Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 i...

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Main Authors: Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, Iris M Heid
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-06-01
Series:PLoS Genetics
Online Access:https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003500&type=printable
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author Joshua C Randall
Thomas W Winkler
Zoltán Kutalik
Sonja I Berndt
Anne U Jackson
Keri L Monda
Tuomas O Kilpeläinen
Tõnu Esko
Reedik Mägi
Shengxu Li
Tsegaselassie Workalemahu
Mary F Feitosa
Damien C Croteau-Chonka
Felix R Day
Tove Fall
Teresa Ferreira
Stefan Gustafsson
Adam E Locke
Iain Mathieson
Andre Scherag
Sailaja Vedantam
Andrew R Wood
Liming Liang
Valgerdur Steinthorsdottir
Gudmar Thorleifsson
Emmanouil T Dermitzakis
Antigone S Dimas
Fredrik Karpe
Josine L Min
George Nicholson
Deborah J Clegg
Thomas Person
Jon P Krohn
Sabrina Bauer
Christa Buechler
Kristina Eisinger
DIAGRAM Consortium
Amélie Bonnefond
Philippe Froguel
MAGIC Investigators
Jouke-Jan Hottenga
Inga Prokopenko
Lindsay L Waite
Tamara B Harris
Albert Vernon Smith
Alan R Shuldiner
Wendy L McArdle
Mark J Caulfield
Patricia B Munroe
Henrik Grönberg
Yii-Der Ida Chen
Guo Li
Jacques S Beckmann
Toby Johnson
Unnur Thorsteinsdottir
Maris Teder-Laving
Kay-Tee Khaw
Nicholas J Wareham
Jing Hua Zhao
Najaf Amin
Ben A Oostra
Aldi T Kraja
Michael A Province
L Adrienne Cupples
Nancy L Heard-Costa
Jaakko Kaprio
Samuli Ripatti
Ida Surakka
Francis S Collins
Jouko Saramies
Jaakko Tuomilehto
Antti Jula
Veikko Salomaa
Jeanette Erdmann
Christian Hengstenberg
Christina Loley
Heribert Schunkert
Claudia Lamina
H Erich Wichmann
Eva Albrecht
Christian Gieger
Andrew A Hicks
Asa Johansson
Peter P Pramstaller
Sekar Kathiresan
Elizabeth K Speliotes
Brenda Penninx
Anna-Liisa Hartikainen
Marjo-Riitta Jarvelin
Ulf Gyllensten
Dorret I Boomsma
Harry Campbell
James F Wilson
Stephen J Chanock
Martin Farrall
Anuj Goel
Carolina Medina-Gomez
Fernando Rivadeneira
Karol Estrada
André G Uitterlinden
Albert Hofman
M Carola Zillikens
Martin den Heijer
Lambertus A Kiemeney
Andrea Maschio
Per Hall
Jonathan Tyrer
Alexander Teumer
Henry Völzke
Peter Kovacs
Anke Tönjes
Massimo Mangino
Tim D Spector
Caroline Hayward
Igor Rudan
Alistair S Hall
Nilesh J Samani
Antony Paul Attwood
Jennifer G Sambrook
Joseph Hung
Lyle J Palmer
Marja-Liisa Lokki
Juha Sinisalo
Gabrielle Boucher
Heikki Huikuri
Mattias Lorentzon
Claes Ohlsson
Niina Eklund
Johan G Eriksson
Cristina Barlassina
Carlo Rivolta
Ilja M Nolte
Harold Snieder
Melanie M Van der Klauw
Jana V Van Vliet-Ostaptchouk
Pablo V Gejman
Jianxin Shi
Kevin B Jacobs
Zhaoming Wang
Stephan J L Bakker
Irene Mateo Leach
Gerjan Navis
Pim van der Harst
Nicholas G Martin
Sarah E Medland
Grant W Montgomery
Jian Yang
Daniel I Chasman
Paul M Ridker
Lynda M Rose
Terho Lehtimäki
Olli Raitakari
Devin Absher
Carlos Iribarren
Hanneke Basart
Kees G Hovingh
Elina Hyppönen
Chris Power
Denise Anderson
John P Beilby
Jennie Hui
Jennifer Jolley
Hendrik Sager
Stefan R Bornstein
Peter E H Schwarz
Kati Kristiansson
Markus Perola
Jaana Lindström
Amy J Swift
Matti Uusitupa
Mustafa Atalay
Timo A Lakka
Rainer Rauramaa
Jennifer L Bolton
Gerry Fowkes
Ross M Fraser
Jackie F Price
Krista Fischer
Kaarel Krjutå Kov
Andres Metspalu
Evelin Mihailov
Claudia Langenberg
Jian'an Luan
Ken K Ong
Peter S Chines
Sirkka M Keinanen-Kiukaanniemi
Timo E Saaristo
Sarah Edkins
Paul W Franks
Göran Hallmans
Dmitry Shungin
Andrew David Morris
Colin N A Palmer
Raimund Erbel
Susanne Moebus
Markus M Nöthen
Sonali Pechlivanis
Kristian Hveem
Narisu Narisu
Anders Hamsten
Steve E Humphries
Rona J Strawbridge
Elena Tremoli
Harald Grallert
Barbara Thorand
Thomas Illig
Wolfgang Koenig
Martina Müller-Nurasyid
Annette Peters
Bernhard O Boehm
Marcus E Kleber
Winfried März
Bernhard R Winkelmann
Johanna Kuusisto
Markku Laakso
Dominique Arveiler
Giancarlo Cesana
Kari Kuulasmaa
Jarmo Virtamo
John W G Yarnell
Diana Kuh
Andrew Wong
Lars Lind
Ulf de Faire
Bruna Gigante
Patrik K E Magnusson
Nancy L Pedersen
George Dedoussis
Maria Dimitriou
Genovefa Kolovou
Stavroula Kanoni
Kathleen Stirrups
Lori L Bonnycastle
Inger Njølstad
Tom Wilsgaard
Andrea Ganna
Emil Rehnberg
Aroon Hingorani
Mika Kivimaki
Meena Kumari
Themistocles L Assimes
Inês Barroso
Michael Boehnke
Ingrid B Borecki
Panos Deloukas
Caroline S Fox
Timothy Frayling
Leif C Groop
Talin Haritunians
David Hunter
Erik Ingelsson
Robert Kaplan
Karen L Mohlke
Jeffrey R O'Connell
David Schlessinger
David P Strachan
Kari Stefansson
Cornelia M van Duijn
Gonçalo R Abecasis
Mark I McCarthy
Joel N Hirschhorn
Lu Qi
Ruth J F Loos
Cecilia M Lindgren
Kari E North
Iris M Heid
author_facet Joshua C Randall
Thomas W Winkler
Zoltán Kutalik
Sonja I Berndt
Anne U Jackson
Keri L Monda
Tuomas O Kilpeläinen
Tõnu Esko
Reedik Mägi
Shengxu Li
Tsegaselassie Workalemahu
Mary F Feitosa
Damien C Croteau-Chonka
Felix R Day
Tove Fall
Teresa Ferreira
Stefan Gustafsson
Adam E Locke
Iain Mathieson
Andre Scherag
Sailaja Vedantam
Andrew R Wood
Liming Liang
Valgerdur Steinthorsdottir
Gudmar Thorleifsson
Emmanouil T Dermitzakis
Antigone S Dimas
Fredrik Karpe
Josine L Min
George Nicholson
Deborah J Clegg
Thomas Person
Jon P Krohn
Sabrina Bauer
Christa Buechler
Kristina Eisinger
DIAGRAM Consortium
Amélie Bonnefond
Philippe Froguel
MAGIC Investigators
Jouke-Jan Hottenga
Inga Prokopenko
Lindsay L Waite
Tamara B Harris
Albert Vernon Smith
Alan R Shuldiner
Wendy L McArdle
Mark J Caulfield
Patricia B Munroe
Henrik Grönberg
Yii-Der Ida Chen
Guo Li
Jacques S Beckmann
Toby Johnson
Unnur Thorsteinsdottir
Maris Teder-Laving
Kay-Tee Khaw
Nicholas J Wareham
Jing Hua Zhao
Najaf Amin
Ben A Oostra
Aldi T Kraja
Michael A Province
L Adrienne Cupples
Nancy L Heard-Costa
Jaakko Kaprio
Samuli Ripatti
Ida Surakka
Francis S Collins
Jouko Saramies
Jaakko Tuomilehto
Antti Jula
Veikko Salomaa
Jeanette Erdmann
Christian Hengstenberg
Christina Loley
Heribert Schunkert
Claudia Lamina
H Erich Wichmann
Eva Albrecht
Christian Gieger
Andrew A Hicks
Asa Johansson
Peter P Pramstaller
Sekar Kathiresan
Elizabeth K Speliotes
Brenda Penninx
Anna-Liisa Hartikainen
Marjo-Riitta Jarvelin
Ulf Gyllensten
Dorret I Boomsma
Harry Campbell
James F Wilson
Stephen J Chanock
Martin Farrall
Anuj Goel
Carolina Medina-Gomez
Fernando Rivadeneira
Karol Estrada
André G Uitterlinden
Albert Hofman
M Carola Zillikens
Martin den Heijer
Lambertus A Kiemeney
Andrea Maschio
Per Hall
Jonathan Tyrer
Alexander Teumer
Henry Völzke
Peter Kovacs
Anke Tönjes
Massimo Mangino
Tim D Spector
Caroline Hayward
Igor Rudan
Alistair S Hall
Nilesh J Samani
Antony Paul Attwood
Jennifer G Sambrook
Joseph Hung
Lyle J Palmer
Marja-Liisa Lokki
Juha Sinisalo
Gabrielle Boucher
Heikki Huikuri
Mattias Lorentzon
Claes Ohlsson
Niina Eklund
Johan G Eriksson
Cristina Barlassina
Carlo Rivolta
Ilja M Nolte
Harold Snieder
Melanie M Van der Klauw
Jana V Van Vliet-Ostaptchouk
Pablo V Gejman
Jianxin Shi
Kevin B Jacobs
Zhaoming Wang
Stephan J L Bakker
Irene Mateo Leach
Gerjan Navis
Pim van der Harst
Nicholas G Martin
Sarah E Medland
Grant W Montgomery
Jian Yang
Daniel I Chasman
Paul M Ridker
Lynda M Rose
Terho Lehtimäki
Olli Raitakari
Devin Absher
Carlos Iribarren
Hanneke Basart
Kees G Hovingh
Elina Hyppönen
Chris Power
Denise Anderson
John P Beilby
Jennie Hui
Jennifer Jolley
Hendrik Sager
Stefan R Bornstein
Peter E H Schwarz
Kati Kristiansson
Markus Perola
Jaana Lindström
Amy J Swift
Matti Uusitupa
Mustafa Atalay
Timo A Lakka
Rainer Rauramaa
Jennifer L Bolton
Gerry Fowkes
Ross M Fraser
Jackie F Price
Krista Fischer
Kaarel Krjutå Kov
Andres Metspalu
Evelin Mihailov
Claudia Langenberg
Jian'an Luan
Ken K Ong
Peter S Chines
Sirkka M Keinanen-Kiukaanniemi
Timo E Saaristo
Sarah Edkins
Paul W Franks
Göran Hallmans
Dmitry Shungin
Andrew David Morris
Colin N A Palmer
Raimund Erbel
Susanne Moebus
Markus M Nöthen
Sonali Pechlivanis
Kristian Hveem
Narisu Narisu
Anders Hamsten
Steve E Humphries
Rona J Strawbridge
Elena Tremoli
Harald Grallert
Barbara Thorand
Thomas Illig
Wolfgang Koenig
Martina Müller-Nurasyid
Annette Peters
Bernhard O Boehm
Marcus E Kleber
Winfried März
Bernhard R Winkelmann
Johanna Kuusisto
Markku Laakso
Dominique Arveiler
Giancarlo Cesana
Kari Kuulasmaa
Jarmo Virtamo
John W G Yarnell
Diana Kuh
Andrew Wong
Lars Lind
Ulf de Faire
Bruna Gigante
Patrik K E Magnusson
Nancy L Pedersen
George Dedoussis
Maria Dimitriou
Genovefa Kolovou
Stavroula Kanoni
Kathleen Stirrups
Lori L Bonnycastle
Inger Njølstad
Tom Wilsgaard
Andrea Ganna
Emil Rehnberg
Aroon Hingorani
Mika Kivimaki
Meena Kumari
Themistocles L Assimes
Inês Barroso
Michael Boehnke
Ingrid B Borecki
Panos Deloukas
Caroline S Fox
Timothy Frayling
Leif C Groop
Talin Haritunians
David Hunter
Erik Ingelsson
Robert Kaplan
Karen L Mohlke
Jeffrey R O'Connell
David Schlessinger
David P Strachan
Kari Stefansson
Cornelia M van Duijn
Gonçalo R Abecasis
Mark I McCarthy
Joel N Hirschhorn
Lu Qi
Ruth J F Loos
Cecilia M Lindgren
Kari E North
Iris M Heid
author_sort Joshua C Randall
collection DOAJ
description Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
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spelling doaj-art-2a376c2631d74ba1a23a7f38df8168352025-08-20T02:31:02ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-06-0196e100350010.1371/journal.pgen.1003500Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.Joshua C RandallThomas W WinklerZoltán KutalikSonja I BerndtAnne U JacksonKeri L MondaTuomas O KilpeläinenTõnu EskoReedik MägiShengxu LiTsegaselassie WorkalemahuMary F FeitosaDamien C Croteau-ChonkaFelix R DayTove FallTeresa FerreiraStefan GustafssonAdam E LockeIain MathiesonAndre ScheragSailaja VedantamAndrew R WoodLiming LiangValgerdur SteinthorsdottirGudmar ThorleifssonEmmanouil T DermitzakisAntigone S DimasFredrik KarpeJosine L MinGeorge NicholsonDeborah J CleggThomas PersonJon P KrohnSabrina BauerChrista BuechlerKristina EisingerDIAGRAM ConsortiumAmélie BonnefondPhilippe FroguelMAGIC InvestigatorsJouke-Jan HottengaInga ProkopenkoLindsay L WaiteTamara B HarrisAlbert Vernon SmithAlan R ShuldinerWendy L McArdleMark J CaulfieldPatricia B MunroeHenrik GrönbergYii-Der Ida ChenGuo LiJacques S BeckmannToby JohnsonUnnur ThorsteinsdottirMaris Teder-LavingKay-Tee KhawNicholas J WarehamJing Hua ZhaoNajaf AminBen A OostraAldi T KrajaMichael A ProvinceL Adrienne CupplesNancy L Heard-CostaJaakko KaprioSamuli RipattiIda SurakkaFrancis S CollinsJouko SaramiesJaakko TuomilehtoAntti JulaVeikko SalomaaJeanette ErdmannChristian HengstenbergChristina LoleyHeribert SchunkertClaudia LaminaH Erich WichmannEva AlbrechtChristian GiegerAndrew A HicksAsa JohanssonPeter P PramstallerSekar KathiresanElizabeth K SpeliotesBrenda PenninxAnna-Liisa HartikainenMarjo-Riitta JarvelinUlf GyllenstenDorret I BoomsmaHarry CampbellJames F WilsonStephen J ChanockMartin FarrallAnuj GoelCarolina Medina-GomezFernando RivadeneiraKarol EstradaAndré G UitterlindenAlbert HofmanM Carola ZillikensMartin den HeijerLambertus A KiemeneyAndrea MaschioPer HallJonathan TyrerAlexander TeumerHenry VölzkePeter KovacsAnke TönjesMassimo ManginoTim D SpectorCaroline HaywardIgor RudanAlistair S HallNilesh J SamaniAntony Paul AttwoodJennifer G SambrookJoseph HungLyle J PalmerMarja-Liisa LokkiJuha SinisaloGabrielle BoucherHeikki HuikuriMattias LorentzonClaes OhlssonNiina EklundJohan G ErikssonCristina BarlassinaCarlo RivoltaIlja M NolteHarold SniederMelanie M Van der KlauwJana V Van Vliet-OstaptchoukPablo V GejmanJianxin ShiKevin B JacobsZhaoming WangStephan J L BakkerIrene Mateo LeachGerjan NavisPim van der HarstNicholas G MartinSarah E MedlandGrant W MontgomeryJian YangDaniel I ChasmanPaul M RidkerLynda M RoseTerho LehtimäkiOlli RaitakariDevin AbsherCarlos IribarrenHanneke BasartKees G HovinghElina HyppönenChris PowerDenise AndersonJohn P BeilbyJennie HuiJennifer JolleyHendrik SagerStefan R BornsteinPeter E H SchwarzKati KristianssonMarkus PerolaJaana LindströmAmy J SwiftMatti UusitupaMustafa AtalayTimo A LakkaRainer RauramaaJennifer L BoltonGerry FowkesRoss M FraserJackie F PriceKrista FischerKaarel Krjutå KovAndres MetspaluEvelin MihailovClaudia LangenbergJian'an LuanKen K OngPeter S ChinesSirkka M Keinanen-KiukaanniemiTimo E SaaristoSarah EdkinsPaul W FranksGöran HallmansDmitry ShunginAndrew David MorrisColin N A PalmerRaimund ErbelSusanne MoebusMarkus M NöthenSonali PechlivanisKristian HveemNarisu NarisuAnders HamstenSteve E HumphriesRona J StrawbridgeElena TremoliHarald GrallertBarbara ThorandThomas IlligWolfgang KoenigMartina Müller-NurasyidAnnette PetersBernhard O BoehmMarcus E KleberWinfried MärzBernhard R WinkelmannJohanna KuusistoMarkku LaaksoDominique ArveilerGiancarlo CesanaKari KuulasmaaJarmo VirtamoJohn W G YarnellDiana KuhAndrew WongLars LindUlf de FaireBruna GigantePatrik K E MagnussonNancy L PedersenGeorge DedoussisMaria DimitriouGenovefa KolovouStavroula KanoniKathleen StirrupsLori L BonnycastleInger NjølstadTom WilsgaardAndrea GannaEmil RehnbergAroon HingoraniMika KivimakiMeena KumariThemistocles L AssimesInês BarrosoMichael BoehnkeIngrid B BoreckiPanos DeloukasCaroline S FoxTimothy FraylingLeif C GroopTalin HarituniansDavid HunterErik IngelssonRobert KaplanKaren L MohlkeJeffrey R O'ConnellDavid SchlessingerDavid P StrachanKari StefanssonCornelia M van DuijnGonçalo R AbecasisMark I McCarthyJoel N HirschhornLu QiRuth J F LoosCecilia M LindgrenKari E NorthIris M HeidGiven the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003500&type=printable
spellingShingle Joshua C Randall
Thomas W Winkler
Zoltán Kutalik
Sonja I Berndt
Anne U Jackson
Keri L Monda
Tuomas O Kilpeläinen
Tõnu Esko
Reedik Mägi
Shengxu Li
Tsegaselassie Workalemahu
Mary F Feitosa
Damien C Croteau-Chonka
Felix R Day
Tove Fall
Teresa Ferreira
Stefan Gustafsson
Adam E Locke
Iain Mathieson
Andre Scherag
Sailaja Vedantam
Andrew R Wood
Liming Liang
Valgerdur Steinthorsdottir
Gudmar Thorleifsson
Emmanouil T Dermitzakis
Antigone S Dimas
Fredrik Karpe
Josine L Min
George Nicholson
Deborah J Clegg
Thomas Person
Jon P Krohn
Sabrina Bauer
Christa Buechler
Kristina Eisinger
DIAGRAM Consortium
Amélie Bonnefond
Philippe Froguel
MAGIC Investigators
Jouke-Jan Hottenga
Inga Prokopenko
Lindsay L Waite
Tamara B Harris
Albert Vernon Smith
Alan R Shuldiner
Wendy L McArdle
Mark J Caulfield
Patricia B Munroe
Henrik Grönberg
Yii-Der Ida Chen
Guo Li
Jacques S Beckmann
Toby Johnson
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Maris Teder-Laving
Kay-Tee Khaw
Nicholas J Wareham
Jing Hua Zhao
Najaf Amin
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L Adrienne Cupples
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Anna-Liisa Hartikainen
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Nilesh J Samani
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Jennifer G Sambrook
Joseph Hung
Lyle J Palmer
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Juha Sinisalo
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Heikki Huikuri
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Ilja M Nolte
Harold Snieder
Melanie M Van der Klauw
Jana V Van Vliet-Ostaptchouk
Pablo V Gejman
Jianxin Shi
Kevin B Jacobs
Zhaoming Wang
Stephan J L Bakker
Irene Mateo Leach
Gerjan Navis
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Nicholas G Martin
Sarah E Medland
Grant W Montgomery
Jian Yang
Daniel I Chasman
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Lynda M Rose
Terho Lehtimäki
Olli Raitakari
Devin Absher
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Hanneke Basart
Kees G Hovingh
Elina Hyppönen
Chris Power
Denise Anderson
John P Beilby
Jennie Hui
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Hendrik Sager
Stefan R Bornstein
Peter E H Schwarz
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Markus Perola
Jaana Lindström
Amy J Swift
Matti Uusitupa
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Rainer Rauramaa
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Gerry Fowkes
Ross M Fraser
Jackie F Price
Krista Fischer
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Evelin Mihailov
Claudia Langenberg
Jian'an Luan
Ken K Ong
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Sirkka M Keinanen-Kiukaanniemi
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Sarah Edkins
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Dmitry Shungin
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Markus M Nöthen
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Kristian Hveem
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Elena Tremoli
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Thomas Illig
Wolfgang Koenig
Martina Müller-Nurasyid
Annette Peters
Bernhard O Boehm
Marcus E Kleber
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Bernhard R Winkelmann
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Markku Laakso
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Kari Kuulasmaa
Jarmo Virtamo
John W G Yarnell
Diana Kuh
Andrew Wong
Lars Lind
Ulf de Faire
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Patrik K E Magnusson
Nancy L Pedersen
George Dedoussis
Maria Dimitriou
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Stavroula Kanoni
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Lori L Bonnycastle
Inger Njølstad
Tom Wilsgaard
Andrea Ganna
Emil Rehnberg
Aroon Hingorani
Mika Kivimaki
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Themistocles L Assimes
Inês Barroso
Michael Boehnke
Ingrid B Borecki
Panos Deloukas
Caroline S Fox
Timothy Frayling
Leif C Groop
Talin Haritunians
David Hunter
Erik Ingelsson
Robert Kaplan
Karen L Mohlke
Jeffrey R O'Connell
David Schlessinger
David P Strachan
Kari Stefansson
Cornelia M van Duijn
Gonçalo R Abecasis
Mark I McCarthy
Joel N Hirschhorn
Lu Qi
Ruth J F Loos
Cecilia M Lindgren
Kari E North
Iris M Heid
Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
PLoS Genetics
title Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
title_full Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
title_fullStr Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
title_full_unstemmed Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
title_short Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
title_sort sex stratified genome wide association studies including 270 000 individuals show sexual dimorphism in genetic loci for anthropometric traits
url https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003500&type=printable
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