Rare and low-frequency coding variants alter human adult height

Eirini Marouli, Mariaelisa Graff, Carolina Medina-Gomez, 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, Goncalo Abecasis, Katja K. Aben, Linda S. Adair, Dewan S. Alam, Eva Albrecht, Kristine H. Allin, Matthew Allison, Philippe Amouyel, Emil V. Appel, Dominique Arveiler, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Bernhard Banas, Lia E. Bang, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Heiner Boeing, Ellen W. Demerath, Pamela J. Schreiner, 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 journalArticlepeer-review

360 Scopus citations


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
Issue number7640
StatePublished - Feb 9 2017

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