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Rare and low-frequency coding variants alter human adult height


Marouli, E and Graff, M and Medina-Gomez, C and Lo, KS and Wood, AR and Kjaer, TR and Fine, RS and Lu, Y and Schurmann, C and Highland, HM and Rueger, S and Thorleifsson, G and Justice, AE and Lamparter, D and Stirrups, KE and Turcot, V and Young, KL and Winkler, TW and Esko, T and Karaderi, T and Locke, AE and Masca, NGD and Ng, MCY and Mudgal, P and Rivas, MA and Hewitt, AW, et al, Rare and low-frequency coding variants alter human adult height, Nature, 542, (7640) pp. 186-190. ISSN 0028-0836 (2017) [Refereed Article]

Copyright Statement

2017 Macmillan Publishers

DOI: doi:10.1038/nature21039


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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:118186
Year Published:2017
Web of Science® Times Cited:336
Deposited By:Menzies Institute for Medical Research
Deposited On:2017-07-06
Last Modified:2022-08-26

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