Rare and low-frequency coding variants alter human adult height

Eirini Marouli, Mariaelisa Graff, Carolina Medina-Gómez, 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, Tonu Esko, Tugce Karaderi & 31 andre Adam E Locke, Nicholas G D Masca, Maggie C Y Ng, Poorva Mudgal, Manuel A Rivas, Sailaja Vedantam, Anubha Mahajan, Xiuqing Guo, Goncalo R Abecasis, Katja K Aben, Linda S Adair, Dewan S Alam, Eva Albrecht, Kristine Højgaard Allin, Matthew A Allison, Philippe Amouyel, Emil Vincent Rosenbaum Appel, Dominique Arveiler, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Bernhard Banas, Lia E Bang, Marianne Benn, Sven Bergmann, Ivan Brandslund, Cramer Christensen, Torben Hansen, Gorm B Jensen, Marit E Jørgensen, EPIC-InterAct Consortium

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Resumé

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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind542
Udgave nummer7640
Sider (fra-til)186-190
ISSN0028-0836
DOI
StatusUdgivet - 9. feb. 2017

Fingeraftryk

Alleles
Insulin-Like Growth Factor Binding Protein 4
Pregnancy-Associated Plasma Protein-A
Multifactorial Inheritance
Genome-Wide Association Study
Sample Size
Growth
In Vitro Techniques

Citer dette

Marouli, E., Graff, M., Medina-Gómez, C., Lo, K. S., Wood, A. R., Kjaer, T. R., ... EPIC-InterAct 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-Gómez, 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, Tonu ; 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 R ; Aben, Katja K ; Adair, Linda S ; Alam, Dewan S ; Albrecht, Eva ; Allin, Kristine Højgaard ; Allison, Matthew A ; Amouyel, Philippe ; Appel, Emil Vincent Rosenbaum ; Arveiler, Dominique ; Asselbergs, Folkert W ; Auer, Paul L ; Balkau, Beverley ; Banas, Bernhard ; Bang, Lia E ; Benn, Marianne ; Bergmann, Sven ; Brandslund, Ivan ; Christensen, Cramer ; Hansen, Torben ; Jensen, Gorm B ; Jørgensen, Marit E ; EPIC-InterAct Consortium. / Rare and low-frequency coding variants alter human adult height. I: Nature. 2017 ; Bind 542, Nr. 7640. s. 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.",
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Marouli, E, Graff, M, Medina-Gómez, 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, GR, Aben, KK, Adair, LS, Alam, DS, Albrecht, E, Allin, KH, Allison, MA, Amouyel, P, Appel, EVR, Arveiler, D, Asselbergs, FW, Auer, PL, Balkau, B, Banas, B, Bang, LE, Benn, M, Bergmann, S, Brandslund, I, Christensen, C, Hansen, T, Jensen, GB, Jørgensen, ME & EPIC-InterAct Consortium 2017, 'Rare and low-frequency coding variants alter human adult height', Nature, bind 542, nr. 7640, s. 186-190. https://doi.org/10.1038/nature21039

Rare and low-frequency coding variants alter human adult height. / Marouli, Eirini; Graff, Mariaelisa; Medina-Gómez, 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, Tonu; 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 R; Aben, Katja K; Adair, Linda S; Alam, Dewan S; Albrecht, Eva; Allin, Kristine Højgaard; Allison, Matthew A; Amouyel, Philippe; Appel, Emil Vincent Rosenbaum; Arveiler, Dominique; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Banas, Bernhard; Bang, Lia E; Benn, Marianne; Bergmann, Sven; Brandslund, Ivan; Christensen, Cramer; Hansen, Torben; Jensen, Gorm B; Jørgensen, Marit E; EPIC-InterAct Consortium.

I: Nature, Bind 542, Nr. 7640, 09.02.2017, s. 186-190.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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

AU - Marouli, Eirini

AU - Graff, Mariaelisa

AU - Medina-Gómez, 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, Tonu

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 R

AU - Aben, Katja K

AU - Adair, Linda S

AU - Alam, Dewan S

AU - Albrecht, Eva

AU - Allin, Kristine Højgaard

AU - Allison, Matthew A

AU - Amouyel, Philippe

AU - Appel, Emil Vincent Rosenbaum

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 - Brandslund, Ivan

AU - Christensen, Cramer

AU - Hansen, Torben

AU - Jensen, Gorm B

AU - Jørgensen, Marit E

AU - EPIC-InterAct 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.

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nature21039

DO - 10.1038/nature21039

M3 - Journal article

VL - 542

SP - 186

EP - 190

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7640

ER -

Marouli E, Graff M, Medina-Gómez 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