Rare and low-frequency coding variants alter human adult height

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

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, 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, Gonçalo R; Aben, Katja K; Adair, Linda S; Alam, Dewan S; Albrecht, Eva; Allin, Kristine H; Allison, Matthew A; Amouyel, Philippe; Appel, Emil V; Arveiler, Dominique; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Banas, Bernhard; Bang, Lia E.; Benn, Marianne; Bergmann, Sven M.; Bielak, Lawrence F; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Oxvig, Claus; EPIC-InterAct Consortium.

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

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, EV, Arveiler, D, Asselbergs, FW, Auer, PL, Balkau, B, Banas, B, Bang, LE, Benn, M, Bergmann, SM, Bielak, LF, Blüher, M, Boeing, H, Boerwinkle, E, Oxvig, C & EPIC-InterAct 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

APA

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

CBE

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 EV, Arveiler D, Asselbergs FW, Auer PL, Balkau B, Banas B, Bang LE, Benn M, Bergmann SM, Bielak LF, Blüher M, Boeing H, Boerwinkle E, Oxvig C, 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

MLA

Vancouver

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

Author

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, 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, Gonçalo R ; Aben, Katja K ; Adair, Linda S ; Alam, Dewan S ; Albrecht, Eva ; Allin, Kristine H ; Allison, Matthew A ; Amouyel, Philippe ; Appel, Emil V ; Arveiler, Dominique ; Asselbergs, Folkert W ; Auer, Paul L ; Balkau, Beverley ; Banas, Bernhard ; Bang, Lia E. ; Benn, Marianne ; Bergmann, Sven M. ; Bielak, Lawrence F ; Blüher, Matthias ; Boeing, Heiner ; Boerwinkle, Eric ; Oxvig, Claus ; EPIC-InterAct Consortium. / Rare and low-frequency coding variants alter human adult height. In: Nature. 2017 ; Vol. 542, No. 7640. pp. 186-190.

Bibtex

@article{5e467502193f4d56a800e6adc3e020ae,
title = "Rare and low-frequency coding variants alter human adult height",
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.",
keywords = "Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",
author = "Eirini Marouli and Mariaelisa Graff and Carolina Medina-G{\'o}mez 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 Abecasis, {Gon{\cc}alo R} and Aben, {Katja K} and Adair, {Linda S} and Alam, {Dewan S} and Eva Albrecht and Allin, {Kristine H} and Allison, {Matthew A} and Philippe Amouyel and Appel, {Emil V} 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 Bergmann, {Sven M.} and Bielak, {Lawrence F} and Matthias Bl{\"u}her and Heiner Boeing and Eric Boerwinkle and Claus Oxvig and {EPIC-InterAct 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",
number = "7640",

}

RIS

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, 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, Gonçalo R

AU - Aben, Katja K

AU - Adair, Linda S

AU - Alam, Dewan S

AU - Albrecht, Eva

AU - Allin, Kristine H

AU - Allison, Matthew A

AU - Amouyel, Philippe

AU - Appel, Emil V

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 M.

AU - Bielak, Lawrence F

AU - Blüher, Matthias

AU - Boeing, Heiner

AU - Boerwinkle, Eric

AU - Oxvig, Claus

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

C2 - 28146470

VL - 542

SP - 186

EP - 190

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7640

ER -