Rare and low-frequency coding variants alter human adult height

Eirini Marouli, Mariaelisa Graff, Carolina Medina-Gomez, Ken Sin Lo, Andrew R. Wood, Troels R. Kjaer, Rebecca S. Fine, Yingchang Lu, Claudia Schurmann, Heather M. Highland, Sina Rüeger, Gudmar Thorleifsson, Anne E. Justice, David Lamparter, Kathleen E. Stirrups, Valérie Turcot, Kristin L. Young, Thomas W. Winkler, Tõnu Esko, Tugce Karaderi & 239 others Adam E. Locke, Nicholas G D Masca, Maggie C Y Ng, Poorva Mudgal, Manuel A. Rivas, Sailaja Vedantam, Anubha Mahajan, Xiuqing Guo, Goncalo Abecasis, Katja K. Aben, Linda S. Adair, Dewan S. Alam, Eva Albrecht, Kristine H. Allin, Matthew Allison, Philippe Amouyel, Emil V R Appel, Dominique Arveiler, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Bernhard Banas, Lia E. Bang, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Lori L. Bonnycastle, Jette Bork-Jensen, Michiel L. Bots, Erwin P. Bottinger, Donald W. Bowden, Ivan Brandslund, Gerome Breen, Murray H. Brilliant, Linda Broer, Amber A. Burt, Adam S. Butterworth, David J. Carey, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Yii Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, Massimiliano Cocca, Francis S. Collins, James P. Cook, Janie Corley, Jordi Corominas Galbany, Amanda J. Cox, Gabriel Cuellar-Partida, John Danesh, Gail Davies, Paul I W De Bakker, Gert J. De Borst, Simon De Denus, Mark C H De Groot, Renée De Mutsert, Ian J. Deary, George V. Dedoussis, Ellen W. Demerath, Anneke I. Den Hollander, Joe G. Dennis, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Alison M. Dunning, Douglas F. Easton, Tapani Ebeling, Todd L. Edwards, Patrick T. Ellinor, Paul Elliott, Evangelos Evangelou, Aliki Eleni Farmaki, Jessica D. Faul, Mary F. Feitosa, Shuang Feng, Ele Ferrannini, Marco M. Ferrario, Jean Ferrieres, Jose C. Florez, Ian Ford, Myriam Fornage, Paul W. Franks, Ruth Frikke-Schmidt, Tessel E. Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Ayush Giri, Giorgia Girotto, Scott D. Gordon, Penny Gordon-Larsen, Mathias Gorski, Niels Grarup, Megan L. Grove, Vilmundur Gudnason, Stefan Gustafsson, Torben Hansen, Kathleen Mullan Harris, Tamara B. Harris, Andrew T. Hattersley, Caroline Hayward, Liang He, Iris M. Heid, Kauko Heikkilä, Øyvind Helgeland, Jussi Hernesniemi, Alex W. Hewitt, Lynne J. Hocking, Mette Hollensted, Oddgeir L. Holmen, G. Kees Hovingh, Joanna M M Howson, Carel B. Hoyng, Paul L. Huang, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne U. Jackson, Jan Håkan Jansson, Gail P. Jarvik, Gorm B. Jensen, Min A. Jhun, Yucheng Jia, Xuejuan Jiang, Stefan Johansson, Marit E. Jørgensen, Torben Jørgensen, Pekka Jousilahti, J. Wouter Jukema, Bratati Kahali, René S. Kahn, Mika Kähönen, Pia R. Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon L R Kardia, Fredrik Karpe, Frank Kee, Renske Keeman, Lambertus A. Kiemeney, Hidetoshi Kitajima, Kirsten B. Kluivers, Thomas Kocher, Pirjo Komulainen, Jukka Kontto, Jaspal S. Kooner, Charles Kooperberg, Peter Kovacs, Jennifer Kriebel, Helena Kuivaniemi, Sébastien Küry, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Timo A. Lakka, Ethan M. Lange, Leslie A. Lange, Carl D. Langefeld, Claudia Langenberg, Eric B. Larson, I. Te Lee, Terho Lehtimäki, Cora E. Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Honghuang Lin, Li An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Yeheng Liu, Yongmei Liu, Artitaya Lophatananon, Jian'An Luan, Steven A. Lubitz, Leo Pekka Lyytikäinen, David Mackey, Pamela A F Madden, Alisa K. Manning, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas G. Martin, Angela L. Mazul, Karina Meidtner, Andres Metspalu, Paul Mitchell, Karen L. Mohlke, Dennis O. Mook-Kanamori, Anna Morgan, Andrew D. Morris, Andrew P. Morris, Martina Müller-Nurasyid, Patricia B. Munroe, Mike A. Nalls, Matthias Nauck, Christopher P. Nelson, Matt Neville, Sune F. Nielsen, Kjell Nikus, Pål R. Njølstad, Børge G. Nordestgaard, Ioanna Ntalla, Jeffrey R. O'Connel, Heikki Oksa, Loes M Olde Loohuis, Roel A. Ophoff, Katharine R. Owen, Chris J. Packard, Sandosh Padmanabhan, Colin N A Palmer, Gerard Pasterkamp, Aniruddh P. Patel, Alison Pattie, Oluf Pedersen, Peggy L. Peissig, Gina M. Peloso, Craig E. Pennell, Carol A. Wang, MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium

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Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Original languageEnglish
Pages (from-to)186-190
Number of pages5
JournalNature
Volume542
Issue number7640
DOIs
Publication statusPublished - 9 Feb 2017

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Genes
Alleles
Insulin-Like Growth Factor Binding Protein 4
Pregnancy-Associated Plasma Protein-A
Growth Disorders
Multifactorial Inheritance
Genome-Wide Association Study
Insulin
Somatomedins
Proteoglycans
Glycosaminoglycans
Gene Frequency
Sample Size
Biological Availability
Association reactions
Phenotype
Growth
In Vitro Techniques
Intercellular Signaling Peptides and Proteins

Cite this

Marouli, E., Graff, M., Medina-Gomez, C., Lo, K. S., Wood, A. R., Kjaer, T. R., ... ReproGen Consortium (2017). Rare and low-frequency coding variants alter human adult height. Nature, 542(7640), 186-190. https://doi.org/10.1038/nature21039
Marouli, Eirini ; Graff, Mariaelisa ; Medina-Gomez, Carolina ; Lo, Ken Sin ; Wood, Andrew R. ; Kjaer, Troels R. ; Fine, Rebecca S. ; Lu, Yingchang ; Schurmann, Claudia ; Highland, Heather M. ; Rüeger, Sina ; Thorleifsson, Gudmar ; Justice, Anne E. ; Lamparter, David ; Stirrups, Kathleen E. ; Turcot, Valérie ; Young, Kristin L. ; Winkler, Thomas W. ; Esko, Tõnu ; Karaderi, Tugce ; Locke, Adam E. ; Masca, Nicholas G D ; Ng, Maggie C Y ; Mudgal, Poorva ; Rivas, Manuel A. ; Vedantam, Sailaja ; Mahajan, Anubha ; Guo, Xiuqing ; Abecasis, Goncalo ; Aben, Katja K. ; Adair, Linda S. ; Alam, Dewan S. ; Albrecht, Eva ; Allin, Kristine H. ; Allison, Matthew ; Amouyel, Philippe ; Appel, Emil V R ; Arveiler, Dominique ; Asselbergs, Folkert W. ; Auer, Paul L. ; Balkau, Beverley ; Banas, Bernhard ; Bang, Lia E. ; Benn, Marianne ; Bergmann, Sven ; Bielak, Lawrence F. ; Blüher, Matthias ; Boeing, Heiner ; Boerwinkle, Eric ; Böger, Carsten A. ; Bonnycastle, Lori L. ; Bork-Jensen, Jette ; Bots, Michiel L. ; Bottinger, Erwin P. ; Bowden, Donald W. ; Brandslund, Ivan ; Breen, Gerome ; Brilliant, Murray H. ; Broer, Linda ; Burt, Amber A. ; Butterworth, Adam S. ; Carey, David J. ; Caulfield, Mark J. ; Chambers, John C. ; Chasman, Daniel I. ; Chen, Yii Der Ida ; Chowdhury, Rajiv ; Christensen, Cramer ; Chu, Audrey Y. ; Cocca, Massimiliano ; Collins, Francis S. ; Cook, James P. ; Corley, Janie ; Galbany, Jordi Corominas ; Cox, Amanda J. ; Cuellar-Partida, Gabriel ; Danesh, John ; Davies, Gail ; De Bakker, Paul I W ; De Borst, Gert J. ; De Denus, Simon ; De Groot, Mark C H ; De Mutsert, Renée ; Deary, Ian J. ; Dedoussis, George V. ; Demerath, Ellen W. ; Den Hollander, Anneke I. ; Dennis, Joe G. ; Di Angelantonio, Emanuele ; Drenos, Fotios ; Du, Mengmeng ; Dunning, Alison M. ; Easton, Douglas F. ; Ebeling, Tapani ; Edwards, Todd L. ; Ellinor, Patrick T. ; Elliott, Paul ; Evangelou, Evangelos ; Farmaki, Aliki Eleni ; Faul, Jessica D. ; Feitosa, Mary F. ; Feng, Shuang ; Ferrannini, Ele ; Ferrario, Marco M. ; Ferrieres, Jean ; Florez, Jose C. ; Ford, Ian ; Fornage, Myriam ; Franks, Paul W. ; Frikke-Schmidt, Ruth ; Galesloot, Tessel E. ; Gan, Wei ; Gandin, Ilaria ; Gasparini, Paolo ; Giedraitis, Vilmantas ; Giri, Ayush ; Girotto, Giorgia ; Gordon, Scott D. ; Gordon-Larsen, Penny ; Gorski, Mathias ; Grarup, Niels ; Grove, Megan L. ; Gudnason, Vilmundur ; Gustafsson, Stefan ; Hansen, Torben ; Harris, Kathleen Mullan ; Harris, Tamara B. ; Hattersley, Andrew T. ; Hayward, Caroline ; He, Liang ; Heid, Iris M. ; Heikkilä, Kauko ; Helgeland, Øyvind ; Hernesniemi, Jussi ; Hewitt, Alex W. ; Hocking, Lynne J. ; Hollensted, Mette ; Holmen, Oddgeir L. ; Hovingh, G. Kees ; Howson, Joanna M M ; Hoyng, Carel B. ; Huang, Paul L. ; Hveem, Kristian ; Ikram, M. Arfan ; Ingelsson, Erik ; Jackson, Anne U. ; Jansson, Jan Håkan ; Jarvik, Gail P. ; Jensen, Gorm B. ; Jhun, Min A. ; Jia, Yucheng ; Jiang, Xuejuan ; Johansson, Stefan ; Jørgensen, Marit E. ; Jørgensen, Torben ; Jousilahti, Pekka ; Jukema, J. Wouter ; Kahali, Bratati ; Kahn, René S. ; Kähönen, Mika ; Kamstrup, Pia R. ; Kanoni, Stavroula ; Kaprio, Jaakko ; Karaleftheri, Maria ; Kardia, Sharon L R ; Karpe, Fredrik ; Kee, Frank ; Keeman, Renske ; Kiemeney, Lambertus A. ; Kitajima, Hidetoshi ; Kluivers, Kirsten B. ; Kocher, Thomas ; Komulainen, Pirjo ; Kontto, Jukka ; Kooner, Jaspal S. ; Kooperberg, Charles ; Kovacs, Peter ; Kriebel, Jennifer ; Kuivaniemi, Helena ; Küry, Sébastien ; Kuusisto, Johanna ; La Bianca, Martina ; Laakso, Markku ; Lakka, Timo A. ; Lange, Ethan M. ; Lange, Leslie A. ; Langefeld, Carl D. ; Langenberg, Claudia ; Larson, Eric B. ; Lee, I. Te ; Lehtimäki, Terho ; Lewis, Cora E. ; Li, Huaixing ; Li, Jin ; Li-Gao, Ruifang ; Lin, Honghuang ; Lin, Li An ; Lin, Xu ; Lind, Lars ; Lindström, Jaana ; Linneberg, Allan ; Liu, Yeheng ; Liu, Yongmei ; Lophatananon, Artitaya ; Luan, Jian'An ; Lubitz, Steven A. ; Lyytikäinen, Leo Pekka ; Mackey, David ; Madden, Pamela A F ; Manning, Alisa K. ; Männistö, Satu ; Marenne, Gaëlle ; Marten, Jonathan ; Martin, Nicholas G. ; Mazul, Angela L. ; Meidtner, Karina ; Metspalu, Andres ; Mitchell, Paul ; Mohlke, Karen L. ; Mook-Kanamori, Dennis O. ; Morgan, Anna ; Morris, Andrew D. ; Morris, Andrew P. ; Müller-Nurasyid, Martina ; Munroe, Patricia B. ; Nalls, Mike A. ; Nauck, Matthias ; Nelson, Christopher P. ; Neville, Matt ; Nielsen, Sune F. ; Nikus, Kjell ; Njølstad, Pål R. ; Nordestgaard, Børge G. ; Ntalla, Ioanna ; O'Connel, Jeffrey R. ; Oksa, Heikki ; Loohuis, Loes M Olde ; Ophoff, Roel A. ; Owen, Katharine R. ; Packard, Chris J. ; Padmanabhan, Sandosh ; Palmer, Colin N A ; Pasterkamp, Gerard ; Patel, Aniruddh P. ; Pattie, Alison ; Pedersen, Oluf ; Peissig, Peggy L. ; Peloso, Gina M. ; Pennell, Craig E. ; Wang, Carol A. ; MAGIC Investigators ; The EPIC-InterAct Consortium ; EPIC-CVD Consortium ; CHD Exome+ Consortium ; ExomeBP Consortium ; T2D-Genes Consortium ; GoT2D Genes Consortium ; Global Lipids Genetics Consortium ; ReproGen Consortium. / Rare and low-frequency coding variants alter human adult height. In: Nature. 2017 ; Vol. 542, No. 7640. pp. 186-190.
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abstract = "Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8{\%}) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.",
author = "Eirini Marouli and Mariaelisa Graff and Carolina Medina-Gomez and Lo, {Ken Sin} and Wood, {Andrew R.} and Kjaer, {Troels R.} and Fine, {Rebecca S.} and Yingchang Lu and Claudia Schurmann and Highland, {Heather M.} and Sina R{\"u}eger and Gudmar Thorleifsson and Justice, {Anne E.} and David Lamparter and Stirrups, {Kathleen E.} and Val{\'e}rie Turcot and Young, {Kristin L.} and Winkler, {Thomas W.} and T{\~o}nu Esko and Tugce Karaderi and Locke, {Adam E.} and Masca, {Nicholas G D} and Ng, {Maggie C Y} and Poorva Mudgal and Rivas, {Manuel A.} and Sailaja Vedantam and Anubha Mahajan and Xiuqing Guo and Goncalo Abecasis and Aben, {Katja K.} and Adair, {Linda S.} and Alam, {Dewan S.} and Eva Albrecht and Allin, {Kristine H.} and Matthew Allison and Philippe Amouyel and Appel, {Emil V R} and Dominique Arveiler and Asselbergs, {Folkert W.} and Auer, {Paul L.} and Beverley Balkau and Bernhard Banas and Bang, {Lia E.} and Marianne Benn and Sven Bergmann and Bielak, {Lawrence F.} and Matthias Bl{\"u}her and Heiner Boeing and Eric Boerwinkle and B{\"o}ger, {Carsten A.} and Bonnycastle, {Lori L.} and Jette Bork-Jensen and Bots, {Michiel L.} and Bottinger, {Erwin P.} and Bowden, {Donald W.} and Ivan Brandslund and Gerome Breen and Brilliant, {Murray H.} and Linda Broer and Burt, {Amber A.} and Butterworth, {Adam S.} and Carey, {David J.} and Caulfield, {Mark J.} and Chambers, {John C.} and Chasman, {Daniel I.} and Chen, {Yii Der Ida} and Rajiv Chowdhury and Cramer Christensen and Chu, {Audrey Y.} and Massimiliano Cocca and Collins, {Francis S.} and Cook, {James P.} and Janie Corley and Galbany, {Jordi Corominas} and Cox, {Amanda J.} and Gabriel Cuellar-Partida and John Danesh and Gail Davies and {De Bakker}, {Paul I W} and {De Borst}, {Gert J.} and {De Denus}, Simon and {De Groot}, {Mark C H} and {De Mutsert}, Ren{\'e}e and Deary, {Ian J.} and Dedoussis, {George V.} and Demerath, {Ellen W.} and {Den Hollander}, {Anneke I.} and Dennis, {Joe G.} and {Di Angelantonio}, Emanuele and Fotios Drenos and Mengmeng Du and Dunning, {Alison M.} and Easton, {Douglas F.} and Tapani Ebeling and Edwards, {Todd L.} and Ellinor, {Patrick T.} and Paul Elliott and Evangelos Evangelou and Farmaki, {Aliki Eleni} and Faul, {Jessica D.} and Feitosa, {Mary F.} and Shuang Feng and Ele Ferrannini and Ferrario, {Marco M.} and Jean Ferrieres and Florez, {Jose C.} and Ian Ford and Myriam Fornage and Franks, {Paul W.} and Ruth Frikke-Schmidt and Galesloot, {Tessel E.} and Wei Gan and Ilaria Gandin and Paolo Gasparini and Vilmantas Giedraitis and Ayush Giri and Giorgia Girotto and Gordon, {Scott D.} and Penny Gordon-Larsen and Mathias Gorski and Niels Grarup and Grove, {Megan L.} and Vilmundur Gudnason and Stefan Gustafsson and Torben Hansen and Harris, {Kathleen Mullan} and Harris, {Tamara B.} and Hattersley, {Andrew T.} and Caroline Hayward and Liang He and Heid, {Iris M.} and Kauko Heikkil{\"a} and {\O}yvind Helgeland and Jussi Hernesniemi and Hewitt, {Alex W.} and Hocking, {Lynne J.} and Mette Hollensted and Holmen, {Oddgeir L.} and Hovingh, {G. Kees} and Howson, {Joanna M M} and Hoyng, {Carel B.} and Huang, {Paul L.} and Kristian Hveem and Ikram, {M. Arfan} and Erik Ingelsson and Jackson, {Anne U.} and Jansson, {Jan H{\aa}kan} and Jarvik, {Gail P.} and Jensen, {Gorm B.} and Jhun, {Min A.} and Yucheng Jia and Xuejuan Jiang and Stefan Johansson and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Pekka Jousilahti and Jukema, {J. Wouter} and Bratati Kahali and Kahn, {Ren{\'e} S.} and Mika K{\"a}h{\"o}nen and Kamstrup, {Pia R.} and Stavroula Kanoni and Jaakko Kaprio and Maria Karaleftheri and Kardia, {Sharon L R} and Fredrik Karpe and Frank Kee and Renske Keeman and Kiemeney, {Lambertus A.} and Hidetoshi Kitajima and Kluivers, {Kirsten B.} and Thomas Kocher and Pirjo Komulainen and Jukka Kontto and Kooner, {Jaspal S.} and Charles Kooperberg and Peter Kovacs and Jennifer Kriebel and Helena Kuivaniemi and S{\'e}bastien K{\"u}ry and Johanna Kuusisto and {La Bianca}, Martina and Markku Laakso and Lakka, {Timo A.} and Lange, {Ethan M.} and Lange, {Leslie A.} and Langefeld, {Carl D.} and Claudia Langenberg and Larson, {Eric B.} and Lee, {I. Te} and Terho Lehtim{\"a}ki and Lewis, {Cora E.} and Huaixing Li and Jin Li and Ruifang Li-Gao and Honghuang Lin and Lin, {Li An} and Xu Lin and Lars Lind and Jaana Lindstr{\"o}m and Allan Linneberg and Yeheng Liu and Yongmei Liu and Artitaya Lophatananon and Jian'An Luan and Lubitz, {Steven A.} and Lyytik{\"a}inen, {Leo Pekka} and David Mackey and Madden, {Pamela A F} and Manning, {Alisa K.} and Satu M{\"a}nnist{\"o} and Ga{\"e}lle Marenne and Jonathan Marten and Martin, {Nicholas G.} and Mazul, {Angela L.} and Karina Meidtner and Andres Metspalu and Paul Mitchell and Mohlke, {Karen L.} and Mook-Kanamori, {Dennis O.} and Anna Morgan and Morris, {Andrew D.} and Morris, {Andrew P.} and Martina M{\"u}ller-Nurasyid and Munroe, {Patricia B.} and Nalls, {Mike A.} and Matthias Nauck and Nelson, {Christopher P.} and Matt Neville and Nielsen, {Sune F.} and Kjell Nikus and Nj{\o}lstad, {P{\aa}l R.} and Nordestgaard, {B{\o}rge G.} and Ioanna Ntalla and O'Connel, {Jeffrey R.} and Heikki Oksa and Loohuis, {Loes M Olde} and Ophoff, {Roel A.} and Owen, {Katharine R.} and Packard, {Chris J.} and Sandosh Padmanabhan and Palmer, {Colin N A} and Gerard Pasterkamp and Patel, {Aniruddh P.} and Alison Pattie and Oluf Pedersen and Peissig, {Peggy L.} and Peloso, {Gina M.} and Pennell, {Craig E.} and Wang, {Carol A.} and {MAGIC Investigators} and {The EPIC-InterAct Consortium} and {EPIC-CVD Consortium} and {CHD Exome+ Consortium} and {ExomeBP Consortium} and {T2D-Genes Consortium} and {GoT2D Genes Consortium} and {Global Lipids Genetics Consortium} and {ReproGen Consortium}",
year = "2017",
month = "2",
day = "9",
doi = "10.1038/nature21039",
language = "English",
volume = "542",
pages = "186--190",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "7640",

}

Marouli, E, Graff, M, Medina-Gomez, C, Lo, KS, Wood, AR, Kjaer, TR, Fine, RS, Lu, Y, Schurmann, C, Highland, HM, Rüeger, S, Thorleifsson, G, Justice, AE, Lamparter, D, Stirrups, KE, Turcot, V, Young, KL, Winkler, TW, Esko, T, Karaderi, T, Locke, AE, Masca, NGD, Ng, MCY, Mudgal, P, Rivas, MA, Vedantam, S, Mahajan, A, Guo, X, Abecasis, G, Aben, KK, Adair, LS, Alam, DS, Albrecht, E, Allin, KH, Allison, M, Amouyel, P, Appel, EVR, Arveiler, D, Asselbergs, FW, Auer, PL, Balkau, B, Banas, B, Bang, LE, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boeing, H, Boerwinkle, E, Böger, CA, Bonnycastle, LL, Bork-Jensen, J, Bots, ML, Bottinger, EP, Bowden, DW, Brandslund, I, Breen, G, Brilliant, MH, Broer, L, Burt, AA, Butterworth, AS, Carey, DJ, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, YDI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Collins, FS, Cook, JP, Corley, J, Galbany, JC, Cox, AJ, Cuellar-Partida, G, Danesh, J, Davies, G, De Bakker, PIW, De Borst, GJ, De Denus, S, De Groot, MCH, De Mutsert, R, Deary, IJ, Dedoussis, GV, Demerath, EW, Den Hollander, AI, Dennis, JG, Di Angelantonio, E, Drenos, F, Du, M, Dunning, AM, Easton, DF, Ebeling, T, Edwards, TL, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, AE, Faul, JD, Feitosa, MF, Feng, S, Ferrannini, E, Ferrario, MM, Ferrieres, J, Florez, JC, Ford, I, Fornage, M, Franks, PW, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, P, Giedraitis, V, Giri, A, Girotto, G, Gordon, SD, Gordon-Larsen, P, Gorski, M, Grarup, N, Grove, ML, Gudnason, V, Gustafsson, S, Hansen, T, Harris, KM, Harris, TB, Hattersley, AT, Hayward, C, He, L, Heid, IM, Heikkilä, K, Helgeland, Ø, Hernesniemi, J, Hewitt, AW, Hocking, LJ, Hollensted, M, Holmen, OL, Hovingh, GK, Howson, JMM, Hoyng, CB, Huang, PL, Hveem, K, Ikram, MA, Ingelsson, E, Jackson, AU, Jansson, JH, Jarvik, GP, Jensen, GB, Jhun, MA, Jia, Y, Jiang, X, Johansson, S, Jørgensen, ME, Jørgensen, T, Jousilahti, P, Jukema, JW, Kahali, B, Kahn, RS, Kähönen, M, Kamstrup, PR, Kanoni, S, Kaprio, J, Karaleftheri, M, Kardia, SLR, Karpe, F, Kee, F, Keeman, R, Kiemeney, LA, Kitajima, H, Kluivers, KB, Kocher, T, Komulainen, P, Kontto, J, Kooner, JS, Kooperberg, C, Kovacs, P, Kriebel, J, Kuivaniemi, H, Küry, S, Kuusisto, J, La Bianca, M, Laakso, M, Lakka, TA, Lange, EM, Lange, LA, Langefeld, CD, Langenberg, C, Larson, EB, Lee, IT, Lehtimäki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, H, Lin, LA, Lin, X, Lind, L, Lindström, J, Linneberg, A, Liu, Y, Liu, Y, Lophatananon, A, Luan, JA, Lubitz, SA, Lyytikäinen, LP, Mackey, D, Madden, PAF, Manning, AK, Männistö, S, Marenne, G, Marten, J, Martin, NG, Mazul, AL, Meidtner, K, Metspalu, A, Mitchell, P, Mohlke, KL, Mook-Kanamori, DO, Morgan, A, Morris, AD, Morris, AP, Müller-Nurasyid, M, Munroe, PB, Nalls, MA, Nauck, M, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njølstad, PR, Nordestgaard, BG, Ntalla, I, O'Connel, JR, Oksa, H, Loohuis, LMO, Ophoff, RA, Owen, KR, Packard, CJ, Padmanabhan, S, Palmer, CNA, Pasterkamp, G, Patel, AP, Pattie, A, Pedersen, O, Peissig, PL, Peloso, GM, Pennell, CE, Wang, CA, MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium & ReproGen Consortium 2017, 'Rare and low-frequency coding variants alter human adult height' Nature, vol. 542, no. 7640, pp. 186-190. https://doi.org/10.1038/nature21039

Rare and low-frequency coding variants alter human adult height. / Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R.; Kjaer, Troels R.; Fine, Rebecca S.; Lu, Yingchang; Schurmann, Claudia; Highland, Heather M.; Rüeger, Sina; Thorleifsson, Gudmar; Justice, Anne E.; Lamparter, David; Stirrups, Kathleen E.; Turcot, Valérie; Young, Kristin L.; Winkler, Thomas W.; Esko, Tõnu; Karaderi, Tugce; Locke, Adam E.; Masca, Nicholas G D; Ng, Maggie C Y; Mudgal, Poorva; Rivas, Manuel A.; Vedantam, Sailaja; Mahajan, Anubha; Guo, Xiuqing; Abecasis, Goncalo; Aben, Katja K.; Adair, Linda S.; Alam, Dewan S.; Albrecht, Eva; Allin, Kristine H.; Allison, Matthew; Amouyel, Philippe; Appel, Emil V R; Arveiler, Dominique; Asselbergs, Folkert W.; Auer, Paul L.; Balkau, Beverley; Banas, Bernhard; Bang, Lia E.; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F.; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A.; Bonnycastle, Lori L.; Bork-Jensen, Jette; Bots, Michiel L.; Bottinger, Erwin P.; Bowden, Donald W.; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H.; Broer, Linda; Burt, Amber A.; Butterworth, Adam S.; Carey, David J.; Caulfield, Mark J.; Chambers, John C.; Chasman, Daniel I.; Chen, Yii Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y.; Cocca, Massimiliano; Collins, Francis S.; Cook, James P.; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J.; Cuellar-Partida, Gabriel; Danesh, John; Davies, Gail; De Bakker, Paul I W; De Borst, Gert J.; De Denus, Simon; De Groot, Mark C H; De Mutsert, Renée; Deary, Ian J.; Dedoussis, George V.; Demerath, Ellen W.; Den Hollander, Anneke I.; Dennis, Joe G.; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dunning, Alison M.; Easton, Douglas F.; Ebeling, Tapani; Edwards, Todd L.; Ellinor, Patrick T.; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki Eleni; Faul, Jessica D.; Feitosa, Mary F.; Feng, Shuang; Ferrannini, Ele; Ferrario, Marco M.; Ferrieres, Jean; Florez, Jose C.; Ford, Ian; Fornage, Myriam; Franks, Paul W.; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Giri, Ayush; Girotto, Giorgia; Gordon, Scott D.; Gordon-Larsen, Penny; Gorski, Mathias; Grarup, Niels; Grove, Megan L.; Gudnason, Vilmundur; Gustafsson, Stefan; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; He, Liang; Heid, Iris M.; Heikkilä, Kauko; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W.; Hocking, Lynne J.; Hollensted, Mette; Holmen, Oddgeir L.; Hovingh, G. Kees; Howson, Joanna M M; Hoyng, Carel B.; Huang, Paul L.; Hveem, Kristian; Ikram, M. Arfan; Ingelsson, Erik; Jackson, Anne U.; Jansson, Jan Håkan; Jarvik, Gail P.; Jensen, Gorm B.; Jhun, Min A.; Jia, Yucheng; Jiang, Xuejuan; Johansson, Stefan; Jørgensen, Marit E.; Jørgensen, Torben; Jousilahti, Pekka; Jukema, J. Wouter; Kahali, Bratati; Kahn, René S.; Kähönen, Mika; Kamstrup, Pia R.; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L R; Karpe, Fredrik; Kee, Frank; Keeman, Renske; Kiemeney, Lambertus A.; Kitajima, Hidetoshi; Kluivers, Kirsten B.; Kocher, Thomas; Komulainen, Pirjo; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kovacs, Peter; Kriebel, Jennifer; Kuivaniemi, Helena; Küry, Sébastien; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lakka, Timo A.; Lange, Ethan M.; Lange, Leslie A.; Langefeld, Carl D.; Langenberg, Claudia; Larson, Eric B.; Lee, I. Te; Lehtimäki, Terho; Lewis, Cora E.; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Li An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Yeheng; Liu, Yongmei; Lophatananon, Artitaya; Luan, Jian'An; Lubitz, Steven A.; Lyytikäinen, Leo Pekka; Mackey, David; Madden, Pamela A F; Manning, Alisa K.; Männistö, Satu; Marenne, Gaëlle; Marten, Jonathan; Martin, Nicholas G.; Mazul, Angela L.; Meidtner, Karina; Metspalu, Andres; Mitchell, Paul; Mohlke, Karen L.; Mook-Kanamori, Dennis O.; Morgan, Anna; Morris, Andrew D.; Morris, Andrew P.; Müller-Nurasyid, Martina; Munroe, Patricia B.; Nalls, Mike A.; Nauck, Matthias; Nelson, Christopher P.; Neville, Matt; Nielsen, Sune F.; Nikus, Kjell; Njølstad, Pål R.; Nordestgaard, Børge G.; Ntalla, Ioanna; O'Connel, Jeffrey R.; Oksa, Heikki; Loohuis, Loes M Olde; Ophoff, Roel A.; Owen, Katharine R.; Packard, Chris J.; Padmanabhan, Sandosh; Palmer, Colin N A; Pasterkamp, Gerard; Patel, Aniruddh P.; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L.; Peloso, Gina M.; Pennell, Craig E.; Wang, Carol A.; MAGIC Investigators; The EPIC-InterAct Consortium; EPIC-CVD Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium.

In: Nature, Vol. 542, No. 7640, 09.02.2017, p. 186-190.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare and low-frequency coding variants alter human adult height

AU - Marouli, Eirini

AU - Graff, Mariaelisa

AU - Medina-Gomez, Carolina

AU - Lo, Ken Sin

AU - Wood, Andrew R.

AU - Kjaer, Troels R.

AU - Fine, Rebecca S.

AU - Lu, Yingchang

AU - Schurmann, Claudia

AU - Highland, Heather M.

AU - Rüeger, Sina

AU - Thorleifsson, Gudmar

AU - Justice, Anne E.

AU - Lamparter, David

AU - Stirrups, Kathleen E.

AU - Turcot, Valérie

AU - Young, Kristin L.

AU - Winkler, Thomas W.

AU - Esko, Tõnu

AU - Karaderi, Tugce

AU - Locke, Adam E.

AU - Masca, Nicholas G D

AU - Ng, Maggie C Y

AU - Mudgal, Poorva

AU - Rivas, Manuel A.

AU - Vedantam, Sailaja

AU - Mahajan, Anubha

AU - Guo, Xiuqing

AU - Abecasis, Goncalo

AU - Aben, Katja K.

AU - Adair, Linda S.

AU - Alam, Dewan S.

AU - Albrecht, Eva

AU - Allin, Kristine H.

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Appel, Emil V R

AU - Arveiler, Dominique

AU - Asselbergs, Folkert W.

AU - Auer, Paul L.

AU - Balkau, Beverley

AU - Banas, Bernhard

AU - Bang, Lia E.

AU - Benn, Marianne

AU - Bergmann, Sven

AU - Bielak, Lawrence F.

AU - Blüher, Matthias

AU - Boeing, Heiner

AU - Boerwinkle, Eric

AU - Böger, Carsten A.

AU - Bonnycastle, Lori L.

AU - Bork-Jensen, Jette

AU - Bots, Michiel L.

AU - Bottinger, Erwin P.

AU - Bowden, Donald W.

AU - Brandslund, Ivan

AU - Breen, Gerome

AU - Brilliant, Murray H.

AU - Broer, Linda

AU - Burt, Amber A.

AU - Butterworth, Adam S.

AU - Carey, David J.

AU - Caulfield, Mark J.

AU - Chambers, John C.

AU - Chasman, Daniel I.

AU - Chen, Yii Der Ida

AU - Chowdhury, Rajiv

AU - Christensen, Cramer

AU - Chu, Audrey Y.

AU - Cocca, Massimiliano

AU - Collins, Francis S.

AU - Cook, James P.

AU - Corley, Janie

AU - Galbany, Jordi Corominas

AU - Cox, Amanda J.

AU - Cuellar-Partida, Gabriel

AU - Danesh, John

AU - Davies, Gail

AU - De Bakker, Paul I W

AU - De Borst, Gert J.

AU - De Denus, Simon

AU - De Groot, Mark C H

AU - De Mutsert, Renée

AU - Deary, Ian J.

AU - Dedoussis, George V.

AU - Demerath, Ellen W.

AU - Den Hollander, Anneke I.

AU - Dennis, Joe G.

AU - Di Angelantonio, Emanuele

AU - Drenos, Fotios

AU - Du, Mengmeng

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Ebeling, Tapani

AU - Edwards, Todd L.

AU - Ellinor, Patrick T.

AU - Elliott, Paul

AU - Evangelou, Evangelos

AU - Farmaki, Aliki Eleni

AU - Faul, Jessica D.

AU - Feitosa, Mary F.

AU - Feng, Shuang

AU - Ferrannini, Ele

AU - Ferrario, Marco M.

AU - Ferrieres, Jean

AU - Florez, Jose C.

AU - Ford, Ian

AU - Fornage, Myriam

AU - Franks, Paul W.

AU - Frikke-Schmidt, Ruth

AU - Galesloot, Tessel E.

AU - Gan, Wei

AU - Gandin, Ilaria

AU - Gasparini, Paolo

AU - Giedraitis, Vilmantas

AU - Giri, Ayush

AU - Girotto, Giorgia

AU - Gordon, Scott D.

AU - Gordon-Larsen, Penny

AU - Gorski, Mathias

AU - Grarup, Niels

AU - Grove, Megan L.

AU - Gudnason, Vilmundur

AU - Gustafsson, Stefan

AU - Hansen, Torben

AU - Harris, Kathleen Mullan

AU - Harris, Tamara B.

AU - Hattersley, Andrew T.

AU - Hayward, Caroline

AU - He, Liang

AU - Heid, Iris M.

AU - Heikkilä, Kauko

AU - Helgeland, Øyvind

AU - Hernesniemi, Jussi

AU - Hewitt, Alex W.

AU - Hocking, Lynne J.

AU - Hollensted, Mette

AU - Holmen, Oddgeir L.

AU - Hovingh, G. Kees

AU - Howson, Joanna M M

AU - Hoyng, Carel B.

AU - Huang, Paul L.

AU - Hveem, Kristian

AU - Ikram, M. Arfan

AU - Ingelsson, Erik

AU - Jackson, Anne U.

AU - Jansson, Jan Håkan

AU - Jarvik, Gail P.

AU - Jensen, Gorm B.

AU - Jhun, Min A.

AU - Jia, Yucheng

AU - Jiang, Xuejuan

AU - Johansson, Stefan

AU - Jørgensen, Marit E.

AU - Jørgensen, Torben

AU - Jousilahti, Pekka

AU - Jukema, J. Wouter

AU - Kahali, Bratati

AU - Kahn, René S.

AU - Kähönen, Mika

AU - Kamstrup, Pia R.

AU - Kanoni, Stavroula

AU - Kaprio, Jaakko

AU - Karaleftheri, Maria

AU - Kardia, Sharon L R

AU - Karpe, Fredrik

AU - Kee, Frank

AU - Keeman, Renske

AU - Kiemeney, Lambertus A.

AU - Kitajima, Hidetoshi

AU - Kluivers, Kirsten B.

AU - Kocher, Thomas

AU - Komulainen, Pirjo

AU - Kontto, Jukka

AU - Kooner, Jaspal S.

AU - Kooperberg, Charles

AU - Kovacs, Peter

AU - Kriebel, Jennifer

AU - Kuivaniemi, Helena

AU - Küry, Sébastien

AU - Kuusisto, Johanna

AU - La Bianca, Martina

AU - Laakso, Markku

AU - Lakka, Timo A.

AU - Lange, Ethan M.

AU - Lange, Leslie A.

AU - Langefeld, Carl D.

AU - Langenberg, Claudia

AU - Larson, Eric B.

AU - Lee, I. Te

AU - Lehtimäki, Terho

AU - Lewis, Cora E.

AU - Li, Huaixing

AU - Li, Jin

AU - Li-Gao, Ruifang

AU - Lin, Honghuang

AU - Lin, Li An

AU - Lin, Xu

AU - Lind, Lars

AU - Lindström, Jaana

AU - Linneberg, Allan

AU - Liu, Yeheng

AU - Liu, Yongmei

AU - Lophatananon, Artitaya

AU - Luan, Jian'An

AU - Lubitz, Steven A.

AU - Lyytikäinen, Leo Pekka

AU - Mackey, David

AU - Madden, Pamela A F

AU - Manning, Alisa K.

AU - Männistö, Satu

AU - Marenne, Gaëlle

AU - Marten, Jonathan

AU - Martin, Nicholas G.

AU - Mazul, Angela L.

AU - Meidtner, Karina

AU - Metspalu, Andres

AU - Mitchell, Paul

AU - Mohlke, Karen L.

AU - Mook-Kanamori, Dennis O.

AU - Morgan, Anna

AU - Morris, Andrew D.

AU - Morris, Andrew P.

AU - Müller-Nurasyid, Martina

AU - Munroe, Patricia B.

AU - Nalls, Mike A.

AU - Nauck, Matthias

AU - Nelson, Christopher P.

AU - Neville, Matt

AU - Nielsen, Sune F.

AU - Nikus, Kjell

AU - Njølstad, Pål R.

AU - Nordestgaard, Børge G.

AU - Ntalla, Ioanna

AU - O'Connel, Jeffrey R.

AU - Oksa, Heikki

AU - Loohuis, Loes M Olde

AU - Ophoff, Roel A.

AU - Owen, Katharine R.

AU - Packard, Chris J.

AU - Padmanabhan, Sandosh

AU - Palmer, Colin N A

AU - Pasterkamp, Gerard

AU - Patel, Aniruddh P.

AU - Pattie, Alison

AU - Pedersen, Oluf

AU - Peissig, Peggy L.

AU - Peloso, Gina M.

AU - Pennell, Craig E.

AU - Wang, Carol A.

AU - MAGIC Investigators

AU - The EPIC-InterAct Consortium

AU - EPIC-CVD Consortium

AU - CHD Exome+ Consortium

AU - ExomeBP Consortium

AU - T2D-Genes Consortium

AU - GoT2D Genes Consortium

AU - Global Lipids Genetics Consortium

AU - ReproGen Consortium

PY - 2017/2/9

Y1 - 2017/2/9

N2 - Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

AB - Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

UR - http://www.scopus.com/inward/record.url?scp=85012918562&partnerID=8YFLogxK

U2 - 10.1038/nature21039

DO - 10.1038/nature21039

M3 - Article

VL - 542

SP - 186

EP - 190

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7640

ER -

Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR et al. Rare and low-frequency coding variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. https://doi.org/10.1038/nature21039