Abstract
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.
Original language | English |
---|---|
Article number | e1003500 |
Journal | PLoS Genetics |
Volume | 9 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2013 |
Externally published | Yes |
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In: PLoS Genetics, Vol. 9, No. 6, e1003500, 06.2013.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits
AU - Randall, Joshua C.
AU - Winkler, Thomas W.
AU - Kutalik, Zoltán
AU - Berndt, Sonja I.
AU - Jackson, Anne U.
AU - Monda, Keri L.
AU - Kilpeläinen, Tuomas O.
AU - Esko, Tõnu
AU - Mägi, Reedik
AU - Li, Shengxu
AU - Workalemahu, Tsegaselassie
AU - Feitosa, Mary F.
AU - Croteau-Chonka, Damien C.
AU - Day, Felix R.
AU - Fall, Tove
AU - Ferreira, Teresa
AU - Gustafsson, Stefan
AU - Locke, Adam E.
AU - Mathieson, Iain
AU - Scherag, Andre
AU - Vedantam, Sailaja
AU - Wood, Andrew R.
AU - Liang, Liming
AU - Steinthorsdottir, Valgerdur
AU - Thorleifsson, Gudmar
AU - Dermitzakis, Emmanouil T.
AU - Dimas, Antigone S.
AU - Karpe, Fredrik
AU - Min, Josine L.
AU - Nicholson, George
AU - Clegg, Deborah J.
AU - Person, Thomas
AU - Krohn, Jon P.
AU - Bauer, Sabrina
AU - Buechler, Christa
AU - Eisinger, Kristina
AU - Bonnefond, Amélie
AU - Froguel, Philippe
AU - Hottenga, Jouke Jan
AU - Prokopenko, Inga
AU - Waite, Lindsay L.
AU - Harris, Tamara B.
AU - Smith, Albert Vernon
AU - Shuldiner, Alan R.
AU - McArdle, Wendy L.
AU - Caulfield, Mark J.
AU - Munroe, Patricia B.
AU - Grönberg, Henrik
AU - Chen, Yii Der Ida
AU - Li, Guo
AU - Beckmann, Jacques S.
AU - Johnson, Toby
AU - Thorsteinsdottir, Unnur
AU - Teder-Laving, Maris
AU - Khaw, Kay Tee
AU - Wareham, Nicholas J.
AU - Zhao, Jing Hua
AU - Amin, Najaf
AU - Oostra, Ben A.
AU - Kraja, Aldi T.
AU - Province, Michael A.
AU - Cupples, L. Adrienne
AU - Heard-Costa, Nancy L.
AU - Kaprio, Jaakko
AU - Ripatti, Samuli
AU - Surakka, Ida
AU - Collins, Francis S.
AU - Saramies, Jouko
AU - Tuomilehto, Jaakko
AU - Jula, Antti
AU - Salomaa, Veikko
AU - Erdmann, Jeanette
AU - Hengstenberg, Christian
AU - Loley, Christina
AU - Schunkert, Heribert
AU - Lamina, Claudia
AU - Wichmann, H. Erich
AU - Albrecht, Eva
AU - Gieger, Christian
AU - Hicks, Andrew A.
AU - Johansson, Åsa
AU - Pramstaller, Peter P.
AU - Kathiresan, Sekar
AU - Speliotes, Elizabeth K.
AU - Penninx, Brenda
AU - Hartikainen, Anna Liisa
AU - Jarvelin, Marjo Riitta
AU - Gyllensten, Ulf
AU - Boomsma, Dorret I.
AU - Campbell, Harry
AU - Wilson, James F.
AU - Chanock, Stephen J.
AU - Farrall, Martin
AU - Goel, Anuj
AU - Medina-Gomez, Carolina
AU - Rivadeneira, Fernando
AU - Estrada, Karol
AU - Uitterlinden, André G.
AU - Hofman, Albert
AU - Zillikens, M. Carola
AU - den Heijer, Martin
AU - Kiemeney, Lambertus A.
AU - Maschio, Andrea
AU - Hall, Per
AU - Tyrer, Jonathan
AU - Teumer, Alexander
AU - Völzke, Henry
AU - Kovacs, Peter
AU - Tönjes, Anke
AU - Mangino, Massimo
AU - Spector, Tim D.
AU - Hayward, Caroline
AU - Rudan, Igor
AU - Hall, Alistair S.
AU - Samani, Nilesh J.
AU - Attwood, Antony Paul
AU - Sambrook, Jennifer G.
AU - Hung, Joseph
AU - Palmer, Lyle J.
AU - Lokki, Marja Liisa
AU - Sinisalo, Juha
AU - Boucher, Gabrielle
AU - Huikuri, Heikki
AU - Lorentzon, Mattias
AU - Ohlsson, Claes
AU - Eklund, Niina
AU - Eriksson, Johan G.
AU - Barlassina, Cristina
AU - Rivolta, Carlo
AU - Nolte, Ilja M.
AU - Snieder, Harold
AU - van der Klauw, Melanie M.
AU - van Vliet-Ostaptchouk, Jana V.
AU - Gejman, Pablo V.
AU - Shi, Jianxin
AU - Jacobs, Kevin B.
AU - Wang, Zhaoming
AU - Bakker, Stephan J.L.
AU - Mateo Leach, Irene
AU - Navis, Gerjan
AU - van der Harst, Pim
AU - Martin, Nicholas G.
AU - Medland, Sarah E.
AU - Montgomery, Grant W.
AU - Yang, Jian
AU - Chasman, Daniel I.
AU - Ridker, Paul M.
AU - Rose, Lynda M.
AU - Lehtimäki, Terho
AU - Raitakari, Olli
AU - Absher, Devin
AU - Iribarren, Carlos
AU - Basart, Hanneke
AU - Hovingh, Kees G.
AU - Hyppönen, Elina
AU - Power, Chris
AU - Anderson, Denise
AU - Beilby, John P.
AU - Hui, Jennie
AU - Jolley, Jennifer
AU - Sager, Hendrik
AU - Bornstein, Stefan R.
AU - Schwarz, Peter E.H.
AU - Kristiansson, Kati
AU - Perola, Markus
AU - Lindström, Jaana
AU - Swift, Amy J.
AU - Uusitupa, Matti
AU - Atalay, Mustafa
AU - Lakka, Timo A.
AU - Rauramaa, Rainer
AU - Bolton, Jennifer L.
AU - Fowkes, Gerry
AU - Fraser, Ross M.
AU - Price, Jackie F.
AU - Fischer, Krista
AU - KrjutÅkov, Kaarel
AU - Metspalu, Andres
AU - Mihailov, Evelin
AU - Langenberg, Claudia
AU - Luan, Jian'an
AU - Ong, Ken K.
AU - Chines, Peter S.
AU - Keinanen-Kiukaanniemi, Sirkka M.
AU - Saaristo, Timo E.
AU - Edkins, Sarah
AU - Franks, Paul W.
AU - Hallmans, Göran
AU - Shungin, Dmitry
AU - da Morris, Andrewvid
AU - Palmer, Colin N.A.
AU - Erbel, Raimund
AU - Moebus, Susanne
AU - Nöthen, Markus M.
AU - Pechlivanis, Sonali
AU - Hveem, Kristian
AU - Narisu, Narisu
AU - Hamsten, Anders
AU - Humphries, Steve E.
AU - Strawbridge, Rona J.
AU - Tremoli, Elena
AU - Grallert, Harald
AU - Thorand, Barbara
AU - Illig, Thomas
AU - Koenig, Wolfgang
AU - Müller-Nurasyid, Martina
AU - Peters, Annette
AU - Boehm, Bernhard O.
AU - Kleber, Marcus E.
AU - März, Winfried
AU - Winkelmann, Bernhard R.
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - Arveiler, Dominique
AU - Cesana, Giancarlo
AU - Kuulasmaa, Kari
AU - Virtamo, Jarmo
AU - Yarnell, John W.G.
AU - Kuh, Diana
AU - Wong, Andrew
AU - Lind, Lars
AU - de Faire, Ulf
AU - Gigante, Bruna
AU - Magnusson, Patrik K.E.
AU - Pedersen, Nancy L.
AU - Dedoussis, George
AU - Dimitriou, Maria
AU - Kolovou, Genovefa
AU - Kanoni, Stavroula
AU - Stirrups, Kathleen
AU - Bonnycastle, Lori L.
AU - Njølstad, Inger
AU - Wilsgaard, Tom
AU - Ganna, Andrea
AU - Rehnberg, Emil
AU - Hingorani, Aroon
AU - Kivimaki, Mika
AU - Kumari, Meena
AU - Assimes, Themistocles L.
AU - Barroso, Inês
AU - Boehnke, Michael
AU - Borecki, Ingrid B.
AU - Deloukas, Panos
AU - Fox, Caroline S.
AU - Frayling, Timothy
AU - Groop, Leif C.
AU - Haritunians, Talin
AU - Hunter, David
AU - Ingelsson, Erik
AU - Kaplan, Robert
AU - Mohlke, Karen L.
AU - O'Connell, Jeffrey R.
AU - Schlessinger, David
AU - Strachan, David P.
AU - Stefansson, Kari
AU - van Duijn, Cornelia M.
AU - Abecasis, Gonçalo R.
AU - McCarthy, Mark I.
AU - Hirschhorn, Joel N.
AU - Qi, Lu
AU - Loos, Ruth J.F.
AU - Lindgren, Cecilia M.
AU - North, Kari E.
AU - Heid, Iris M.
N1 - Funding Information: I have read the journal's policy and we have the following conflicts: Kari Stefansson, Valgerdur Steinthorsdottir, and Gudmar Thorleifsson are employed by deCODE Genetics with stock/stock options in the company. Inês Barroso and spouse own stock in Incyte Ltd and GlaxoSmithKline. Nilesh J Samani holds a Chair supported by the British Heart Foundation and is an NIHR Senior Investigator.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84879677633&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003500
DO - 10.1371/journal.pgen.1003500
M3 - Article
C2 - 23754948
AN - SCOPUS:84879677633
SN - 1553-7390
VL - 9
JO - PLoS Genetics
JF - PLoS Genetics
IS - 6
M1 - e1003500
ER -