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 publication

DOI

10.1038/nature21039

Type

Journal article

Journal

Nature

Publication Date

02/2017

Volume

542

Pages

186 - 190

Addresses

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.

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