Rare and low-frequency coding variants alter human adult height



Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R, Kjaer, Troels R, Fine, Rebecca S, Lu, Yingchang, Schurmann, Claudia, Highland, Heather M
et al (show 363 more authors) (2017) Rare and low-frequency coding variants alter human adult height. NATURE, 542 (7640). pp. 186-190.

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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.

Item Type: Article
Uncontrolled Keywords: EPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators, Humans, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Glycoproteins, Glycosaminoglycans, Proteoglycans, Intercellular Signaling Peptides and Proteins, Somatomedins, Cell Adhesion Molecules, Receptors, Androgen, Body Height, Gene Frequency, Multifactorial Inheritance, Phenotype, Alleles, Genome, Human, Adult, Female, Male, Interferon Regulatory Factors, Hedgehog Proteins, Interleukin-11 Receptor alpha Subunit, Genetic Variation, Proteolysis, ADAMTS Proteins, NADPH Oxidase 4, NADPH Oxidases
Depositing User: Symplectic Admin
Date Deposited: 02 Mar 2017 10:47
Last Modified: 16 Dec 2022 01:15
DOI: 10.1038/nature21039
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3005990