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; 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; Kristine H Allin; Emil V. Appel; Lia E Bang; Marianne Benn; Jette Bork-Jensen; Ruth Frikke-Schmidt; Niels Grarup; Torben Hansen; Mette Hollensted; Gorm B Jensen; Marit E Jørgensen; Torben Jørgensen; Pia R Kamstrup; Allan Linneberg; Sune F Nielsen; Børge G Nordestgaard; Oluf Pedersen; Anne Tybjaerg-Hansen; Henrik Vestergaard; Tune H Pers; EPIC-InterAct Consortium

doi:10.1038/nature21039

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 KaraderiAdam 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, Kristine H Allin, Emil V. Appel, Lia E Bang, Marianne Benn, Jette Bork-Jensen, Ruth Frikke-Schmidt, Niels Grarup, Torben Hansen, Mette Hollensted, Gorm B Jensen, Marit E Jørgensen, Torben Jørgensen, Pia R Kamstrup, Allan Linneberg, Sune F Nielsen, Børge G Nordestgaard, Oluf Pedersen, Anne Tybjaerg-Hansen, Henrik Vestergaard, Tune H Pers, EPIC-InterAct Consortium

277 Citations (Scopus)

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 language	English
Journal	Nature
Volume	542
Issue number	7640
Pages (from-to)	186-190
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature21039
Publication status	Published - 9 Feb 2017

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Marouli, E., Graff, M., Medina-Gomez, C., Lo, K. S., Wood, A. R., Kjaer, T. R., Fine, R. S., Lu, Y., Schurmann, C., Highland, H. M., Rüeger, S., Thorleifsson, G., Justice, A. E., Lamparter, D., Stirrups, K. E., Turcot, V., Young, K. L., Winkler, T. W., Esko, T., ... 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, 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, Allin, KH, Appel, EV, Bang, LE, Benn, M, Bork-Jensen, J, Frikke-Schmidt, R , Grarup, N , Hansen, T, Hollensted, M, Jensen, GB, Jørgensen, ME, Jørgensen, T, Kamstrup, PR, Linneberg, A, Nielsen, SF, Nordestgaard, BG , Pedersen, O , Tybjaerg-Hansen, A , Vestergaard, H , Pers, TH & 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

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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.",

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 Allin, {Kristine H} and Appel, {Emil V.} and Bang, {Lia E} and Marianne Benn and Jette Bork-Jensen and Ruth Frikke-Schmidt and Niels Grarup and Torben Hansen and Mette Hollensted and Jensen, {Gorm B} and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen and Kamstrup, {Pia R} and Allan Linneberg and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and Oluf Pedersen and Anne Tybjaerg-Hansen and Henrik Vestergaard and Pers, {Tune H} and {EPIC-InterAct Consortium}",

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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 - Allin, Kristine H

AU - Appel, Emil V.

AU - Bang, Lia E

AU - Benn, Marianne

AU - Bork-Jensen, Jette

AU - Frikke-Schmidt, Ruth

AU - Grarup, Niels

AU - Hansen, Torben

AU - Hollensted, Mette

AU - Jensen, Gorm B

AU - Jørgensen, Marit E

AU - Jørgensen, Torben

AU - Kamstrup, Pia R

AU - Linneberg, Allan

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - Pedersen, Oluf

AU - Tybjaerg-Hansen, Anne

AU - Vestergaard, Henrik

AU - Pers, Tune H

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.

U2 - 10.1038/nature21039

DO - 10.1038/nature21039

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SN - 0028-0836

VL - 542

SP - 186

EP - 190

JO - Nature

JF - Nature

IS - 7640

ER -

Rare and low-frequency coding variants alter human adult height

Abstract

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