Rare and low-frequency coding variants alter human adult height

Eirini Marouli, Mariaelisa Graff, Carolina Medina-Gómez, Ken Sin Lo, Andrew R Wood, Troels R Kjaer, Rebecca S Fine, Yingchang Lu, Claudia Schurmann, Heather M. Highland, Sina Rüeger, Gudmar Thorleifsson, Anne E Justice, David Lamparter, Kathleen E Stirrups, Valérie Turcot, Kristin L Young, Thomas W Winkler, Tõnu Esko, Tugce KaraderiAdam E. Locke, Nicholas G D Masca, Maggie C Y Ng, Poorva Mudgal, Manuel A. Rivas, Sailaja Vedantam, Anubha Mahajan, Xiuqing Guo, Gonçalo R Abecasis, Katja K Aben, Linda S Adair, Dewan S Alam, Eva Albrecht, Kristine H Allin, Matthew A Allison, Philippe Amouyel, Emil V Appel, Dominique Arveiler, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Bernhard Banas, Lia E. Bang, Marianne Benn, Sven M. Bergmann, Lawrence F Bielak, Matthias Blüher, Heiner Boeing, Eric Boerwinkle, Claus Oxvig, EPIC InterAct Consortium

    Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

    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
    JournalNature
    Volume542
    Issue7640
    Pages (from-to)186-190
    Number of pages5
    ISSN0028-0836
    DOIs
    Publication statusPublished - 9 Feb 2017

    Keywords

    • Journal Article
    • Research Support, N.I.H., Extramural
    • Research Support, Non-U.S. Gov't

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