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Nature Research, Nature, 7640(542), p. 186-190, 2017

DOI: 10.1038/nature21039

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Rare and low-frequency coding variants alter human adult height

Journal article published in 2016 by Leen M. ‘t Hart, Leen M. \textquoterightt Hart, Ar R. Wood, Kristin L. Young, Thomas W. Winkler, Sailaja Vedantam, Paul Iw W. de Bakker, Gert J. de Borst, Simon de Denus, Mark Ch H. de Groot, Renée de Mutsert, Anneke I. den Hollander, J. Wouter Jukema, Sander W. van der Laan, Cornelia M. van Duijn and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record. ; 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. ; See Supplementary notes for full acknowledgement list