Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Berndt, S.I.; Gustafsson, S.; Mägi, R.; Ganna, A.; Wheeler, E.; Feitosa, M.F.; Justice, A.E.; Monda, K.L.; Croteau Chonka, D.C.; Day, F.R.; Esko, T.; Fall, T.; Ferreira, T.; Gentilini, D.; Jackson, A.U.; Luan, J.; Randall, J.C.; Vedantam, S.; Willer, C.J.; Winkler, T.W.; Wood, A.R.; Workalemahu, T.; Hu, Y.; Lee, S.H.; Liang, L.; Lin, D.; Min, J.L.; Neale, B.M.; Thorleifsson, G.; Yang, J.; Albrecht, E.; Amin, N.; Bragg Gresham, J.L.; Cadby, G.; den Heijer, M.; Eklund, N.; Fischer, K.; Goel, A.; Hottenga, J.; Huffman, J.E.; Jarick, I.; Johansson, Å.; Johnson, T.; Kanoni, S.; Kleber, M.E.; König, I.R.; Kristiansson, K.; Kutalik, Z.; Lamina, C.; Lecoeur, C.; Li, G.; Mangino, M.; Mcardle, W.L.; Medina Gomez, C.; Müller Nurasyid, M.; Ngwa, J.S.; Nolte, I.M.; Paternoster, L.; Pechlivanis, S.; Perola, M.; Peters, M.J.; Preuss, M.; Rose, L.M.; Shi, J.; Shungin, D.; Smith, A.V.; Strawbridge, R.J.; Surakka, I.; Teumer, A.; Trip, M.D.; Tyrer, J.; Van Vliet Ostaptchouk, J.V.; Vandenput, L.; Waite, L.L.; Zhao, J.H.; Absher, D.; Asselbergs, F.W.; Atalay, M.; Attwood, A.P.; Balmforth, A.J.; Basart, H.; Beilby, J.; Bonnycastle, L.L.; Brambilla, P.; Bruinenberg, M.; Campbell, H.; Chasman, D.I.; Chines, P.S.; Collins, F.S.; Connell, J.M.; Cookson, W.O.; de Faire, U.; de Vegt, F.; Dei, M.; Dimitriou, M.; Edkins, S.; Estrada, K.; Evans, D.M.; Farrall, M.; Ferrario, M.M.; Ferrières, J.; Franke, L.; Frau, F.; Gejman, P.V.; Grallert, H.; Grönberg, H.; Gudnason, V.; Hall, A.S.; Hall, P.; Hartikainen, A.; Hayward, C.; Heard Costa, N.L.; Heath, A.C.; Hebebrand, J.; Homuth, G.; F. B., H.; Hunt, S.E.; Hyppönen, E.; Iribarren, C.; Jacobs, K.B.; Jansson, J.; Jula, A.; Kähönen, M.; Kathiresan, S.; Kee, F.; Khaw, K.; Kivimäki, M.; Koenig, W.; Kraja, A.T.; Kumari, M.; Kuulasmaa, K.; Kuusisto, J.; Laitinen, J.H.; Lakka, T.A.; Langenberg, C.; Launer, L.J.; Lind, L.; Lindström, J.; Liu, J.; Liuzzi, A.; Lokki, M.; Lorentzon, M.; Madden, P.A.; Magnusson, P.K.; Manunta, P.; Marek, D.; März, W.; Mateo Leach, I.; Mcknight, B.; Medland, S.E.; Mihailov, E.; Milani, L.; Montgomery, G.W.; Mooser, V.; Mühleisen, T.W.; Munroe, P.B.; Musk, A.W.; Narisu, N.; Navis, G.; Nicholson, G.; Nohr, E.A.; Ong, K.K.; Oostra, B.A.; Palmer, C.N.A.; Palotie, A.; Peden, J.F.; Pedersen, N.; Peters, A.; Polasek, O.; Pouta, A.; Pramstaller, P.P.; Prokopenko, I.; Pütter, C.; Radhakrishnan, A.; Raitakari, O.; Rendon, A.; Rivadeneira, F.; Rudan, I.; Saaristo, T.E.; Sambrook, J.G.; Sanders, A.R.; Sanna, S.; Saramies, J.; Schipf, S.; Schreiber, S.; Schunkert, H.; Shin, S.; Signorini, S.; Sinisalo, J.; Skrobek, B.; Soranzo, N.; Stančáková, A.; Stark, K.; Stephens, J.C.; Stirrups, K.; Stolk, R.P.; Stumvoll, M.; Swift, A.J.; Theodoraki, E.V.; Thorand, B.; Tregouet, D.; Tremoli, E.; Van der Klauw, M.M.; van Meurs, J.B.J.; Vermeulen, S.H.; Viikari, J.; Virtamo, J.; Vitart, V.; Waeber, G.; Wang, Z.; Widén, E.; Wild, S.H.; Willemsen, G.; Winkelmann, B.R.; Witteman, J.C.M.; Wolffenbuttel, B.H.R.; Wong, A.; Wright, A.F.; Zillikens, M.C.; Amouyel, P.; Boehm, B.O.; Boerwinkle, E.; Boomsma, D.I.; Caulfield, M.J.; Chanock, S.J.; Cupples, L.A.; Cusi, D.; Dedoussis, G.V.; Erdmann, J.; Eriksson, J.G.; Franks, P.W.; Froguel, P.; Gieger, C.; Gyllensten, U.; Hamsten, A.; Harris, T.B.; Hengstenberg, C.; Hicks, A.A.; Hingorani, A.; Hinney, A.; Hofman, A.; Hovingh, K.G.; Hveem, K.; Illig, T.; Jarvelin, M.; Jöckel, K.; Keinanen Kiukaanniemi, S.M.; Kiemeney, L.A.; Kuh, D.; Laakso, M.; Lehtimäki, T.; Levinson, D.F.; Martin, N.G.; Metspalu, A.; Morris, A.D.; Nieminen, M.S.; Njølstad, I.; Ohlsson, C.; Oldehinkel, A.J.; Ouwehand, W.H.; Palmer, L.J.; Penninx, B.; Power, C.; Province, M.A.; Psaty, B.M.; Qi, L.; Rauramaa, R.; Ridker, P.M.; Ripatti, S.; Salomaa, V.; Samani, N.J.; Snieder, H.; Sørensen, T.I.A.; Spector, T.D.; Stefansson, K.; Tönjes, A.; Tuomilehto, J.; Uitterlinden, A.G.; Uusitupa, M.; van der Harst, P.; Vollenweider, P.; Wallaschofski, H.; Wareham, N.J.; Watkins, H.; Wichmann, H.; Wilson, J.F.; Abecasis, G.R.; Assimes, T.L.; Barroso, I.; Boehnke, M.; Borecki, I.B.; Deloukas, P.; Fox, C.S.; Frayling, T.; Groop, L.C.; Haritunian, T.; Heid, I.M.; Hunter, D.; Kaplan, R.C.; Karpe, F.; Moffatt, M.F.; Mohlke, K.L.; O'Connell, J.R.; Pawitan, Y.; Schadt, E.E.; Schlessinger, D.; Steinthorsdottir, V.; Strachan, D.P.; Thorsteinsdottir, U.; van Duijn, C.M.; Visscher, P.M.; Di Blasio, A.M.; Hirschhorn, J.N.; Lindgren, C.M.; Morris, A.P.; Meyre, D.; Scherag, A.; Mccarthy, M.I.; Speliotes, E.K.; North, K.E.; Loos, R.J.F.; Ingelsson, E.

doi:10.1038/ng.2606

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture / S.I. Berndt, S. Gustafsson, R. Mägi, A. Ganna, E. Wheeler, M.F. Feitosa, A.E. Justice, K.L. Monda, D.C. Croteau-Chonka, F.R. Day, T. Esko, T. Fall, T. Ferreira, D. Gentilini, A.U. Jackson, J. Luan, J.C. Randall, S. Vedantam, C.J. Willer, T.W. Winkler, A.R. Wood, T. Workalemahu, Y. Hu, S.H. Lee, L. Liang, D. Lin, J.L. Min, B.M. Neale, G. Thorleifsson, J. Yang, E. Albrecht, N. Amin, J.L. Bragg-Gresham, G. Cadby, M. den Heijer, N. Eklund, K. Fischer, A. Goel, J. Hottenga, J.E. Huffman, I. Jarick, Å. Johansson, T. Johnson, S. Kanoni, M.E. Kleber, I.R. König, K. Kristiansson, Z. Kutalik, C. Lamina, C. Lecoeur, G. Li, M. Mangino, W.L. McArdle, C. Medina-Gomez, M. Müller-Nurasyid, J.S. Ngwa, I.M. Nolte, L. Paternoster, S. Pechlivanis, M. Perola, M.J. Peters, M. Preuss, L.M. Rose, J. Shi, D. Shungin, A.V. Smith, R.J. Strawbridge, I. Surakka, A. Teumer, M.D. Trip, J. Tyrer, J.V. Van Vliet-Ostaptchouk, L. Vandenput, L.L. Waite, J.H. Zhao, D. Absher, F.W. Asselbergs, M. Atalay, A.P. Attwood, A.J. Balmforth, H. Basart, J. Beilby, L.L. Bonnycastle, P. Brambilla, M. Bruinenberg, H. Campbell, D.I. Chasman, P.S. Chines, F.S. Collins, J.M. Connell, W.O. Cookson, U. de Faire, F. de Vegt, M. Dei, M. Dimitriou, S. Edkins, K. Estrada, D.M. Evans, M. Farrall, M.M. Ferrario, J. Ferrières, L. Franke, F. Frau, P.V. Gejman, H. Grallert, H. Grönberg, V. Gudnason, A.S. Hall, P. Hall, A. Hartikainen, C. Hayward, N.L. Heard-Costa, A.C. Heath, J. Hebebrand, G. Homuth, F.B. Hu, S.E. Hunt, E. Hyppönen, C. Iribarren, K.B. Jacobs, J. Jansson, A. Jula, M. Kähönen, S. Kathiresan, F. Kee, K. Khaw, M. Kivimäki, W. Koenig, A.T. Kraja, M. Kumari, K. Kuulasmaa, J. Kuusisto, J.H. Laitinen, T.A. Lakka, C. Langenberg, L.J. Launer, L. Lind, J. Lindström, J. Liu, A. Liuzzi, M. Lokki, M. Lorentzon, P.A. Madden, P.K. Magnusson, P. Manunta, D. Marek, W. März, I. Mateo Leach, B. McKnight, S.E. Medland, E. Mihailov, L. Milani, G.W. Montgomery, V. Mooser, T.W. Mühleisen, P.B. Munroe, A.W. Musk, N. Narisu, G. Navis, G. Nicholson, E.A. Nohr, K.K. Ong, B.A. Oostra, C.N.A. Palmer, A. Palotie, J.F. Peden, N. Pedersen, A. Peters, O. Polasek, A. Pouta, P.P. Pramstaller, I. Prokopenko, C. Pütter, A. Radhakrishnan, O. Raitakari, A. Rendon, F. Rivadeneira, I. Rudan, T.E. Saaristo, J.G. Sambrook, A.R. Sanders, S. Sanna, J. Saramies, S. Schipf, S. Schreiber, H. Schunkert, S. Shin, S. Signorini, J. Sinisalo, B. Skrobek, N. Soranzo, A. Stančáková, K. Stark, J.C. Stephens, K. Stirrups, R.P. Stolk, M. Stumvoll, A.J. Swift, E.V. Theodoraki, B. Thorand, D. Tregouet, E. Tremoli, M.M. Van der Klauw, J.B.J. van Meurs, S.H. Vermeulen, J. Viikari, J. Virtamo, V. Vitart, G. Waeber, Z. Wang, E. Widén, S.H. Wild, G. Willemsen, B.R. Winkelmann, J.C.M. Witteman, B.H.R. Wolffenbuttel, A. Wong, A.F. Wright, M.C. Zillikens, P. Amouyel, B.O. Boehm, E. Boerwinkle, D.I. Boomsma, M.J. Caulfield, S.J. Chanock, L.A. Cupples, D. Cusi, G.V. Dedoussis, J. Erdmann, J.G. Eriksson, P.W. Franks, P. Froguel, C. Gieger, U. Gyllensten, A. Hamsten, T.B. Harris, C. Hengstenberg, A.A. Hicks, A. Hingorani, A. Hinney, A. Hofman, K.G. Hovingh, K. Hveem, T. Illig, M. Jarvelin, K. Jöckel, S.M. Keinanen-Kiukaanniemi, L.A. Kiemeney, D. Kuh, M. Laakso, T. Lehtimäki, D.F. Levinson, N.G. Martin, A. Metspalu, A.D. Morris, M.S. Nieminen, I. Njølstad, C. Ohlsson, A.J. Oldehinkel, W.H. Ouwehand, L.J. Palmer, B. Penninx, C. Power, M.A. Province, B.M. Psaty, L. Qi, R. Rauramaa, P.M. Ridker, S. Ripatti, V. Salomaa, N.J. Samani, H. Snieder, T.I.A. Sørensen, T.D. Spector, K. Stefansson, A. Tönjes, J. Tuomilehto, A.G. Uitterlinden, M. Uusitupa, P. van der Harst, P. Vollenweider, H. Wallaschofski, N.J. Wareham, H. Watkins, H. Wichmann, J.F. Wilson, G.R. Abecasis, T.L. Assimes, I. Barroso, M. Boehnke, I.B. Borecki, P. Deloukas, C.S. Fox, T. Frayling, L.C. Groop, T. Haritunian, I.M. Heid, D. Hunter, R.C. Kaplan, F. Karpe, M.F. Moffatt, K.L. Mohlke, J.R. O'Connell, Y. Pawitan, E.E. Schadt, D. Schlessinger, V. Steinthorsdottir, D.P. Strachan, U. Thorsteinsdottir, C.M. van Duijn, P.M. Visscher, A.M. Di Blasio, J.N. Hirschhorn, C.M. Lindgren, A.P. Morris, D. Meyre, A. Scherag, M.I. McCarthy, E.K. Speliotes, K.E. North, R.J.F. Loos, E. Ingelsson. - In: NATURE GENETICS. - ISSN 1061-4036. - 45:5(2013 May), pp. 501-512.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

S. I. Berndt;S. Gustafsson;R. Mägi;A. Ganna;E. Wheeler;M. F. Feitosa;A. E. Justice;K. L. Monda;D. C. Croteau Chonka;F. R. Day;T. Esko;T. Fall;T. Ferreira;D. Gentilini;A. U. Jackson;J. Luan;J. C. Randall;S. Vedantam;C. J. Willer;T. W. Winkler;A. R. Wood;T. Workalemahu;Y. Hu;S. H. Lee;L. Liang;D. Lin;J. L. Min;B. M. Neale;G. Thorleifsson;J. Yang;E. Albrecht;N. Amin;J. L. Bragg Gresham;G. Cadby;M. den Heijer;N. Eklund;K. Fischer;A. Goel;J. Hottenga;J. E. Huffman;I. Jarick;Å. Johansson;T. Johnson;S. Kanoni;M. E. Kleber;I. R. König;K. Kristiansson;Z. Kutalik;C. Lamina;C. Lecoeur;G. Li;M. Mangino;W. L. McArdle;C. Medina Gomez;M. Müller Nurasyid;J. S. Ngwa;I. M. Nolte;L. Paternoster;S. Pechlivanis;M. Perola;M. J. Peters;M. Preuss;L. M. Rose;J. Shi;D. Shungin;A. V. Smith;R. J. Strawbridge;I. Surakka;A. Teumer;M. D. Trip;J. Tyrer;J. V. Van Vliet Ostaptchouk;L. Vandenput;L. L. Waite;J. H. Zhao;D. Absher;F. W. Asselbergs;M. Atalay;A. P. Attwood;A. J. Balmforth;H. Basart;J. Beilby;L. L. Bonnycastle;P. Brambilla;M. Bruinenberg;H. Campbell;D. I. Chasman;P. S. Chines;F. S. Collins;J. M. Connell;W. O. Cookson;U. de Faire;F. de Vegt;M. Dei;M. Dimitriou;S. Edkins;K. Estrada;D. M. Evans;M. Farrall;M. M. Ferrario;J. Ferrières;L. Franke;F. Frau;P. V. Gejman;H. Grallert;H. Grönberg;V. Gudnason;A. S. Hall;P. Hall;A. Hartikainen;C. Hayward;N. L. Heard Costa;A. C. Heath;J. Hebebrand;G. Homuth;F. B. Hu;S. E. Hunt;E. Hyppönen;C. Iribarren;K. B. Jacobs;J. Jansson;A. Jula;M. Kähönen;S. Kathiresan;F. Kee;K. Khaw;M. Kivimäki;W. Koenig;A. T. Kraja;M. Kumari;K. Kuulasmaa;J. Kuusisto;J. H. Laitinen;T. A. Lakka;C. Langenberg;L. J. Launer;L. Lind;J. Lindström;J. Liu;A. Liuzzi;M. Lokki;M. Lorentzon;P. A. Madden;P. K. Magnusson;P. Manunta;D. Marek;W. März;I. Mateo Leach;B. McKnight;S. E. Medland;E. Mihailov;L. Milani;G. W. Montgomery;V. Mooser;T. W. Mühleisen;P. B. Munroe;A. W. Musk;N. Narisu;G. Navis;G. Nicholson;E. A. Nohr;K. K. Ong;B. A. Oostra;C. N. A. Palmer;A. Palotie;J. F. Peden;N. Pedersen;A. Peters;O. Polasek;A. Pouta;P. P. Pramstaller;I. Prokopenko;C. Pütter;A. Radhakrishnan;O. Raitakari;A. Rendon;F. Rivadeneira;I. Rudan;T. E. Saaristo;J. G. Sambrook;A. R. Sanders;S. Sanna;J. Saramies;S. Schipf;S. Schreiber;H. Schunkert;S. Shin;S. Signorini;J. Sinisalo;B. Skrobek;N. Soranzo;A. Stančáková;K. Stark;J. C. Stephens;K. Stirrups;R. P. Stolk;M. Stumvoll;A. J. Swift;E. V. Theodoraki;B. Thorand;D. Tregouet;E. Tremoli;M. M. Van der Klauw;J. B. J. van Meurs;S. H. Vermeulen;J. Viikari;J. Virtamo;V. Vitart;G. Waeber;Z. Wang;E. Widén;S. H. Wild;G. Willemsen;B. R. Winkelmann;J. C. M. Witteman;B. H. R. Wolffenbuttel;A. Wong;A. F. Wright;M. C. Zillikens;P. Amouyel;B. O. Boehm;E. Boerwinkle;D. I. Boomsma;M. J. Caulfield;S. J. Chanock;L. A. Cupples;D. Cusi;G. V. Dedoussis;J. Erdmann;J. G. Eriksson;P. W. Franks;P. Froguel;C. Gieger;U. Gyllensten;A. Hamsten;T. B. Harris;C. Hengstenberg;A. A. Hicks;A. Hingorani;A. Hinney;A. Hofman;K. G. Hovingh;K. Hveem;T. Illig;M. Jarvelin;K. Jöckel;S. M. Keinanen Kiukaanniemi;L. A. Kiemeney;D. Kuh;M. Laakso;T. Lehtimäki;D. F. Levinson;N. G. Martin;A. Metspalu;A. D. Morris;M. S. Nieminen;I. Njølstad;C. Ohlsson;A. J. Oldehinkel;W. H. Ouwehand;L. J. Palmer;B. Penninx;C. Power;M. A. Province;B. M. Psaty;L. Qi;R. Rauramaa;P. M. Ridker;S. Ripatti;V. Salomaa;N. J. Samani;H. Snieder;T. I. A. Sørensen;T. D. Spector;K. Stefansson;A. Tönjes;J. Tuomilehto;A. G. Uitterlinden;M. Uusitupa;P. van der Harst;P. Vollenweider;H. Wallaschofski;N. J. Wareham;H. Watkins;H. Wichmann;J. F. Wilson;G. R. Abecasis;T. L. Assimes;I. Barroso;M. Boehnke;I. B. Borecki;P. Deloukas;C. S. Fox;T. Frayling;L. C. Groop;T. Haritunian;I. M. Heid;D. Hunter;R. C. Kaplan;F. Karpe;M. F. Moffatt;K. L. Mohlke;J. R. O'Connell;Y. Pawitan;E. E. Schadt;D. Schlessinger;V. Steinthorsdottir;D. P. Strachan;U. Thorsteinsdottir;C. M. van Duijn;P. M. Visscher;A. M. Di Blasio;J. N. Hirschhorn;C. M. Lindgren;A. P. Morris;D. Meyre;A. Scherag;M. I. McCarthy;E. K. Speliotes;K. E. North;R. J. F. Loos;E. Ingelsson

2013

Abstract

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Scheda breve

Scheda completa

Scheda completa (DC)

	Parole chiave
	
			body-mass index; extreme obesity; missing heritability; common variants; confer risk; early-onset; association; population; expression; sortilin
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore BIO/18 - Genetica
Settore BIO/11 - Biologia Molecolare
Settore BIO/14 - Farmacologia
		
	Data di pubblicazione
	
			mag-2013
		
	Rivista in ANCE
	
			NATURE GENETICS
		
	DOI
	
			https://dx.doi.org/10.1038/ng.2606
		
	Tipologia
	
			Article (author)
		
	Appare nelle tipologie:
	
			01 - Articolo su periodico

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