on, Massachuse s, Uni ed S a es o Ame ica, 12 Depa men o Neu ology, Bos on Uni e si y School o Medicine, Bos on, Massachuse s, Uni ed S a es o Ame ica, 13 Depa men o Immunology, Gene ics and Pa hology and Science o Li e Labo a o y, Uppsala Uni e si y, Uppsala, Sweden, 14 No o No disk Founda ion Cen e o Basic Me abolic Resea ch, Sec ion o Me abolic Gene ics, Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen, Copenhagen, Denma k, 15 S eno Diabe es Cen e , Gen o e, Denma k, 16 Depa men o Epidemiology and Popula ion Heal h, Albe Eins ein College o Medicine, B onx, New Yo k, Uni ed S a es o Ame ica, 17 Howa d Uni e si y, Depa men o In e nal Medicine, Washing on DC, Uni ed S a es o Ame ica, 18 Depa men o Clinical Sciences, Gene ic and Molecula Epidemiology Uni , Lund Uni e si y, Malmo ¨, Sweden, 19 Depa men o Biobank Resea ch, UmeåUni e si y, Umeå, Sweden, 20 Depa men o Twin Resea ch and Gene ic Epidemiology, King’s College London, London, Uni ed Kingdom, 21 Popula ion Sciences B anch, Na ional Hea , Lung, and Blood Ins i u e, Na ional Ins i u es o Heal h, The F amingham Hea S udy, F amingham, Massachuse s, Uni ed S a es o Ame ica, 22 Cell and De elopmen al Biology G adua e P og am, Weill Co nell G adua e School o Medical Sciences, Co nell Uni e si y, New Yo k, New Yo k, Uni ed S a es o Ame ica, 23 Icahn Ins i u e o Genomics and Mul iscale Biology, Icahn School o Medicine a Moun Sinai, New Yo k, New Yo k, Uni ed S a es o Ame ica, 24 Depa men o P e en i e Medicine, No hwes e n Uni e si y Feinbe g School o Medicine, Chicago, Illinois, Uni ed S a es o Ame ica, 25 Channing Di ision o Ne wo k Medicine, Depa men o Medicine, B igham and Women’s Hospi al and Ha a d Medical School, Bos on, Massachuse s, Uni ed S a es o Ame ica, 26 Ins i u e o Social and P e en i e Medicine, Lausanne Uni e si y Hospi al, Lausanne, Swi ze land, 27 Swiss Ins i u e o Bioin o ma ics, Lausanne, Swi ze land, 28 MRC Human Gene ics Uni , Ins i u e o Gene ics and Molecula Medicine, Uni e si y o Edinbu gh, Wes e n Gene al Hospi al, Edinbu gh, Uni ed Kingdom, 29 Depa men o Epidemiology and Bios a is ics, School o Public Heal h, Impe ial College London, London, Uni ed Kingdom, 30 Depa men o Ca diology, Ealing Hospi al HNS T us , Middlesex, Uni ed Kingdom, 31 Depa men o Epidemiology, School o Public Heal h, Uni e si y o Michigan, Ann A bo , Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 2 / 26 Founda ion; Academy o Finland (102318; 104781, 120315, 123885, 129619, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 250207, 258753, 41071, 77299, 124243, 1114194, 24300796); Acca e Cen e o Child and Adolescen Psychia y; Ac ion on Hea ing Loss (G51); Agence Na ionale de la Reche che; Agency o Heal h Ca e Policy Resea ch (HS06516); Age UK Resea ch in o Ageing Fund; Åke Wibe g Founda ion; ALF/LUA Resea ch G an in Go henbu g; ALFEDIAM; ALK-Abello´ A/S (Hø sholm, Denma k); Ame ican Hea Associa ion (13POST16500011, 10SDG269004); A dix Medical; A h i is Resea ch UK; Associa ion Diabè e Risque Vasculai e; As aZeneca; Aus alian Associa ed B ewe s; Aus alian Na ional Heal h and Medical Resea ch Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); A e a Resea ch Ins i u e; Baye Diagnos ics; Bec on Dickinson; Biobanking and Biomolecula Resou ces Resea ch In as uc u e (BBMRI –NL, 184.021.007); Biocen um Helsinki; Bos on Obesi y Nu i ion Resea ch Cen e (DK46200); B i ish Hea Founda ion (RG/10/12/28456, SP/04/002); Canada Founda ion o Inno a ion; Canadian Ins i u es o Heal h Resea ch (FRN-CCT-83028); Cance Resea ch UK; Ca dionics; Cen e o Medical Sys ems Biology; Cen e o Excellence in Complex Disease Gene ics and SALVECen e o Excellence in Genomics (EXCEGEN); Chie Scien is O ice o he Sco ish Go e nmen ; Ci y o Kuopio; Coho es San e ´TGIR; Con a de P oje s E ´ a -Re ´gion; C oa ian Science Founda ion (8875); Danish Agency o Science, Technology and Inno a ion; Danish Council o Independen Resea ch (DFF– 1333-00124, DFF–1331-007308); Danish Diabe es Academy; Danish Medical Resea ch Council; Depa men o Psychology and Educa ion o he VU Uni e si y Ams e dam; Diabe es Hil s- und Fo schungs onds Deu schland; Du ch B ain Founda ion; Du ch Minis y o Jus ice; Emil Aal onen Founda ion; E asmus Medical Cen e ; E asmus Uni e si y; Es onian Go e nmen (IUT20- 60, IUT24-6); Es onian Minis y o Educa ion and Resea ch (3.2.0304.11-0312); Eu opean Commission (230374, 284167, 323195, 692145, FP7 Eu HEALTHAgeing-277849, FP7 BBMRI-LPC 313010, n 602633, HEALTH-F2-2008-201865- GEFOS, HEALTH-F4-2007-201413, FP6 LSHM-CT- 2004-005272, FP5 QLG2-CT-2002-01254, FP6 LSHG-CT-2006-01947, FP7 HEALTH-F4-2007- 201413, FP7 279143, FP7 201668, FP7 305739, FP6 LSHG-CT-2006-018947, HEALTH-F4-2007- 201413, QLG1-CT-2001-01252); Eu opean Regional De elopmen Fund; Eu opean Science Founda ion (Eu oSTRESS p ojec FP-006, ESF, EU/ Michigan, Uni ed S a es o Ame ica, 32 Es onian Genome Cen e , Uni e si y o Ta u, Ta u, Es onia, 33 Depa men o In e nal Medicine, In e nal Medicine, Lausanne Uni e si y Hospi al, Lausanne, Swi ze land, 34 Di ision o Public Heal h Sciences, F ed Hu chinson Cance Resea ch Cen e , Sea le, Washing on, Uni ed S a es o Ame ica, 35 Uni e si y o Lille, CNRS, Ins i u Pas eu de Lille, UMR 8199 - EGID, Lille, F ance, 36 Ins i u e o Communi y Medicine, Uni e si y Medicine G ei swald, G ei swald, Ge many, 37 DZHK (Ge man Cen e o Ca dio ascula Resea ch), pa ne si e G ei swald, G ei swald, Ge many, 38 Icelandic Hea Associa ion, Kopa ogu , Iceland, 39 Facul y o Medicine, Uni e si y o Iceland, Reykja ik, Iceland, 40 ISER, Uni e si y o Essex, Colches e , Essex, Uni ed Kingdom, 41 V h Depa men o Medicine, Medical Facul y Mannheim, Heidelbe g Uni e si y, Mannheim, Ge many, 42 Ins i u e o Nu i ion, F ied ich Schille Uni e si y Jena, Jena, Ge many, 43 Depa men o Bios a is ical Sciences, Di ision o Public Heal h Sciences, Wake Fo es School o Medicine, Wins on-Salem, No h Ca olina, Uni ed S a es o Ame ica, 44 Ka olinska Ins i u e , Respi a o y Uni , Depa men o Medicine Solna, S ockholm, Sweden, 45 Gene ic Epidemiology, QIMR Be gho e Medical Resea ch Ins i u e, B isbane, Aus alia, 46 Cen e o S a is ical Gene ics, Depa men o Bios a is ics, Uni e si y o Michigan, Ann A bo , Michigan, Uni ed S a es o Ame ica, 47 Depa men o Clinical Chemis y, Fimlab Labo a o ies, Tampe e, Finland, 48 Depa men o Clinical Chemis y, Uni e si y o Tampe e School o Medicine, Tampe e, Finland, 49 Depa men o Biological Psychology, V ije Uni e si ei , Ams e dam, The Ne he lands, 50 EMGO+ Ins i u e, V ije Uni e si ei & VU Uni e si y Medical Cen e , Ams e dam, The Ne he lands, 51 Depa men o Public and Occupa ional Heal h, VU Uni e si y Medical Cen e , Ams e dam, The Ne he lands, 52 Depa men o Psychia y, EMGO Ins i u e o Heal h and Ca e Resea ch and Neu oscience Campus Ams e dam, VU Uni e si y Medical Cen e /GGZ InGees , Ams e dam, The Ne he lands, 53 Depa men o Gene ics, Uni e si y o No h Ca olina, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 54 Na ional Ins i u e o Heal h and Wel a e, Depa men o Heal h, Helsinki, Finland, 55 Ins i u e o Molecula Medicine Finland, Uni e si y o Helsinki, Helsinki, Finland, 56 Gene ic Epidemiology Uni , Depa men o Epidemiology, E asmus MC, Ro e dam, The Ne he lands, 57 Depa men o Human Gene ics, Leiden Uni e si y Medical Cen e , Leiden, The Ne he lands, 58 Ins i u e o Molecula Medicine, Uni e si y o Texas Heal h Science Cen e a Hous on, Hous on, Texas, Uni ed S a es o Ame ica, 59 Di ision o Epidemiology, Human Gene ics, and En i onmen al Sciences, Uni e si y o Texas Heal h Science Cen e a Hous on, Hous on, Texas, Uni ed S a es o Ame ica, 60 Kuopio Resea ch Ins i u e o Exe cise Medicine, Kuopio, Finland, 61 Cen e o Gene ic O igins o Heal h and Disease, Uni e si y o Wes e n Aus alia, C awley, Wes e n Aus alia, Aus alia, 62 T ansla ional Ge on ology B anch, Na ional Ins i u e on Aging, Bal imo e, Ma yland, Uni ed S a es o Ame ica, 63 Depa men o Epidemiology, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, G oningen, The Ne he lands, 64 Human Gene ics, Genome Ins i u e o Singapo e, Agency o Science, Technology and Resea ch o Singapo e, Singapo e, 65 Genomics Resea ch Cen e, Ins i u e o Heal h and Biomedical Inno a ion, Queensland Uni e si y o Technology, B isbane, Queensland, Aus alia, 66 Gene ics o Complex T ai s, Uni e si y o Exe e Medical School, Uni e si y o Exe e , Exe e , Uni ed Kingdom, 67 Depa men o Immunology, Gene ics and Pa hology, Uppsala Uni e si y, Uppsala, Sweden, 68 Di ision o Endoc inology, Diabe es, and Nu i ion, Uni e si y o Ma yland School o Medicine, Bal imo e, Ma yland, Uni ed S a es o Ame ica, 69 Ve e ans A ai s Ma yland Heal h Ca e Sys em, Uni e si y o Ma yland, Bal imo e, Ma yland, Uni ed S a es o Ame ica, 70 Cen e o Bone and A h i is Resea ch, Depa men o In e nal Medicine and Clinical Nu i ion, Ins i u e o Medicine, Sahlg enska Academy, Uni e si y o Go henbu g, Go henbu g, Sweden, 71 Epidemiology P og am, Uni e si y o Hawaii Cance Cen e , Honolulu, Hawaii, Uni ed S a es o Ame ica, 72 Resea ch Cen e o P e en ion and Heal h, Glos up Uni e si y Hospi al, Glos up, Denma k, 73 Depa men o Public Heal h, Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen, Copenhagen, Denma k, 74 Depa men o Nu i ion, Gillings School o Global Public Heal h, Uni e si y o No h Ca olina a Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 75 INSERM U-1018, CESP, Renal and Ca dio ascula Epidemiology, UVSQ-UPS, Villejui , F ance, 76 Cen e o Li e Cou se Heal h Resea ch, Facul y o Medicine, Uni e si y o Oulu, Oulu, Finland, 77 Uni o P ima y Ca e, Oulu Uni e si y Hospi al, Oulu, Finland, 78 Bussel on Popula ion Medical Resea ch Ins i u e, Nedlands, Wes e n Aus alia, Aus alia, 79 Pa hWes Labo a o y Medicine o WA, Si Cha les Gai dne Hospi al, Nedlands, Wes e n Aus alia, Aus alia, 80 School o Pa hology and Labo a o y Medicine, The Uni e si y o Wes e n Aus alia, C awley, Wes e n Aus alia, Aus alia, 81 Diabe es and Obesi y Resea ch Ins i u e, Ceda s-Sinai Medical Cen e , Los Angeles, Cali o nia, Uni ed S a es o Ame ica, 82 Depa men o Medical Gene ics, Uni e si y o Lausanne, Lausanne, Swi ze land, 83 Depa men o Epidemiology and P e en ion, Di ision o Public Heal h Sciences, Wake Fo es School o Medicine, Wins on-Salem, No h Ca olina, Uni ed S a es o Ame ica, 84 Depa men o In e nal Medicine, Wake Fo es School o Medicine, Wins on-Salem, No h Ca olina, Uni ed S a es o Ame ica, 85 Texas Biomedical Resea ch Ins i u e, San An onio, Texas, Uni ed S a es o Ame ica, 86 Medical Genomics and Me abolic Gene ics B anch, Na ional Human Genome Resea ch Ins i u e, NIH, Be hesda, Ma yland, Uni ed S a es o Ame ica, 87 USC-O ice o Popula ion S udies Founda ion, Inc., Uni e si y o San Ca los, Cebu Ci y, Philippines, 88 Depa men o Nu i ion and Die e ics, Uni e si y o San Ca los, Cebu Ci y, Philippines, 89 Is i u o di Rice ca Gene ica e Biomedica (IRGB), Consiglio Nazionale Delle Rice che (CNR), Ci adella Uni e si a ia di Monse a o, Monse a o, I aly, 90 Depa men o Gene ics, Ru ge s Uni e si y, Pisca away, New Je sey, Uni ed S a es o Ame ica, Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 3 / 26 QLRT-2001-01254); Facul y o Biology and Medicine o Lausanne; Fede al Minis y o Educa ion and Resea ch (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 03IS2061A); Fede al S a e o Mecklenbu g - Wes Pome ania; Fe ´de ´ a ion F anc¸aise de Ca diologie; Finnish Cul u al Founda ion; Finnish Diabe es Associa ion; Finnish Founda ion o Ca dio ascula Resea ch; Finnish Hea Associa ion; Food S anda ds Agency; Fonda ion de F ance; Fonds San e ´; Gene ic Associa ion In o ma ion Ne wo k o he Founda ion o he Na ional Ins i u es o Heal h; Ge man Diabe es Associa ion; Ge man Fede al Minis y o Educa ion and Resea ch (BMBF, 01ER1206, 01ER1507); Ge man Resea ch Council (SFB-1052, SPP 1629 TO 718/2-1); GlaxoSmi hKline; Go¨ an Gus a ssons Founda ion; Go¨ ebo g Medical Socie y; Heal h and Sa e y Execu i e; Hea Founda ion o No he n Sweden; Icelandic Hea Associa ion; Icelandic Pa liamen ; Impe ial College Heal hca e NHS T us ; INSERM, Re ´seaux en San e ´ Publique, In e ac ions en e les de ´ e minan s de la san e ´; In e eg IV Obe hein P og am (A28); I alian Minis y o Economy and Finance; I alian Minis y o Heal h (ICS110.1/RF97.71); John D and Ca he ine T MacA hu Founda ion; Juho Vainio Founda ion; King’s College London; Kjell och Ma¨ a Beije s Founda ion; Kuopio Uni e si y Hospi al; Kuopio, Tampe e and Tu ku Uni e si y Hospi al Medical Funds (X51001); Leiden Uni e si y Medical Cen e ; Lilly; LMUinno a i ; Lundbeck Founda ion; Lundbe g Founda ion; Medical Resea ch Council o Canada; MEKOS Labo a o ies (Denma k); Me ck San e ´; Mid-A lan ic Nu i ion Obesi y Resea ch Cen e (P30 DK72488); Minis è e de l’E ´conomie, de l’Inno a ion e des Expo a ions; Minis y o Heal h, Wel a e and Spo s o he Ne he lands; Minis y o Cul u al A ai s o he Fede al S a e o Mecklenbu g-Wes Pome ania; Minis y o Educa ion and Cul u e o Finland (627;2004-2011); Minis y o Educa ion, Cul u e and Science o he Ne he lands; MRC Human Gene ics Uni ; MRC-GlaxoSmi hKline Pilo P og amme G an (G0701863); Municipali y o Ro e dam; Ne he lands Bioin o ma ics Cen e (2008.024); Ne he lands Conso ium o Heal hy Aging (050-060-810); Ne he lands Genomics Ini ia i e; Ne he lands O ganisa ion o Heal h Resea ch and De elopmen (904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, Addic ion-31160008, Middelg oo -911-09-032, Spinozap emie 56-464-14192); Ne he lands O ganisa ion o Heal h Resea ch and De elopmen (2010/31471/ZONMW); Ne he lands O ganisa ion o Scien i ic Resea ch (10-000-1002, GB-MW 940-38-011, 100-001-004, 60-60600-97-118, 261- 98-710, GB-MaGW 480-01-006, GB-MaGW 480- 91 Depa men o S a is ics and Bios a is ics, Ru ge s Uni e si y, Pisca away, New Je sey, Uni ed S a es o Ame ica, 92 Cen e o Global Heal h Resea ch, Ushe Ins i u e o Popula ion Heal h Sciences and In o ma ics, Edinbu gh, Sco land, 93 MRC In eg a i e Epidemiology Uni & School o Social and Communi y Medicine, Uni e si y o B is ol, B is ol, Uni ed Kingdom, 94 Uni e si y o Ma yland School o Medicine, Depa men o Epidemiology & Public Heal h, Bal imo e, Ma yland, Uni ed S a es o Ame ica, 95 Depa men o In e nal Medicine B, Uni e si y Medicine G ei swald, G ei swald, Ge many, 96 Depa men o Medicine, Oulu Uni e si y Hospi al, Oulu, Finland, 97 Ins i u e o Clinical Medicine, Facul y o Medicine, Uni e si y o Oulu, Oulu, Finland, 98 Di ision o Endoc inology, Bos on Child en’s Hospi al, Bos on, Massachuse s, Uni ed S a es o Ame ica, 99 Depa men o Gene ics, Ha a d Medical School, Bos on, Massachuse s, Uni ed S a es o Ame ica, 100 B oad Ins i u e o he Massachuse s Ins i u e o Technology and Ha a d Uni e si y, Camb idge, Massachuse s, Uni ed S a es o Ame ica, 101 Su ey Resea ch Cen e , Ins i u e o Social Resea ch, Uni e si y o Michigan, Ann A bo , Michigan, Uni ed S a es o Ame ica, 102 Resea ch Uni o Molecula Epidemiology, Helmhol z Zen um Mu¨nchen - Ge man Resea ch Cen e o En i onmen al Heal h, Neuhe be g, Ge many, 103 Ins i u e o Gene ic Epidemiology, Helmhol z Zen um Mu¨nchen, Ge man Resea ch Cen e o En i onmen al Heal h, Neuhe be g, Ge many, 104 Ins i u e o Epidemiology II, Helmhol z Zen um Mu¨nchen-Ge man Resea ch Cen e o En i onmen al Heal h, Neuhe be g, Ge many, 105 Ge man Cen e o Diabe es Resea ch (DZD), Mu¨nchen-Neuhe be g, Ge many, 106 Labo a o y o Neu ogene ics, Na ional Ins i u e on Aging, Be hesda, Ma yland, Uni ed S a es o Ame ica, 107 Di ision o Genomic Medicine, Na ional Human Genome Resea ch Ins i u e, Na ional Ins i u es o Heal h, Be hesda, Ma yland, Uni ed S a es o Ame ica, 108 Musculoskele al Resea ch P og amme, Di ision o Applied Medicine, Uni e si y o Abe deen, Fo es e hill, Abe deen, Uni ed Kingdom, 109 Gene a ion Sco land, Cen e o Genomic and Expe imen al Medicine, Uni e si y o Edinbu gh, Edinbu gh, Uni ed Kingdom, 110 S . Ola Hospi al, T ondheim Uni e si y Hospi al, T ondheim, No way, 111 Ins i u e o Nu i ional Medicine, Klinikum Rech s de Isa , Technische Uni e si a ¨ Mu¨nchen, Munich, Ge many, 112 NCA Ins i u e, VU Uni e si y & VU Medical Cen e , Ams e dam, The Ne he lands, 113 Depa men o Human Gene ics, Wellcome T us Sange Ins i u e, Hinx on, Camb idge, Uni ed Kingdom, 114 School o Popula ion Heal h, The Uni e si y o Wes e n Aus alia, C awley, Wes e n Aus alia, Aus alia, 115 Depa men o Pedia ics, Tampe e Uni e si y Hospi al, Tampe e, Finland, 116 Depa men o Pedia ics, Uni e si y o Tampe e School o Medicine, Tampe e, Finland, 117 Depa men o Pulmona y Physiology and Sleep Medicine, Si Cha les Gai dne Hospi al, Nedlands, Wes e n Aus alia, Aus alia, 118 School o Medicine and Pha macology, The Uni e si y o Wes e n Aus alia, C awley, Wes e n Aus alia, Aus alia, 119 Depa men o Physiology, Ins i u e o Neu oscience and Physiology, Sahlg enska Academy, Uni e si y o Go henbu g, Go henbu g, Sweden, 120 Depa men o Medicine, Uni e si y o Tu ku, Tu ku, Finland, 121 Di ision o Medicine, Tu ku Uni e si y Hospi al, Tu ku, Finland, 122 Na ional Ins i u e o Heal h and Wel a e, Depa men o Heal h, Helsinki, Finland, 123 Depa men o Medicine and Abdominal Cen e : Endoc inology, Uni e si y o Helsinki and Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland, 124 Mine a Founda ion Ins i u e o Medical Resea ch, Helsinki, Finland, 125 Depa men o Public Heal h, Facul y o Medicine, Uni e si y o Spli , Spli , C oa ia, 126 Depa men o Medicine, Uni e si y o Eas e n Finland and Kuopio Uni e si y Hospi al, Kuopio, Finland, 127 HUNT Resea ch Cen e, Depa men o Public Heal h and Gene al P ac ice, No wegian Uni e si y o Science and Technology, Le ange , No way, 128 Depa men o Clinical Physiology, Tampe e Uni e si y Hospi al, Tampe e, Finland, 129 Depa men o Clinical Physiology, Uni e si y o Tampe e School o Medicine, Tampe e, Finland, 130 Ins i u e o Biomedicine, Physiology, Uni e si y o Eas e n Finland, Kuopio Campus, Finland, 131 Neu oepidemiology Sec ion, Na ional Ins i u e on Aging, Na ional Ins i u es o Heal h, Be hesda, Ma yland, Uni ed S a es o Ame ica, 132 P og am in Medical and Popula ion Gene ics, B oad Ins i u e, Camb idge, Massachuse s, Uni ed S a es o Ame ica, 133 The Big Da a Ins i u e, Uni e si y o Ox o d, Ox o d, Uni ed Kingdom, 134 Ge ia ic Medicine, Sahlg enska Uni e si y Hospi al, Mo ¨lndal, Sweden, 135 Depa men o Public Heal h and P ima y Ca e, Uni e si y o Camb idge, Camb idge, Uni ed Kingdom, 136 INSERM U-1138, E ´quipe 2: Pa hophysiology and The apeu ics o Vascula and Renal diseases Rela ed o Diabe es, Cen e de Reche che des Co delie s, Pa is, F ance, 137 Depa men o Endoc inology, Diabe ology, Nu i ion, and Me abolic Diseases, Bicha Claude Be na d Hospi al, Pa is, F ance, 138 Cen e o Obse a ional Resea ch, Amgen Inc., Thousand Oaks, Cali o nia, Uni ed S a es o Ame ica, 139 Sec ion o Clinical Child and Family S udies, Depa men o Educa ional and Family S udies, V ije Uni e si ei , Ams e dam, The Ne he lands, 140 Dipa imen o di Scienze Biomediche, Uni e si àdegli S udi di Sassa i, Sassa i, I aly, 141 Depa men o Medicine I, Ludwig-Maximilians-Uni e si a ¨ , Munich, Ge many, 142 DZHK (Ge man Cen e o Ca dio ascula Resea ch), pa ne si e Munich Hea Alliance, Munich, Ge many, 143 Depa men o Respi a o y Medicine, Si Cha les Gai dne Hospi al, Nedlands, Wes e n Aus alia, Aus alia, 144 Ins i u e o Clinical Chemis y and Labo a o y Medicine, Uni e si y Medicine G ei swald, G ei swald, Ge many, 145 In e disciplina y Cen e Psychopa hology and Emo ion Regula ion (ICPE), Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, G oningen, The Ne he lands, 146 Ins i u e o Ca dio ascula and Medical Sciences, BHF Glasgow Ca dio ascula Resea ch Cen e, Uni e si y o Glasgow, Glasgow, Uni ed Kingdom, 147 Uni e si y o Ta u, Es onian Genome Cen e, Ta u, Es onia, 148 Genomics o Common Disease, Impe ial College London, London, Uni ed Kingdom, 149 Sou h Os obo hnia Cen al Hospi al, Seina ¨joki, Finland, 150 Depa men o Clinical Physiology and Nuclea Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 4 / 26 07-001, GB-MaGW 452-04-314, GB-MaGW 452- 06-004, 175.010.2003.005, 175.010.2005.011, 481-08-013, 480-05-003, 911-03-012); Neu oscience Campus Ams e dam; NHS Founda ion T us ; No a is Pha maceu icals; No o No disk; O ice Na ional In e p o essionel des Vins; Paa o Nu mi Founda ion; Påhlssons Founda ion; Pa¨i ikki and Saka i Sohlbe g Founda ion; Pie e Fab e; Republic o C oa ia Minis y o Science, Educa ion and Spo (108-1080315-0302); Resea ch Cen e o P e en ion and Heal h, he Capi al Region o Denma k; Resea ch Ins i u e o Diseases in he Elde ly (014-93-015, RIDE2); Roche; Russian Founda ion o Basic Resea ch (NWO-RFBR 047.017.043); Ru ge s Uni e si y Cell and DNA Reposi o y (NIMH U24 MH068457-06); Sano i-A en is; Sco ish Execu i e Heal h Depa men (CZD/16/6); Siemens Heal hca e; Social Insu ance Ins i u ion o Finland (4/26/2010); Social Minis y o he Fede al S a e o Mecklenbu g-Wes Pome ania; Socie ´ e ´ F ancophone du Diabè e; S a e o Ba a ia; S oke Associa ion; Swedish Diabe es Associa ion; Swedish Founda ion o S a egic Resea ch; Swedish Hea -Lung Founda ion (20140543); Swedish Resea ch Council (2015-03657); Swedish Medical Resea ch Council (K2007-66X-20270-01- 3, 2011-2354); Swedish Socie y o Medical Resea ch; Swiss Na ional Science Founda ion (33CSCO-122661, 33CS30-139468, 33CS30- 148401); Tampe e Tube culosis Founda ion; The Ma cus Bo gs o¨m Founda ion; The Royal Socie y; The Wellcome T us (084723/Z/08/Z, 088869/B/09/ Z); Timbe Me chan Vilhelm Bangs Founda ion; Topcon; To s en and Ragna So¨de be g’s Founda ion; UK Depa men o Heal h; UK Diabe es Associa ion; UK Medical Resea ch Council (MC_U106179471, G0500539, G0600705, G0601966, G0700931, G1002319, K013351, MC_UU_12019/1); UK Na ional Ins i u e o Heal h Resea ch BioResou ce Clinical Resea ch Facili y and Biomedical Resea ch Cen e; UK Na ional Ins i u e o Heal h Resea ch (NIHR) Comp ehensi e Biomedical Resea ch Cen e; UK Na ional Ins i u e o Heal h Resea ch (RP-PG- 0407-10371); UmeåUni e si y Ca ee De elopmen Awa d; Uni ed S a es – Is ael Bina ional Science Founda ion G an (2011036); Uni e si y Hospi al Oulu (75617); Uni e si y Medical Cen e G oningen; Uni e si y o Ta u (SP1GVARENG); Na ional Ins i u es o Heal h (AG13196, CA047988, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSC271201100004C, HHSN268200900041C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, Medicine, Tu ku Uni e si y Hospi al, Tu ku, Finland, 151 Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine, Uni e si y o Tu ku, Tu ku, Finland, 152 Human Genomics Labo a o y, Penning on Biomedical Resea ch Cen e , Ba on Rouge, Louisiana, Uni ed S a es o Ame ica, 153 Ha a d Medical School, Bos on, Massachuse s, Uni ed S a es o Ame ica, 154 Social Se ices and Heal h Ca e Depa men , Ci y o Helsinki, Helsinki, Finland, 155 Di ision o Resea ch, Kaise Pe manen e No he n Cali o nia, Oakland, Cali o nia, Uni ed S a es o Ame ica, 156 Di ision o Angiology, Depa men o In e nal Medicine, Medical Uni e si y G az, Aus ia, 157 School o Medicine, Uni e si y o Dundee, Ninewells Hospi al and Medical School, Dundee, Sco land, 158 LIKES Resea ch Cen e o Spo and Heal h Sciences, Jy a ¨skyla ¨, Finland, 159 Na ional Hea and Lung Ins i u e, Impe ial College London, Uni ed Kingdom, 160 Depa men o Endoc inology, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, G oningen, The Ne he lands, 161 Ins i u e o Nu i ion and Func ional Foods, Quebec, Canada, 162 School o Nu i ion, La al Uni e si y, Quebec, Canada, 163 In e acul y Ins i u e o Gene ics and Func ional Genomics, Uni e si y Medicine G ei swald, Ge many, 164 Ins i u e o Cellula Medicine, Newcas le Uni e si y, Newcas le upon Tyne, Uni ed Kingdom, 165 Cen e o Popula ion Heal h Sciences, Ushe Ins i u e o Popula ion Heal h Sciences and In o ma ics, Te io Place, Edinbu gh, Sco land, 166 MRC Uni o Li elong Heal h and Ageing a UCL, London, Uni ed Kingdom, 167 Depa men o In e nal Medicine, E asmus MC, Ro e dam, The Ne he lands, 168 Depa men o P e en i e Medicine, No is Comp ehensi e Cance Cen e , Keck School o Medicine, Uni e si y o Sou he n Cali o nia, Los Angeles, Cali o nia, Uni ed S a es o Ame ica, 169 Depa men o Epidemiology, E asmus MC, Ro e dam, The Ne he lands, 170 Ne he lands Conso ium o Heal hy Aging, Leiden Uni e si y Medical Cen e , Leiden, The Ne he lands, 171 Depa men o Kinesiology, La al Uni e si y, Quebec, Canada, 172 Depa men o Psychia y, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, G oningen, The Ne he lands, 173 Uni e si y o Leipzig, Medical Depa men , Leipzig, Ge many, 174 Ge ia ic Uni , Azienda Sani a ia Fi enze, Flo ence, I aly, 175 School o Public Heal h, Uni e si y o Adelaide, Adelaide, Sou h Aus alia, Aus alia, 176 Depa men o Clinical Physiology and Nuclea Medicine, Kuopio Uni e si y Hospi al, Kuopio, Finland, 177 Depa men o Clinical Epidemiology, Bispebje g and F ede iksbe g Hospi als, The Capi al Region, Copenhagen, Denma k, 178 Cen e o Vascula P e en ion, Danube-Uni e si y K ems, K ems, Aus ia, 179 Diabe es Resea ch G oup, King Abdulaziz Uni e si y, Jeddah, Saudi A abia, 180 Na ional Ins i u e o Heal h Resea ch Biomedical Resea ch Cen e a Guy’s and S . Thomas’ Founda ion T us , London, Uni ed Kingdom, 181 Depa men o Clinical Expe imen al Resea ch, Rigshospi ale , Glos up, Denma k, 182 Depa men o Clinical Medicine, Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen, Copenhagen, Denma k, 183 Synlab Academy, Synlab Se ices LLC, Mannheim, Ge many, 184 Clinical Ins i u e o Medical and Chemical Labo a o y Diagnos ics, Medical Uni e si y o G az, G az, Aus ia, 185 Ins i u e o Medical In o ma ics, Biome y and Epidemiology, Chai o Gene ic Epidemiology, Ludwig-Maximilians- Uni e si a ¨ , Munich, Ge many, 186 Depa men o Epidemiology and Public Heal h, Uni e si y College London, London, Uni ed Kingdom, 187 Labo a o y o Epidemiology and Popula ion Science, Na ional Ins i u e on Aging, Be hesda, Ma yland, Uni ed S a es o Ame ica, 188 Biocen e Oulu, Uni e si y o Oulu, Oulu, Finland, 189 MRC-PHE Cen e o En i onmen and Heal h, Impe ial College London, London, Uni ed Kingdom, 190 Impe ial College Heal hca e NHS T us , London, Uni ed Kingdom, 191 Hamme smi h Hospi al, London, Uni ed Kingdom, 192 Cen e o Genomic and Expe imen al Medicine, Ins i u e o Gene ics and Molecula Medicine, Uni e si y o Edinbu gh, Edinbu gh, Uni ed Kingdom, 193 Wellcome T us Sange Ins i u e, Hinx on, Uni ed Kingdom, 194 NIHR Camb idge Biomedical Resea ch Cen e, Ins i u e o Me abolic Science, Addenb ooke’s Hospi al, Camb idge, Uni ed Kingdom, 195 The Uni e si y o Camb idge Me abolic Resea ch Labo a o ies, Wellcome T us -MRC Ins i u e o Me abolic Science, Camb idge, Uni ed Kingdom, 196 Ox o d Cen e o Diabe es, Endoc inology and Me abolism, Uni e si y o Ox o d, Chu chill Hospi al, Ox o d, Uni ed Kingdom, 197 Ox o d NIHR Biomedical Resea ch Cen e, Ox o d, Uni ed Kingdom, 198 Cen e o Medical Sys ems Biology, Leiden, The Ne he lands, 199 Popula ion Heal h Resea ch Ins i u e, S . Geo ge’s Uni e si y o London, London, Uni ed Kingdom, 200 Di isions o Endoc inology and Gene ics and Cen e o Basic and T ansla ional Obesi y Resea ch, Bos on Child en’s Hospi al, Bos on, Massachuse s, Uni ed S a es o Ame ica, 201 Depa men o Public Heal h & Clinical Medicine, Umeå Uni e si y, Umeå, Sweden, 202 Ca olina Cen e o Genome Sciences, Gillings School o Global Public Heal h, Uni e si y o No h Ca olina a Chapel Hill, Chapel Hill, No h Ca olina, Uni ed S a es o Ame ica, 203 Gene ics o Obesi y and Rela ed Me abolic T ai s P og am, Cha les B on man Ins i u e o Pe sonalized Medicine, Icahn School o Medicine a Moun Sinai, New Yo k, New Yo k, Uni ed S a es o Ame ica, 204 The Mindich Child Heal h and De elopmen Ins i u e, Icahn School o Medicine a Moun Sinai, New Yo k, New Yo k, Uni ed S a es o Ame ica, 205 The Depa men o P e en i e Medicine, The Icahn School o Medicine a Moun Sinai, New Yo k, New Yo k, Uni ed S a es o Ame ica ☯These au ho s con ibu ed equally o his wo k. ‡ These au ho s join ly supe ised his wo k. ¶ Membe ship is lis ed in he Suppo ing In o ma ion. *[email p o ec ed]u (MG); u [email protected] (RJFL); [email protected] (TOK) Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 5 / 26 HHSN268201300029C, HHSN268201500001I, HL36310, HG002651, HL034594, HL054457, HL054481, HL071981, HL084729, HL119443, HL126024, N01-AG12100, N01-AG12109, N01- HC25195, N01-HC55015, N01-HC55016, N01- HC55018, N01-HC55019, N01-HC55020, N01- HC55021, N01-HC55022, N01-HD95159, N01- HD95160, N01-HD95161, N01-HD95162, N01- HD95163, N01-HD95164, N01-HD95165, N01- HD95166, N01-HD95167, N01-HD95168, N01- HD95169, N01-HG65403, N02-HL64278, R01- HD057194, R01-HL087641, R01-HL59367, R01HL-086694, R01-HL088451, R24-HD050924, U01-HG-004402, HHSN268200625226C, UL1- RR025005, UL1-RR025005, UL1-TR-001079, UL1-TR-00040, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, DA12854, MH081802, MH66206, R01- D004215701A, R01-DK075787, R01-DK089256, R01-DK8925601, R01-HL088451, R01-HL117078, R01-DK062370, R01-DK072193, DK091718, DK100383, DK078616, 1Z01-HG000024, HL087660, HL100245, R01DK089256, 2T32HL007055-36, U01-HL072515-06, U01- HL84756, NIA-U01AG009740, RC2-AG036495, RC4-AG039029, R03 AG046389, 263-MA-410953, 263-MD-9164, 263-MD-821336, U01-HG004802, R37CA54281, R01CA63, P01CA33619, U01- CA136792, U01-CA98758, RC2-MH089951, MH085520, R01-D0042157-01A, MH081802, 1RC2-MH089951, 1RC2-MH089995, 1RL1MH08326801, U01-HG007376, 5R01- HL08767902, 5R01MH63706:02, HG004790, N01- WH22110, U01-HG007033, UM1CA182913, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129- 32, 44221); USDA Na ional Ins i u e o Food and Ag icul u e (2007-35205-17883); Va¨s a Go¨ aland Founda ion; Velux Founda ion; Ve e ans A ai s (1 IK2 BX001823); Vleugels Founda ion; VU Uni e si y’s Ins i u e o Heal h and Ca e Resea ch (EMGO+, HEALTH-F4-2007-201413) and Neu oscience Campus Ams e dam; Wellcome T us (090532, 091551, 098051, 098381); Wissenscha so ensi e TMO; and Y jo¨Jahnsson Founda ion. The unde s had no ole in s udy design, da a collec ion and analysis, decision o publish, o p epa a ion o he manusc ip . Compe ing in e es s: We ha e ead he jou nal’s policy and he au ho s o his manusc ip ha e he ollowing compe ing in e es s: Geno yping in he Ely and Fenland s udies was suppo ed in pa by an MRC-GlaxoSmi hKline pilo p og amme g an (G0701863). The RISC S udy was suppo ed in pa by As aZeneca. The D.E.S.I.R. s udy has been suppo ed in pa by INSERM con ac s wi h Lilly, No a is Pha ma, Sano i-A en is, A dix Medical, Abs ac Physical ac i i y (PA) may modi y he gene ic e ec s ha gi e ise o inc eased isk o obe- si y. To iden i y adiposi y loci whose e ec s a e modi ied by PA, we pe o med genome- wide in e ac ion me a-analyses o BMI and BMI-adjus ed wais ci cum e ence and wais -hip a io om up o 200,452 adul s o Eu opean (n = 180,423) o o he ances y (n = 20,029). We s anda dized PA by ca ego izing i in o a dicho omous a iable whe e, on a e age, 23% o pa icipan s we e ca ego ized as inac i e and 77% as physically ac i e. While we eplica e he in e ac ion wi h PA o he s onges known obesi y- isk locus in he FTO gene, o which he e ec is a enua ed by ~30% in physically ac i e indi iduals compa ed o inac i e indi id- uals, we do no iden i y addi ional loci ha a e sensi i e o PA. In addi ional genome-wide me a-analyses adjus ing o PA and in e ac ion wi h PA, we iden i y 11 no el adiposi y loci, sugges ing ha accoun ing o PA o o he en i onmen al ac o s ha con ibu e o a ia ion in adiposi y may acili a e gene disco e y. Au ho summa y Decline in daily physical ac i i y is hough o be a key con ibu o o he global obesi y epidemic. Howe e , he impac o seden a iness on adiposi y may be in pa de e mined by a pe son’s gene ic cons i u ion. The speci ic gene ic a ian s ha a e sensi i e o physi- cal ac i i y and egula e adiposi y emain la gely unknown. He e, we aimed o iden i y gene ic a ian s whose e ec s on adiposi y a e modi ied by physical ac i i y by examining ~2.5 million gene ic a ian s in up o 200,452 indi iduals. We also es ed whe he adjus - ing o physical ac i i y as a co a ia e could lead o he iden i ica ion o no el adiposi y a ian s. We ind obus e idence o in e ac ion wi h physical ac i i y o he s onges known obesi y isk-locus in he FTO gene, o which he body mass index-inc easing e ec is a enua ed by ~30% in physically ac i e indi iduals compa ed o inac i e indi iduals. Ou analyses indica e ha o he simila gene-physical ac i i y in e ac ions may exis , bu be e measu emen o physical ac i i y, la ge sample sizes, and/o imp o ed analy ical me hods will be equi ed o iden i y hem. Adjus ing o physical ac i i y, we iden i y 11 no el adiposi y a ian s, sugges ing ha accoun ing o physical ac i i y o o he en i on- men al ac o s ha con ibu e o a ia ion in adiposi y may acili a e gene disco e y. In oduc ion In ecen decades, we ha e wi nessed a global obesi y epidemic ha may be d i en by changes in li es yle such as easie access o ene gy-dense oods and dec eased physical ac i i y (PA) [1]. Howe e , no e e yone becomes obese in obesogenic en i onmen s. Twin s udies sugges ha changes in body weigh in esponse o li es yle in e en ions a e in pa de e mined by a pe - son’s gene ic cons i u ion [2–4]. Ne e heless, he genes ha a e sensi i e o en i onmen al in luences emain la gely unknown. P e ious s udies sugges ha gene ic suscep ibili y o obesi y, assessed by a gene ic isk sco e o BMI, may be a enua ed by PA [5,6]. A la ge-scale me a-analysis o he FTOobesi y locus in 218,166 adul s showed ha being physically ac i e a enua es he BMI-inc easing e ec o his locus by ~30% [7]. While hese indings sugges ha FTO, and po en ially o he Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 6 / 26 Baye Diagnos ics, Bec on Dickinson, Ca dionics, Me ck San e ´, No o No disk, Pie e Fab e, Roche, and Topcon. In SHIP, genome-wide da a ha e been suppo ed in pa by a join g an om Siemens Heal hca e, E langen, Ge many. p e iously es ablished BMI loci, may in e ac wi h PA, i has been hypo hesized ha loci show- ing he s onges main e ec associa ions in genome-wide associa ion s udies (GWAS) may be he leas sensi i e o en i onmen al and li es yle in luences, and may he e o e no make he bes candida es o in e ac ions [8]. Ye no genome-wide sea ch o no el loci exhibi ing SNP×PA in e ac ion has been pe o med. A genome-wide me a-analysis o geno ype-depen- den pheno ypic a iance o BMI, a ma ke o sensi i i y o en i onmen al exposu es, in ~170,000 pa icipan s iden i ied FTO, bu did no show obus e idence o en i onmen al sen- si i i y o o he loci [9]. Recen genome-wide me a-analyses o adiposi y ai s in >320,000 indi iduals unco e ed loci in e ac ing wi h age and sex, bu also sugges ed ha e y la ge sam- ple sizes a e equi ed o in e ac ion s udies o be success ul [10]. He e, we epo esul s om a la ge-scale genome-wide me a-analysis o SNP×PA in e ac- ions in adiposi y in up o 200,452 adul s. As pa o hese in e ac ion analyses, we also examine whe he adjus ing o PA o join ly es ing o SNP’s main e ec and in e ac ion wi h PA may iden i y no el adiposi y loci. Resul s Iden i ica ion o loci in e ac ing wi h PA We pe o med me a-analyses o esul s om 60 s udies, including up o 180,423 adul s o Eu opean descen and 20,029 adul s o o he ances ies o assess in e ac ions be ween ~2.5 mil- lion geno yped o HapMap-impu ed SNPs and PA on BMI and BMI-adjus ed wais ci cum e - ence (WC adjBMI ) and wais -hip a io (WHR adjBMI ) (S1–S5 Tables). Simila o a p e ious me a- analysis o he in e ac ion be ween FTO and PA [7], we s anda dized PA by ca ego izing i in o a dicho omous a iable whe e on a e age ~23% o pa icipan s we e ca ego ized as inac- i e and ~77% as physically ac i e (see Me hods and S6 Table). On a e age, inac i e indi idu- als had 0.99 kg/m 2 highe BMI, 3.46 cm highe WC, and 0.018 highe WHR han ac i e indi iduals (S4 and S5 Tables). Each s udy i s pe o med genome-wide associa ion analyses o each SNP’s e ec on BMI in he inac i e and ac i e g oups sepa a ely. Co esponding summa y s a is ics om each coho we e subsequen ly me a-analyzed, and he SNP×PA in e ac ion e ec was es ima ed by calcula ing he di e ence in he SNP’s e ec be ween he inac i e and ac i e g oups. To iden- i y sex-speci ic SNP×PA in e ac ions, we pe o med he me a-analyses sepa a ely in men and women, as well as in he combined sample. In addi ion, we ca ied ou me a-analyses in Eu o- pean-ances y s udies only and in Eu opean and o he -ances y s udies combined. We used wo app oaches o iden i y loci whose e ec s a e modi ied by PA. In he i s app oach, we sea ched o genome-wide signi ican SNP×PA in e ac ion e ec s (P INT <5x10 -8 ). As shown in Fig 1, his app oach yielded he highes powe o iden i y c oss-o e in e ac ion e ec s whe e he SNP’s e ec is di ec ionally opposi e be ween he inac i e and ac i e g oups. Howe e , his app oach has low powe o iden i y in e ac ion e ec s whe e he SNP’s e ec is di ec ionally conco dan be ween he inac i e and ac i e g oups (Fig 1). We iden i ied a genome-wide signi ican in e ac ion be ween s986732 in cadhe in 12 (CDH12)and PA on BMI in Eu opean-ances y s udies (be a INT = -0.076 SD/allele, P INT = 3.1x10 -8 , n = 134,767) (S7 Table). The in e ac ion e ec was di ec ionally consis en bu did no eplica e in an indepen- den sample o 31,097 indi iduals (be a INT = -0.019 SD/allele, P INT = 0.52), and he pooled asso- cia ion P alue o he disco e y and eplica ion s ages combined did no each genome-wide signi icance (N TOTAL = 165,864; P INT-TOTAL = 3x10 -7 ) (S1 Fig). No loci showed genome-wide signi ican in e ac ions wi h PA on WC adjBMI o WHR adjBMI .CDH12encodes an in eg al mem- b ane p o ein media ing calcium-dependen cell-cell adhesion in he b ain, whe e i may play a ole in neu ogenesis [11]. While CDH12 s4701252 and s268972 SNPs ha e shown sugges i e Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 7 / 26 Fig 1. Powe o iden i y PA-adjus ed main, join o GxPA in e ac ion e ec s in 200,000 indi iduals (45,000 inac i e, 155,000 ac i e). The plo s compa e powe o iden i y genome-wide signi ican main e ec s (P adjPA <5x10 -8 , dashed black), join e ec s (P JOINT <5x10 -8 , do ed g een) o GxPA in e ac ion e ec s (P INT <5x10 -8 , solid magen a) as well as he powe o iden i y Bon e oni-co ec ed in e ac ion e ec s (P INT <0.05/ numbe o loci, solid o ange) o he SNPs ha eached a genome-wide signi ican PA-adjus ed main e ec associa ion (P adjPA <5x10 -8 ). The powe compu a ions we e based on analy ical powe o mulae p o ided elsewhe e [50] and we e conduc ed a-p io i based on a ious ypes o Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 8 / 26 associa ions wi h wais ci cum e ence (P = 2x10 -6 ) and BMI (P = 5x10 -5 ) in p e ious GWAS [12,13], he SNPs a e no in LD wi h s986732 ( 2 <0.1). In ou second app oach, we es ed in e ac ion o loci showing a genome-wide signi ican main e ec on BMI, WC adjBMI o WHR adjBMI (S7–S12 Tables). We adjus ed he signi icance h eshold o SNP×PA in e ac ion by Bon e oni co ec ion (P = 0.05/numbe o SNPs es ed). As shown in Fig 1, his app oach enhanced ou powe o iden i y in e ac ion e ec s whe e he e is a di e ence in he magni ude o he SNP’s e ec be ween inac i e and ac i e g oups when he SNP’s e ec is di ec ionally conco dan be ween he g oups. We iden i ied a signi i- can SNP×PA in e ac ion o he FTO s9941349 SNP on BMI in he me a-analysis o Eu o- pean-ances y indi iduals; he BMI-inc easing e ec was 33% smalle in ac i e indi iduals (be a ACTIVE = 0.072 SD/allele) han in inac i e indi iduals (be a INACTIVE = 0.106 SD/allele, P INT = 4x10 -5 ). The s9941349 SNP is in s ong LD ( 2 = 0.87) wi h FTO s9939609 o which in e ac ion wi h PA has been p e iously es ablished in a me a-analysis o 218,166 adul s [7]. We iden i ied no loci in e ac ing wi h PA o WC adjBMI o WHR adjBMI . In a p e iously published me a-analysis [7], he FTO locus showed a geog aphic di e ence o he in e ac ion e ec whe e he in e ac ion was mo e p onounced in s udies om No h Ame ica han in hose om Eu ope. To es o geog aphic di e ences in he p esen s udy, we pe o med addi ional me a-analyses o he FTO s9941349 SNP, s a i ied by geog aphic o i- gin (No h Ame ica s. Eu ope). While he in e ac ion e ec was mo e p onounced in s udies om No h Ame ica (be a INT = 0.052 SD/allele, P = 5x10 -4 , N = 63,896) han in hose om Eu ope (be a INT = 0.028 SD/allele, P = 0.006, N = 109,806), we did no ind a s a is ically signi - ican di e ence be ween he egions (P = 0.14). Explained pheno ypic a iance in inac i e and ac i e indi iduals. We es ed whe he he a iance explained by ~1.1 million common a ian s (MAF1%) di e ed be ween he inac i e and ac i e g oups o BMI, WC adjBMI , and WHR adjBMI [14]. In he physically ac i e indi iduals, he a ian s explained ~20% less o a iance in BMI han in inac i e indi iduals (12.4% s. 15.7%, espec i ely; P di e ence = 0.046), sugges ing ha PA may educe he impac o gene ic p edisposi ion o adiposi y o e all. The e was no signi ican di e ence in he a iance explained be ween ac i e and inac i e g oups o WC adjBMI (8.6% o ac i e, 9.3% o inac i e; P di e ence = 0.70) o WHR adjBMI (6.9% o ac i e, 8.0% o inac i e; P di e ence = 0.59). To u he in es iga e di e ences in explained a iance be ween he inac i e and ac i e g oups, we calcula ed a iance explained by subse s o SNPs selec ed based on signi icance h esholds ( anging om P = 5x10 -8 o P = 0.05) o PA-adjus ed SNP associa ion wi h BMI, WC adjBMI o WHR adjBMI [15] (S13 Table). We ound 17–26% smalle explained a iance o BMI in he ac i e g oup han in he inac i e g oup a all P alue h esholds (S13 Table). Iden i ica ion o no el loci when adjus ing o PA o when join ly es ing o SNP main e ec and in e ac ion wi h PA Physical ac i i y con ibu es o a ia ion in BMI, WC adjBMI , and WHR adjBMI , hence, adjus ing o PA as a co a ia e may enhance powe o iden i y no el adiposi y loci. To ha ex en , each s udy pe o med genome-wide analyses o associa ion wi h BMI, WC adjBMI , and WHR adjBMI while adjus ing o PA. Subsequen ly, we pe o med me a-analyses o he s udy-speci ic known ealis ic BMI e ec sizes [51]. Panels A, C, E: Assuming an e ec in inac i e indi iduals simila o a small (R2 INACT ¼0:01%, compa able o he known BMI e ec o he NUDT3 locus), medium (R2 INACT ¼0:07%, compa able o he known BMI e ec o he BDNF locus) and la ge (R2 INACT ¼0:34%, compa able o he known BMI e ec o he FTO locus) ealis ic e ec on BMI and o a ious e ec s in physically ac i e indi iduals ( a ied on he x axis); Panels B,D,F: Assuming an e ec in physically ac i e indi iduals simila o he small, medium and la ge ealis ic e ec s o he NUDT3,BDNF and FTO loci on BMI and o a ious e ec s in inac i e indi iduals ( a ied on x axis). h ps://doi.o g/10.1371/jou nal.pgen.1006528.g001 Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 9 / 26 Me hods Main analyses E hics s a emen . All s udies we e conduc ed acco ding o he Decla a ion o Helsinki. The s udies we e app o ed by he local e hical e iew boa ds and all s udy pa icipan s p o- ided w i en in o med consen o he collec ion o samples and subsequen analyses. Ou come ai s—BMI, WC adjBMI and WHR adjBMI .We examined h ee an h opome ic ai s ela ed o o e all adiposi y (BMI) o body a dis ibu ion (WC adjBMI and WHR adjBMI ) [36] ha we e a ailable om a la ge numbe o s udies. Be o e he associa ion analyses, we cal- cula ed sex-speci ic esiduals by adjus ing o age, age 2 , BMI ( o WC adjBMI and WHR adjBMI ai s only), and o he necessa y s udy-speci ic co a ia es, such as geno ype-de i ed p incipal componen s. Subsequen ly, we no malized he dis ibu ions o sex-speci ic ai esiduals using in e se no mal ans o ma ion. Physical ac i i y. Physical ac i i y was assessed and quan i ied in a ious ways in he pa - icipa ing s udies o he me a-analysis (S1 and S6 Tables). Aiming o amass as la ge a sample size as possible, we ha monized PA by ca ego izing i in o a simple dicho omous a iable— physically inac i e s. ac i e— ha could be de i ed in a ela i ely consis en way in all pa ici- pa ing s udies, and ha would be consis en wi h p e ious indings on gene-physical ac i i y in e ac ions and he ela ionship be ween ac i i y le els and heal h ou comes. In s udies wi h ca ego ical PA da a, indi iduals we e de ined inac i e i hey epo ed ha ing a seden a y occu- pa ion and being seden a y du ing anspo and leisu e- ime (<1 h o mode a e in ensi y lei- su e- ime o commu ing PA pe week). All o he indi iduals we e de ined physically ac i e. P e ious s udies in la ge-scale indi idual coho s ha e demons a ed ha he in e ac ion be ween FTO, o a BMI-inc easing gene ic isk sco e, wi h physical ac i i y, is mos p o- nounced app oxima ely a his ac i i y le el [6,37,38]. In s udies wi h con inuous PA da a, PA a iables we e s anda dized by de ining indi iduals belonging o he lowes sex- and age- adjus ed quin ile o PA le els as inac i e, and all o he indi iduals as ac i e. The s udy-speci ic coding o he dicho omous PA a iable in each s udy is desc ibed in S6 Table. S udy-speci ic associa ion analyses. We included 42 s udies wi h genome-wide da a, 10 s udies wi h Me abochip da a, and eigh s udies wi h bo h genome-wide and Me abochip da a. I bo h genome-wide and Me abochip da a we e a ailable o he same indi idual, we only included he genome-wide da a (S1 Table). S udies wi h genome-wide geno yped da a used ei he A yme ix o Illumina a ays (S2 Table). Following s udy-speci ic quali y con ol mea- su es, he geno ype da a we e impu ed using he HapMap phase II e e ence panel (S2 Table). S udies wi h Me abochip da a used he cus om Illumina HumanCa dio-Me abo BeadChip con aining ~195K SNPs designed o suppo la ge-scale ollow-up o known associa ions wi h me abolic and ca dio ascula ai s [39]. Each s udy an au osomal SNP associa ion analyses wi h BMI, WC adjBMI and WHR adjBMI ac oss hei a ay o gene ic da a using he ollowing lin- ea eg ession models in men and women sepa a ely: 1) ac i e indi iduals only; 2) inac i e indi iduals only; and 3) ac i e and inac i e indi iduals combined, adjus ing o he PA s a- um. In s udies ha included amilies o closely ela ed indi iduals, eg ession coe icien s we e es ima ed using a a iance componen model ha modeled ela edness in men and women combined, wi h sex as a co a ia e, in addi ion o he sex-speci ic analyses. The addi i e gene ic e ec o each SNP and pheno ype associa ion was es ima ed using linea eg ession. Fo s udies wi h a case-con ol design (S1 Table), cases and con ols we e analyzed sepa a ely. Quali y con ol o s udy-speci ic associa ion esul s. All s udy-speci ic iles o he h ee eg ession models lis ed abo e we e p ocessed h ough a s anda dized quali y con ol p o ocol using he EasyQC so wa e [40]. The s udy-speci ic quali y con ol measu es included checks on ile comple eness, ange o es s a is ics, allele equencies, ai ans o ma ion, popula ion Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 16 / 26 s a i ica ion, and il e ing ou o low quali y da a. Checks on ile comple eness included sc eening o missing alleles, e ec es ima es, allele equencies, and o he missing da a. Checks on ange o es s a is ics included sc eening o in alid s a is ics such as P- alues >1 o <0, nega i e s anda d e o s, o SNPs wi h low mino allele coun (MAC, calcula ed as MAFN, whe e MAF is he mino allele equency and N is he sample size) and whe e SNPs wi h MAC<5 in he inac i e o he ac i e g oup we e emo ed. The co ec ness o ai ans- o ma ion o in e se no mal was examined by plo ing 2/median o he s anda d e o wi h he squa e oo o he sample size. Popula ion s a i ica ion was examined by calcula ing he s udy speci ic genomic con ol in la ion ac o (λ GC ) [41]. I a s udy had λ GC >1.1, he s udy analys was con ac ed and asked o e ise he analyses by adjus ing o p incipal componen s. The allele equencies in each s udy we e examined o s and issues and miscoded alleles by plo ing e ec allele equencies agains he co esponding allele equencies om he Hap- Map2 e e ence panel. Finally, low quali y da a we e il e ed ou by emo ing monomo phic SNPs, impu ed SNPs wi h poo impu a ion quali y ( 2_ha <0.3 in MACH [42], obse ed/ expec ed dosage a iance <0.3 in BIMBAM [43], p ope _in o <0.4 in IMPUTE [44]), and geno yped SNPs wi h a low call- a e (<95%) o ha we e ou o Ha dy-Weinbe g equilib ium (P<10 −6 ). Me a-analyses. Be a-coe icien s and s anda d e o s we e combined by an in e se- a i- ance weigh ed ixed e ec me hod, implemen ed using he METAL so wa e [45]. We pe - o med me a-analyses o each o he h ee models (ac i e, inac i e, ac i e + inac i e adjus ed o PA) in men only, in women only, and in men and women combined. S udy-speci ic GWAS esul s we e co ec ed o genomic con ol using all SNPs. S udy-speci ic Me abochip esul s as well as he me a-analysis esul s o GWAS and Me abochip combined we e co - ec ed o genomic con ol using 4,425 SNPs included on he Me abochip o eplica ion o associa ions wi h QT-in e al, a pheno ype no co ela ed wi h BMI, WC adjBMI o WHR adjBMI , a e p uning o SNPs wi hin 500 kb o an an h opome y eplica ion SNP. We excluded SNPs ha 1) we e no a ailable in a leas hal o he maximum sample size in each s a um; 2) had a he e ogenei y I 2 >75%, o 3) we e missing ch omosomal and base posi ion anno a ion in dbSNP. Calcula ion o he signi icance o SNP×PA in e ac ion and o he join signi icance o SNP main e ec and SNP×PA in e ac ion. To iden i y SNP×PA in e ac ions, we used he EasyS a a R package [46] o es o he di e ence in me a-analyzed be a-coe icien s be ween he ac i e and inac i e g oups o he associa ion o each SNP wi h BMI, WC adjBMI and WHR adjBMI . Easys a a es s o di e ences in e ec es ima es be ween he ac i e and inac i e s a a by sub ac ing one be a om he o he (β ac i e −β inac i e ,) and di iding by he o e all s an- da d e o o he di e ence as ollows: Zdi ¼bac i e binac i e i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i SE2 ac i e SE2 inac i e 2 SE2 ac i e SE2 inac i e p whe e is he Spea man ank co ela ion coe icien be ween β ac i e and β inac i e o all genome-wide SNPs. The join signi icance o he SNP main and SNP×PA in e ac ion e ec s was es ima ed using he me hod by Ascha d e al. [16] which is a join es o gene ic main e ec s and gene-en i onmen in e ac ion e ec s whe e gene-en i onmen in e ac ion is calcu- la ed as he di e ence in e ec es ima es be ween wo exposu e s a a, accoun ing o 2 deg ees o eedom. Tes ing o seconda y signals. App oxima e condi ional analyses we e conduc ed using GCTA e sion 1.24 [19]. In he analyses o SNPs iden i ied in ou me a-analyses o Eu opean- ances y indi iduals only, LD co ela ions be ween SNPs we e es ima ed using a e e ence Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 17 / 26 sample comp ised o Eu opean-ances y pa icipan s o he A he oscle osis Risk in Communi- ies (ARIC) s udy. In he analyses o SNPs iden i ied in ou me a-analyses o all ances ies combined, he e e ence sample comp ised 93% o Eu opean-ances y indi iduals and 6% o A ican ances y pa icipan s om ARIC, as well as 1% o CHB and JPT samples om he HapMap2 panel, o app oxima e he ances y mix u e in ou all ances y me a-analyses. To es i ou iden i ied SNPs we e independen seconda y signals ha ell wi hin 1 Mbp o a p e- iously es ablished signal, we used he GCTA—cojo-cond command o condi ion ou lead SNPs on each p e iously es ablished SNP in he same locus. Replica ion analysis o he CDH12 locus. The eplica ion analysis o he CDH12 locus included pa icipan s om he EPIC-No olk (N INACTIVE = 4,755, N ACTIVE = 11,526) and Fen- land s udies (N INACTIVE = 1,213, N ACTIVE = 4,817), and om he andom subcoho o he EPIC-In e Ac Conso ium (N INACTIVE = 2,154, N ACTIVE = 6,632). PA s a um-speci ic es i- ma es o he associa ion o CDH12 wi h BMI we e assessed and me a-analyzed by ixed e ec s me a-analyses, and he di e ences be ween he PA-s a a we e de e mined as desc ibed abo e. Examining he in luence o BMI, WC adjBMI and WHR adjBMI -associa ed loci on o he complex ai s and hei po en ial unc ional oles NHGRI-EBI GWAS ca alog lookups. To iden i y associa ions o he no el BMI, WC adjBMI o WHR adjBMI loci wi h o he complex ai s in published GWAS, we ex ac ed p e- iously epo ed GWAS associa ions wi hin 500 kb and 2 >0.6 wi h any o he lead SNPs, om he GWAS Ca alog o he Na ional Human Genome Resea ch Ins i u e and Eu opean Bioin o ma ics Ins i u e [47] (S14 Table). eQTLs. We examined he cis-associa ions o he no el BMI, WC adjBMI o WHR adjBMI loci wi h he exp ession o nea by genes om a ious issues by pe o ming a look-up in a lib a y o >100 published exp ession da ase s, as desc ibed p e iously by Zhang e al [48]. In addi ion, we examined cis-associa ions using gene exp ession da a de i ed om as ing pe iphe al whole blood in he F amingham Hea S udy [49] (n = 5,206), adjus ing o PA, age, age 2 , sex and coho . Fo each no el locus, we e alua ed he associa ion o all ansc ip s ±1 Mb om he lead SNP. To minimize he po en ial o alse posi i es, we only conside ed associa ions whe e ou lead SNP o i s p oxy ( 2 >0.8) was ei he he peak SNP associa ed wi h he exp es- sion o a gene ansc ip in he egion, o in s ong LD ( 2 >0.8) wi h he peak SNP. O e lap wi h unc ional egula o y elemen s. We used he Unco e ing En ichmen Th ough Simula ion me hod o combine he gene ic associa ion da a wi h he Roadmap Epige- nomics P ojec segmen a ion da a [22]. Fi s , 10,000 se s o andom SNPs we e selec ed among HapMap2 SNPs wi h a MAF >0.05 ha ma ched he o iginal inpu SNPs based on p oximi y o a ansc ip ion s a si e and he numbe o LD pa ne s ( 2 >0.8 in indi iduals o Eu opean ances y in he 1000 Genomes P ojec ). The LD pa ne s we e combined wi h hei o iginal lead SNPs o c ea e 10,000 se s o ma ched andom SNPs and hei espec i e LD pa - ne s. These se s we e in e sec ed wi h he 15-s a e Ch omHMM da a om he Roadmap Epi- genomics P ojec and esul an co-localiza ions we e collapsed om o al SNPs down o loci, which we e hen used o calcula e an empi ical P alue when compa ing he o iginal SNPs o he andom se s. We examined he en ichmen o all loci eaching P<10 −5 o SNP×PA in e - ac ion combined, and o all loci eaching P<5x10 -8 in he PA-adjus ed SNP main e ec model combined. In addi ion, we examined he a ian -speci ic o e lap wi h egula o y ele- men s o each o he index SNPs o he no el BMI, WC adjBMI and WHR adjBMI loci and a i- an s in s ong LD ( 2 >0.8). Es ima ion o a iance explained in inac i e and ac i e g oups. We compa ed a iance explained o BMI, WC adjBMI and WHR adjBMI be ween he ac i e and inac i e g oups using Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 18 / 26 wo app oaches. Fi s , we used a me hod p e iously epo ed by Ku alik e al [15], and selec ed subse s o SNPs based on a ying P alue h esholds ( anging om 5x10 -8 o 0.05) om he SNP main e ec model adjus ed o PA. Each subse o SNPs was clumped in o independen egions using a physical dis ance c i e ion o <500kb, and he mos signi ican lead SNP wi hin he espec i e egion was selec ed. Fo each lead SNP, he explained a iance was calcu- la ed as: 2¼1 1þN F1P 2 ð Þð Þ21 N in he ac i e and inac i e g oups sepa a ely, whe e Nis he sample size and Pis he P alue o SNP main e ec in ac i e o inac i e s a a. Finally, he a iance explained by each subse o SNPs in he ac i e and inac i e s a a was es ima ed by summing up he a iance explained by he SNPs. Second, we applied he LD Sco e eg ession ool de eloped by Bulik-Sulli an e al [14] o quan i y he p opo ion o in la ion due o polygenici y (he i abili y) a he han con ounding (c yp ic ela edness o popula ion s a i ica ion) using me a-analysis summa y esul s. LD Sco e eg ession le e ages LD be ween causal and index a ian s o dis inguish ue signals by eg essing me a-analysis summa y esul s on an ‘LD Sco e’, i.e. he cumula i e gene ic a ia- ion ha an index SNP ags. To ob ain he i abili y es ima es by PA s a a, we eg essed ou summa y esul s om he genome-wide me a-analyses o BMI, WC adjBMI and WHR adjBMI , s a i ied by PA s a us (ac i e and inac i e), on p e-calcula ed LD Sco es a ailable in HapMap3 e e ence samples o up o 1,061,094 a ian s wi h MAF1% and N>10 h pe cen ile o he o al sample size. Suppo ing in o ma ion S1 Acknowledgemen s. A ull lis o acknowledgemen s. (DOCX) S1 Fig. In e ac ion be ween he CDH12 locus and physical ac i i y on BMI in he disco - e y genome-wide me a-analysis (n = 134,767), in he independen eplica ion sample (n = 31,097), and in he disco e y and eplica ion samples combined. (DOCX) S2 Fig. Quan ile-Quan ile and Manha an plo s o he genome-wide me a-analysis esul s o he SNP main e ec adjus ing o physical ac i i y (SNPadjPA), in e ac ion be ween SNP and physical ac i i y, and he join e ec o SNP main e ec and SNP×PA in e ac ion (Join 2d ) in men and women o Eu opean-ances y combined. (DOCX) S3 Fig. Regional associa ion plo s o no el BMI, WCadjBMI o WHRadjBMI loci showing ei he a genome-wide signi ican SNP main e ec when adjus ing o physical ac i i y as a co a ia e, o a genome-wide signi ican join e ec o physical ac i i y-adjus ed SNP main e ec and SNP ×physical ac i i y in e ac ion. (DOCX) S4 Fig. Hea map o P alues o he physical ac i i y-adjus ed SNP main e ec model (PadjPA), he join model (Pjoin ), and he SNPxPA in e ac ion model (Pin ). (DOCX) Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 19 / 26 S1 Table. Basic s udy in o ma ion and desc ip ion o ou come assessmen (BMI, WC, WHR) and Physical ac i i y assessmen . (XLSX) S2 Table. Geno yping and impu a ion pla o ms o he pa icipa ing s udies. (XLSX) S3 Table. Popula ion cha ac e is ics o inac i e and ac i e indi iduals combined in he pa icipa ing s udies. (XLSX) S4 Table. Popula ion cha ac e is ics o inac i e indi iduals in he pa icipa ing s udies. (XLSX) S5 Table. Popula ion cha ac e is ics o ac i e indi iduals in he pa icipa ing s udies. (XLSX) S6 Table. Me hods used o measu ing physical ac i i y and de ini ions o inac i e o s udies pa icipa ing in he me a-analyses. (XLSX) S7 Table. All SNPs ha me signi icance o BMI in he Eu opean only analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physical ac i i y, o join ly accoun - ing o he main and in e ac ion e ec s. (XLSX) S8 Table. All SNPs ha me signi icance o BMI in he all ances y analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physical ac i i y, o join ly accoun - ing o he main and in e ac ion e ec s. (XLSX) S9 Table. All SNPs ha me signi icance o wais ci cum e ence adjus ed o BMI in he Eu opean only analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physical ac i i y, o join ly accoun ing o he main and in e ac ion e ec s. (XLSX) S10 Table. All SNPs ha me signi icance o wais ci cum e ence adjus ed o BMI in he all ances y analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physical ac i i y, o join ly accoun ing o he main and in e ac ion e ec s. (XLSX) S11 Table. All SNPs ha me signi icance o wais - o-hip a io adjus ed o BMI in he Eu opean only analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physical ac i i y, o join ly accoun ing o he main and in e ac ion e ec s. (XLSX) S12 Table. All SNPs ha me signi icance o wais - o-hip a io adjus ed o BMI in he all ances y analyses o a leas one o he app oaches es ed: in e ac ion, adjus ed o physi- cal ac i i y, o join ly accoun ing o he main and in e ac ion e ec s. (XLSX) S13 Table. Va iance explained using P alue h esholds. (XLSX) S14 Table. GWAS ca alog lookups o no el loci and new seconda y signal in known loci. (XLSX) Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 20 / 26 S15 Table. Associa ion o he no el loci wi h cis gene exp ession (cis-eQTL). (XLSX) S16 Table. Associa ion o loci iden i ied o in e ac ion wi h physical ac i i y, o physical ac i i y-adjus ed SNP main e ec , o o join associa ion o SNP main e ec and physical ac i i y in e ac ion, wi h physical ac i i y and seden a y beha iou . (XLSX) S17 Table. Resul s o app oxima e condi ional analyses o iden i y seconda y signals in he no el BMI, WC adjBMI o WHR adjBMI -associa ed loci a . (XLSX) S18 Table. En ichmen o loci in e ac ing wi h PA (P in <10 −5 ) on he le el o BMI wi h unc ional genomic elemen s in adipose, b ain, and muscle issue cell lines om he Road- map Epigenomics P ojec . (XLSX) S19 Table. En ichmen o loci in e ac ing wi h PA (P in <10 −5 ) on he le el o WHRadjBMI wi h unc ional genomic elemen s in adipose, b ain, and muscle issue cell lines om he Roadmap Epigenomics P ojec . (XLSX) S20 Table. En ichmen o loci showing associa ion wi h BMI (P adjPA <5x10 -8 ) wi h unc- ional genomic elemen s in adipose, b ain, and muscle issue cell lines om he Roadmap Epigenomics P ojec . (XLSX) S21 Table. En ichmen o loci showing associa ion wi h WHRadjBMI (P adjPA <5x10 -8 ) wi h unc ional genomic elemen s in adipose, b ain, and muscle issue cell lines om he Roadmap Epigenomics P ojec . (XLSX) S22 Table. Associa ion o no el loci iden i ied o in e ac ion wi h physical ac i i y, o physical ac i i y-adjus ed SNP main e ec , o o join associa ion o he SNP main e ec and physical ac i i y in e ac ion, in GIANT esul s no accoun ing o physical ac i i y. (XLSX) Au ho Con ibu ions Concep ualiza ion: TOK RJFL. Da a cu a ion: TOK LAC RJFL KLMon. Fo mal analysis: RAS KLY AEJ TWW AMa DHa NLHC JSN TSA LQ TW FRe MdH TOK QQ MG TSA LX AYC LAC MC RJFL MFF KEN JDE ADJ JEHa RJK. In es iga ion: AVS TBH GE LJL VG KEN MG AJ KLMon KLY EB PGL JBW NGM GWM DPS GC LJP JHua AWM ALJ JB MFo CBe HMS TR SSn BS YW JBB LSA ZK PMMV TC SBi GWi PV KK ASH KHa SM VS MP JM IR CHup VV IK OPo LY DT BB MMa AB PF RRaw TAL PK MHo KSa RMag THal TEb AMa JL RAS SB NJW JHZ RL SBu AD NA CM D IBB MFF LB RJFL LX NLHC EL JP PJG CSF CTL LAC MB FSC KLMol RNB JT LK TEs HP CS HAK LFB SLRK MAJ PAP SA FRe IB GH PWF JE CO MLo AEJ JOJ TSA LPa GDS TIAS JEHu DJP SP LJH BHS SSa YCC MFu JRO ARS MHa MA AL HVe LQu THu QQ JAS JDF WZhan DRW KH OLH AUJ LLB AJS KK TTan DHe SBa MNH JMJ KF Genome-wide physical ac i i y in e ac ions in adiposi y PLOS Gene ics | h ps://doi.o g/10.1371/jou nal.pgen.1006528 Ap il 27, 2017 21 / 26 NG OPe TWW IMH MO CG HG AP KS CHo CHu RRau BT MMN WZhao BL WRS STT JCC JSK MEK GED TBG GS JHui WM UL CHa LL LH KL AGB LJRT JAN YL MLa JK AS PSC NN WJP G G YM BWJHP AMu CML MIM TTam JA MRJ LQi THan DK KKO AW ÅJ UG EJCdG MHMdM JJH DIB GWa PN AFW NDH SW HC JFW CBo MCV LPe DP MW TMF NVR MCZ FRi AH AGU JLBG SSi FB AMe GRA FC ATe HVo UV MD SG MN RMan IP ATo PJ dM JV VO IMN HS AJO CAH MMan DIC AYC LMR PMR SBi NZ JG UP CK MKu MKi CL LPL NHK MJ MKa¨OTR TL. Supe ision: GRA IB MB IBB CSF TMF IMH RJFL MIM KLMon KEN JRO DPS CM D JNH. W i ing – o iginal d a : MG RAS AEJ KLY MFF LB LQu PWF RJFL TOK. W i ing – e iew & edi ing: MG RAS AEJ KLY MFF TWW LB AYC AMa DHa LX TW NLHC TSA MdH QQ JSN FRe LQu JDE JEHa MC ZK EL JL JEHu WZhan WZhao PJG THal SA PMMV SBi LY ATe AVS MKu MNH JMJ MEK MHo NVR JBW JHZ HS LL CHup GWi WJP YW KK AD KL YL MFo MHa LFB GC TTan RMag PJ dM AUJ JLBG VV JM PN CBe DP ÅJ SSn YCC JE UL MA LSA NA BB JA JB RNB AGB JB AB LLB JBB SB FB SBu HC PSC FSC TC GDS GED ND MD TEb GE TEs JDF MFu KF CG SG JG PGL HG TBG NG G G THu KHa NDH ASH DHe LH LJH OLH CHo JJH JHua THan JHui CHu NHK ALJ JOJ MAH MJ LK HAK IK PK JK KK MKa TAL LJL BL CML MLo RL MMa YM KLMon GWM MHMdM AMu AMe RMan SM NN MN JAN IMN AJO MO KKO SP LPa JP MP AP UP PAP IP HP OTR TR LJRT RRaw PMR LMR IR CS MAS KSa WRS SSa ARS SSi GS BHS JAS HS AS BS AJS TTam STT BT DT LV HVe JV VO MCV UV GWa MW SW AW AFW MCZ NZ CAHai LL UG CO AH FRi AGU LPe JFW CHa OPo FC KH CAHa ATo SBa LJP SLRK RRau TIAS JT VS BWJHP EJCdG DIB TL MMan MLa CBo NGM DK AL WM KS MKi TBH VG HVo LQi MRJ JCC JSK PF CK PV GH OPe NJW CL DRW DJP EB DIC GRA IB MIM TMF JRO CM D MB IMH KLMol DPS CSF CTL JNH RJK ADJ IBB PWF KEN LAC RJFL TOK. 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