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

Randall, J.C.; Winkler, T.W.; Kutalik, Z.; Berndt, S.I.; Jackson, A.U.; Monda, K.L.; Kilpeläinen, T.O.; Esko, T.; Mägi, R.; Li, S.; Workalemahu, T.; Feitosa, M.F.; Croteau Chonka, D.C.; Day, F.R.; Fall, T.; Ferreira, T.; Gustafsson, S.; Locke, A.E.; Mathieson, I.; Scherag, A.; Vedantam, S.; Wood, A.R.; Liang, L.; Steinthorsdottir, V.; Thorleifsson, G.; Dermitzakis, E.T.; Dimas, A.S.; Karpe, F.; Min, J.L.; Nicholson, G.; Clegg, D.J.; Person, T.; Krohn, J.P.; Bauer, S.; Buechler, C.; Eisinger, K.; Bonnefond, A.; Froguel, P.; Hottenga, J.; Prokopenko, I.; Waite, L.L.; Harris, T.B.; Smith, A.V.; Shuldiner, A.R.; Mcardle, W.L.; Caulfield, M.J.; Munroe, P.B.; Grönberg, H.; Chen, Y.I.; Li, G.; Beckmann, J.S.; Johnson, T.; Thorsteinsdottir, U.; Teder Laving, M.; Khaw, K.; Wareham, N.J.; Zhao, J.H.; Amin, N.; Oostra, B.A.; Kraja, A.T.; Province, M.A.; Cupples, L.A.; Heard Costa, N.L.; Kaprio, J.; Ripatti, S.; Surakka, I.; Collins, F.S.; Saramies, J.; Tuomilehto, J.; Jula, A.; Salomaa, V.; Erdmann, J.; Hengstenberg, C.; Loley, C.; Schunkert, H.; Lamina, C.; Wichmann, H.E.; Albrecht, E.; Gieger, C.; Hicks, A.A.; Johansson, A.; Pramstaller, P.P.; Kathiresan, S.; Speliotes, E.K.; Penninx, B.; Hartikainen, A.; Jarvelin, M.; Gyllensten, U.; Boomsma, D.I.; Campbell, H.; Wilson, J.F.; Chanock, S.J.; Farrall, M.; Goel, A.; Medina Gomez, C.; Rivadeneira, F.; Estrada, K.; Uitterlinden, A.G.; Hofman, A.; Zillikens, M.C.; den Heijer, M.; Kiemeney, L.A.; Maschio, A.; Hall, P.; Tyrer, J.; Teumer, A.; Völzke, H.; Kovacs, P.; Tönjes, A.; Mangino, M.; Spector, T.D.; Hayward, C.; Rudan, I.; Hall, A.S.; Samani, N.J.; Attwood, A.P.; Sambrook, J.G.; Hung, J.; Palmer, L.J.; Lokki, M.; Sinisalo, J.; Boucher, G.; Huikuri, H.; Lorentzon, M.; Ohlsson, C.; Eklund, N.; Eriksson, J.G.; Barlassina, C.; Rivolta, C.; Nolte, I.M.; Snieder, H.; Van der Klauw, M.M.; Van Vliet Ostaptchouk, J.V.; Gejman, P.V.; Shi, J.; Jacobs, K.B.; Wang, Z.; Bakker, S.J.L.; Mateo Leach, I.; Navis, G.; van der Harst, P.; Martin, N.G.; Medland, S.E.; Montgomery, G.W.; Yang, J.; Chasman, D.I.; Ridker, P.M.; Rose, L.M.; Lehtimäki, T.; Raitakari, O.; Absher, D.; Iribarren, C.; Basart, H.; Hovingh, K.G.; Hyppönen, E.; Power, C.; Anderson, D.; Beilby, J.P.; Hui, J.; Jolley, J.; Sager, H.; Bornstein, S.R.; Schwarz, P.E.H.; Kristiansson, K.; Perola, M.; Lindström, J.; Swift, A.J.; Uusitupa, M.; Atalay, M.; Lakka, T.A.; Rauramaa, R.; Bolton, J.L.; Fowkes, G.; Fraser, R.M.; Price, J.F.; Fischer, K.; Krjutå Kov, K.; Metspalu, A.; Mihailov, E.; Langenberg, C.; Luan, J.; Ong, K.K.; Chines, P.S.; Keinanen Kiukaanniemi, S.M.; Saaristo, T.E.; Edkins, S.; Franks, P.W.; Hallmans, G.; Shungin, D.; Morris, A.D.; Palmer, C.N.A.; Erbel, R.; Moebus, S.; Nöthen, M.M.; Pechlivanis, S.; Hveem, K.; Narisu, N.; Hamsten, A.; Humphries, S.E.; Strawbridge, R.J.; Tremoli, E.; Grallert, H.; Thorand, B.; Illig, T.; Koenig, W.; Müller Nurasyid, M.; Peters, A.; Boehm, B.O.; Kleber, M.E.; März, W.; Winkelmann, B.R.; Kuusisto, J.; Laakso, M.; Arveiler, D.; Cesana, G.; Kuulasmaa, K.; Virtamo, J.; Yarnell, J.W.G.; Kuh, D.; Wong, A.; Lind, L.; de Faire, U.; Gigante, B.; Magnusson, P.K.E.; Pedersen, N.L.; Dedoussis, G.; Dimitriou, M.; Kolovou, G.; Kanoni, S.; Stirrups, K.; Bonnycastle, L.L.; Njølstad, I.; Wilsgaard, T.; Ganna, A.; Rehnberg, E.; Hingorani, A.; Kivimaki, M.; Kumari, M.; Assimes, T.L.; Barroso, I.; Boehnke, M.; Borecki, I.B.; Deloukas, P.; Fox, C.S.; Frayling, T.; Groop, L.C.; Haritunians, T.; Hunter, D.; Ingelsson, E.; Kaplan, R.; Mohlke, K.L.; O'Connell, J.R.; Schlessinger, D.; Strachan, D.P.; Stefansson, K.; van Duijn, C.M.; Abecasis, G.R.; Mccarthy, M.I.; Hirschhorn, J.N.; Qi, L.; Loos, R.J.F.; Lindgren, C.M.; North, K.E.; Heid, I.M.

doi:10.1371/journal.pgen.1003500

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.

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits / J.C. Randall, T.W. Winkler, Z. Kutalik, S.I. Berndt, A.U. Jackson, K.L. Monda, T.O. Kilpeläinen, T. Esko, R. Mägi, S. Li, T. Workalemahu, M.F. Feitosa, D.C. Croteau-Chonka, F.R. Day, T. Fall, T. Ferreira, S. Gustafsson, A.E. Locke, I. Mathieson, A. Scherag, S. Vedantam, A.R. Wood, L. Liang, V. Steinthorsdottir, G. Thorleifsson, E.T. Dermitzakis, A.S. Dimas, F. Karpe, J.L. Min, G. Nicholson, D.J. Clegg, T. Person, J.P. Krohn, S. Bauer, C. Buechler, K. Eisinger, A. Bonnefond, P. Froguel, J. Hottenga, I. Prokopenko, L.L. Waite, T.B. Harris, A.V. Smith, A.R. Shuldiner, W.L. McArdle, M.J. Caulfield, P.B. Munroe, H. Grönberg, Y.I. Chen, G. Li, J.S. Beckmann, T. Johnson, U. Thorsteinsdottir, M. Teder-Laving, K. Khaw, N.J. Wareham, J.H. Zhao, N. Amin, B.A. Oostra, A.T. Kraja, M.A. Province, L.A. Cupples, N.L. Heard-Costa, J. Kaprio, S. Ripatti, I. Surakka, F.S. Collins, J. Saramies, J. Tuomilehto, A. Jula, V. Salomaa, J. Erdmann, C. Hengstenberg, C. Loley, H. Schunkert, C. Lamina, H.E. Wichmann, E. Albrecht, C. Gieger, A.A. Hicks, A. Johansson, P.P. Pramstaller, S. Kathiresan, E.K. Speliotes, B. Penninx, A. Hartikainen, M. Jarvelin, U. Gyllensten, D.I. Boomsma, H. Campbell, J.F. Wilson, S.J. Chanock, M. Farrall, A. Goel, C. Medina-Gomez, F. Rivadeneira, K. Estrada, A.G. Uitterlinden, A. Hofman, M.C. Zillikens, M. den Heijer, L.A. Kiemeney, A. Maschio, P. Hall, J. Tyrer, A. Teumer, H. Völzke, P. Kovacs, A. Tönjes, M. Mangino, T.D. Spector, C. Hayward, I. Rudan, A.S. Hall, N.J. Samani, A.P. Attwood, J.G. Sambrook, J. Hung, L.J. Palmer, M. Lokki, J. Sinisalo, G. Boucher, H. Huikuri, M. Lorentzon, C. Ohlsson, N. Eklund, J.G. Eriksson, C. Barlassina, C. Rivolta, I.M. Nolte, H. Snieder, M.M. Van der Klauw, J.V. Van Vliet-Ostaptchouk, P.V. Gejman, J. Shi, K.B. Jacobs, Z. Wang, S.J.L. Bakker, I. Mateo Leach, G. Navis, P. van der Harst, N.G. Martin, S.E. Medland, G.W. Montgomery, J. Yang, D.I. Chasman, P.M. Ridker, L.M. Rose, T. Lehtimäki, O. Raitakari, D. Absher, C. Iribarren, H. Basart, K.G. Hovingh, E. Hyppönen, C. Power, D. Anderson, J.P. Beilby, J. Hui, J. Jolley, H. Sager, S.R. Bornstein, P.E.H. Schwarz, K. Kristiansson, M. Perola, J. Lindström, A.J. Swift, M. Uusitupa, M. Atalay, T.A. Lakka, R. Rauramaa, J.L. Bolton, G. Fowkes, R.M. Fraser, J.F. Price, K. Fischer, K. Krjutå Kov, A. Metspalu, E. Mihailov, C. Langenberg, J. Luan, K.K. Ong, P.S. Chines, S.M. Keinanen-Kiukaanniemi, T.E. Saaristo, S. Edkins, P.W. Franks, G. Hallmans, D. Shungin, A.D. Morris, C.N.A. Palmer, R. Erbel, S. Moebus, M.M. Nöthen, S. Pechlivanis, K. Hveem, N. Narisu, A. Hamsten, S.E. Humphries, R.J. Strawbridge, E. Tremoli, H. Grallert, B. Thorand, T. Illig, W. Koenig, M. Müller-Nurasyid, A. Peters, B.O. Boehm, M.E. Kleber, W. März, B.R. Winkelmann, J. Kuusisto, M. Laakso, D. Arveiler, G. Cesana, K. Kuulasmaa, J. Virtamo, J.W.G. Yarnell, D. Kuh, A. Wong, L. Lind, U. de Faire, B. Gigante, P.K.E. Magnusson, N.L. Pedersen, G. Dedoussis, M. Dimitriou, G. Kolovou, S. Kanoni, K. Stirrups, L.L. Bonnycastle, I. Njølstad, T. Wilsgaard, A. Ganna, E. Rehnberg, A. Hingorani, M. Kivimaki, M. Kumari, T.L. Assimes, I. Barroso, M. Boehnke, I.B. Borecki, P. Deloukas, C.S. Fox, T. Frayling, L.C. Groop, T. Haritunians, D. Hunter, E. Ingelsson, R. Kaplan, K.L. Mohlke, J.R. O'Connell, D. Schlessinger, D.P. Strachan, K. Stefansson, C.M. van Duijn, G.R. Abecasis, M.I. McCarthy, J.N. Hirschhorn, L. Qi, R.J.F. Loos, C.M. Lindgren, K.E. North, I.M. Heid. - In: PLOS GENETICS. - ISSN 1553-7390. - 9:6(2013 Jun), pp. e1003500.1-e1003500.19. [10.1371/journal.pgen.1003500]

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

J. C. Randall;T. W. Winkler;Z. Kutalik;S. I. Berndt;A. U. Jackson;K. L. Monda;T. O. Kilpeläinen;T. Esko;R. Mägi;S. Li;T. Workalemahu;M. F. Feitosa;D. C. Croteau Chonka;F. R. Day;T. Fall;T. Ferreira;S. Gustafsson;A. E. Locke;I. Mathieson;A. Scherag;S. Vedantam;A. R. Wood;L. Liang;V. Steinthorsdottir;G. Thorleifsson;E. T. Dermitzakis;A. S. Dimas;F. Karpe;J. L. Min;G. Nicholson;D. J. Clegg;T. Person;J. P. Krohn;S. Bauer;C. Buechler;K. Eisinger;A. Bonnefond;P. Froguel;J. Hottenga;I. Prokopenko;L. L. Waite;T. B. Harris;A. V. Smith;A. R. Shuldiner;W. L. McArdle;M. J. Caulfield;P. B. Munroe;H. Grönberg;Y. I. Chen;G. Li;J. S. Beckmann;T. Johnson;U. Thorsteinsdottir;M. Teder Laving;K. Khaw;N. J. Wareham;J. H. Zhao;N. Amin;B. A. Oostra;A. T. Kraja;M. A. Province;L. A. Cupples;N. L. Heard Costa;J. Kaprio;S. Ripatti;I. Surakka;F. S. Collins;J. Saramies;J. Tuomilehto;A. Jula;V. Salomaa;J. Erdmann;C. Hengstenberg;C. Loley;H. Schunkert;C. Lamina;H. E. Wichmann;E. Albrecht;C. Gieger;A. A. Hicks;A. Johansson;P. P. Pramstaller;S. Kathiresan;E. K. Speliotes;B. Penninx;A. Hartikainen;M. Jarvelin;U. Gyllensten;D. I. Boomsma;H. Campbell;J. F. Wilson;S. J. Chanock;M. Farrall;A. Goel;C. Medina Gomez;F. Rivadeneira;K. Estrada;A. G. Uitterlinden;A. Hofman;M. C. Zillikens;M. den Heijer;L. A. Kiemeney;A. Maschio;P. Hall;J. Tyrer;A. Teumer;H. Völzke;P. Kovacs;A. Tönjes;M. Mangino;T. D. Spector;C. Hayward;I. Rudan;A. S. Hall;N. J. Samani;A. P. Attwood;J. G. Sambrook;J. Hung;L. J. Palmer;M. Lokki;J. Sinisalo;G. Boucher;H. Huikuri;M. Lorentzon;C. Ohlsson;N. Eklund;J. G. Eriksson;C. Barlassina;C. Rivolta;I. M. Nolte;H. Snieder;M. M. Van der Klauw;J. V. Van Vliet Ostaptchouk;P. V. Gejman;J. Shi;K. B. Jacobs;Z. Wang;S. J. L. Bakker;I. Mateo Leach;G. Navis;P. van der Harst;N. G. Martin;S. E. Medland;G. W. Montgomery;J. Yang;D. I. Chasman;P. M. Ridker;L. M. Rose;T. Lehtimäki;O. Raitakari;D. Absher;C. Iribarren;H. Basart;K. G. Hovingh;E. Hyppönen;C. Power;D. Anderson;J. P. Beilby;J. Hui;J. Jolley;H. Sager;S. R. Bornstein;P. E. H. Schwarz;K. Kristiansson;M. Perola;J. Lindström;A. J. Swift;M. Uusitupa;M. Atalay;T. A. Lakka;R. Rauramaa;J. L. Bolton;G. Fowkes;R. M. Fraser;J. F. Price;K. Fischer;K. Krjutå Kov;A. Metspalu;E. Mihailov;C. Langenberg;J. Luan;K. K. Ong;P. S. Chines;S. M. Keinanen Kiukaanniemi;T. E. Saaristo;S. Edkins;P. W. Franks;G. Hallmans;D. Shungin;A. D. Morris;C. N. A. Palmer;R. Erbel;S. Moebus;M. M. Nöthen;S. Pechlivanis;K. Hveem;N. Narisu;A. Hamsten;S. E. Humphries;R. J. Strawbridge;E. Tremoli;H. Grallert;B. Thorand;T. Illig;W. Koenig;M. Müller Nurasyid;A. Peters;B. O. Boehm;M. E. Kleber;W. März;B. R. Winkelmann;J. Kuusisto;M. Laakso;D. Arveiler;G. Cesana;K. Kuulasmaa;J. Virtamo;J. W. G. Yarnell;D. Kuh;A. Wong;L. Lind;U. de Faire;B. Gigante;P. K. E. Magnusson;N. L. Pedersen;G. Dedoussis;M. Dimitriou;G. Kolovou;S. Kanoni;K. Stirrups;L. L. Bonnycastle;I. Njølstad;T. Wilsgaard;A. Ganna;E. Rehnberg;A. Hingorani;M. Kivimaki;M. Kumari;T. L. Assimes;I. Barroso;M. Boehnke;I. B. Borecki;P. Deloukas;C. S. Fox;T. Frayling;L. C. Groop;T. Haritunians;D. Hunter;E. Ingelsson;R. Kaplan;K. L. Mohlke;J. R. O'Connell;D. Schlessinger;D. P. Strachan;K. Stefansson;C. M. van Duijn;G. R. Abecasis;M. I. McCarthy;J. N. Hirschhorn;L. Qi;R. J. F. Loos;C. M. Lindgren;K. E. North;I. M. Heid

2013

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.

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	Parole chiave
	
			Body Weights and Measures ; Genome-Wide Association Study ; Sex Characteristics ; Anthropometry ; Body Height ; Body Mass Index ; Body Weight ; Female ; Genetic Loci ; Genome, Human ; Humans ; Male ; Polymorphism, Single Nucleotide ; Waist Circumference ; Waist-Hip Ratio
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore BIO/18 - Genetica
Settore MED/09 - Medicina Interna
Settore MED/03 - Genetica Medica
		
	Data di pubblicazione
	
			giu-2013
		
	Rivista in ANCE
	
			PLOS GENETICS
		
	DOI
	
			https://dx.doi.org/10.1371/journal.pgen.1003500
		
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			01 - Articolo su periodico

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