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 - 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

M3 - Journal article

C2 - 28146470

VL - 542

SP - 186

EP - 190

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7640

ER -