Rare and low-frequency coding variants alter human adult height

MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium

Research output: Contribution to journalArticle

164 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)186-190
Number of pages5
JournalNature
Volume542
Issue number7640
DOIs
Publication statusPublished - 9 Feb 2017

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Alleles
Insulin-Like Growth Factor Binding Protein 4
Pregnancy-Associated Plasma Protein-A
Growth Disorders
Multifactorial Inheritance
Genome-Wide Association Study
Somatomedins
Proteoglycans
Glycosaminoglycans
Gene Frequency
Sample Size
Biological Availability
Genes
Phenotype
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, ... ReproGen Consortium (2017). Rare and low-frequency coding variants alter human adult height. Nature, 542(7640), 186-190. https://doi.org/10.1038/nature21039

Rare and low-frequency coding variants alter human adult height. / MAGIC Investigators; The EPIC-InterAct Consortium; EPIC-CVD Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium.

In: Nature, Vol. 542, No. 7640, 09.02.2017, p. 186-190.

Research output: Contribution to journalArticle

MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium & ReproGen Consortium 2017, 'Rare and low-frequency coding variants alter human adult height', Nature, vol. 542, no. 7640, pp. 186-190. https://doi.org/10.1038/nature21039
MAGIC Investigators, The EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-Genes Consortium et al. Rare and low-frequency coding variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. https://doi.org/10.1038/nature21039
MAGIC Investigators ; The EPIC-InterAct Consortium ; EPIC-CVD Consortium ; CHD Exome+ Consortium ; ExomeBP Consortium ; T2D-Genes Consortium ; GoT2D Genes Consortium ; Global Lipids Genetics Consortium ; ReproGen Consortium. / Rare and low-frequency coding variants alter human adult height. In: Nature. 2017 ; Vol. 542, No. 7640. pp. 186-190.
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