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, Jennifer Wessel, Jennifer Wessel

    Research output: Contribution to journalArticle

    154 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 (US)
    Pages (from-to)186-190
    Number of pages5
    JournalNature
    Volume542
    Issue number7640
    DOIs
    StatePublished - Feb 9 2017

    Fingerprint

    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, ... Wessel, J. (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; Wessel, Jennifer; Wessel, Jennifer.

    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, Wessel, J & Wessel, J 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 ; Wessel, Jennifer ; Wessel, Jennifer. / Rare and low-frequency coding variants alter human adult height. In: Nature. 2017 ; Vol. 542, No. 7640. pp. 186-190.
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