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; Linda S Adair; Dewan S Alam; Eva Albrecht; Kristine H Allin; Matthew Allison; Philippe Amouyel; Emil V 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; Danielle Posthuma; 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, Linda S Adair, Dewan S Alam, Eva Albrecht, Kristine H Allin, Matthew Allison, Philippe Amouyel, Emil V 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, Danielle Posthuma, EPIC-InterAct 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 language	English
Pages (from-to)	186-190
Number of pages	5
Journal	Nature
Volume	542
Issue number	7640
Early online date	1 Feb 2017
DOIs	https://doi.org/10.1038/nature21039
Publication status	Published - 9 Feb 2017

Funding

Funders	Funder number
National Institute of General Medical Sciences	T32GM096911

Keywords

ADAMTS Proteins
Adult
Alleles
Body Height
Cell Adhesion Molecules
Female
Gene Frequency
Genetic Variation
Genome, Human
Glycoproteins
Glycosaminoglycans
Hedgehog Proteins
Humans
Intercellular Signaling Peptides and Proteins
Interferon Regulatory Factors
Interleukin-11 Receptor alpha Subunit
Journal Article
Male
Multifactorial Inheritance
NADPH Oxidase 4
NADPH Oxidases
Phenotype
Pregnancy-Associated Plasma Protein-A
Procollagen N-Endopeptidase
Proteoglycans
Proteolysis
Receptors, Androgen
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Somatomedins

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Rare and low-frequency coding variants alter human adult heightFinal published version, 5.77 MBLicence: Article 25fa Dutch Copyright Act

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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

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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.",

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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} 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 Danielle Posthuma and {EPIC-InterAct Consortium}",

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doi = "10.1038/nature21039",

language = "English",

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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, EV, Arveiler, D, Asselbergs, FW, Auer, PL, Balkau, B, Banas, B, Bang, LE, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boeing, H, Boerwinkle, E, Posthuma, D & 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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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

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 - Posthuma, Danielle

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 - ADAMTS Proteins

KW - Adult

KW - Alleles

KW - Body Height

KW - Cell Adhesion Molecules

KW - Female

KW - Gene Frequency

KW - Genetic Variation

KW - Genome, Human

KW - Glycoproteins

KW - Glycosaminoglycans

KW - Hedgehog Proteins

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Interferon Regulatory Factors

KW - Interleukin-11 Receptor alpha Subunit

KW - Journal Article

KW - Male

KW - Multifactorial Inheritance

KW - NADPH Oxidase 4

KW - NADPH Oxidases

KW - Phenotype

KW - Pregnancy-Associated Plasma Protein-A

KW - Procollagen N-Endopeptidase

KW - Proteoglycans

KW - Proteolysis

KW - Receptors, Androgen

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

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

KW - Somatomedins

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U2 - 10.1038/nature21039

DO - 10.1038/nature21039

M3 - Article

C2 - 28146470

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

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