@article{d3586164d21c461ba1e35e29c65a583e,
title = "Rare and low-frequency coding variants alter human adult height",
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.",
keywords = "ADAMTS Proteins, Adult, Alleles, Body Height, Cell Adhesion Molecules, Female, Gene Frequency, Genetic Variation, Genome, Human, Glycoproteins, Glycosaminoglycans, Hedgehog Proteins, Humans, Intercellular Signaling Peptides and Proteins, Interferon Regulatory Factors, Interleukin-11 Receptor alpha Subunit, Journal Article, Male, Multifactorial Inheritance, NADPH Oxidase 4, NADPH Oxidases, Phenotype, Pregnancy-Associated Plasma Protein-A, Procollagen N-Endopeptidase, Proteoglycans, Proteolysis, Receptors, Androgen, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Somatomedins",
author = "Eirini Marouli and Mariaelisa Graff and Carolina Medina-Gomez and Lo, \{Ken Sin\} and Wood, \{Andrew R\} and Kjaer, \{Troels R\} and Fine, \{Rebecca S\} and Yingchang Lu and Claudia Schurmann and Highland, \{Heather M\} and Sina R{\"u}eger and Gudmar Thorleifsson and Justice, \{Anne E\} and David Lamparter and Stirrups, \{Kathleen E\} and Val{\'e}rie Turcot and Young, \{Kristin L\} and Winkler, \{Thomas W\} and T{\~o}nu Esko and Tugce Karaderi and Locke, \{Adam E\} and Masca, \{Nicholas G D\} and Ng, \{Maggie C Y\} and Poorva Mudgal and Rivas, \{Manuel A\} and Sailaja Vedantam and Anubha Mahajan and Xiuqing Guo and Goncalo Abecasis and Aben, \{Katja K\} and Adair, \{Linda S\} and Alam, \{Dewan S\} and Eva Albrecht and Allin, \{Kristine H\} and Matthew Allison and Philippe Amouyel and Appel, \{Emil V\} and Dominique Arveiler and Asselbergs, \{Folkert W\} and Auer, \{Paul L\} and Beverley Balkau and Bernhard Banas and Bang, \{Lia E\} and Marianne Benn and Sven Bergmann and Bielak, \{Lawrence F\} and Matthias Bl{\"u}her and Heiner Boeing and Eric Boerwinkle and Danielle Posthuma and \{EPIC-InterAct Consortium\}",
year = "2017",
month = feb,
day = "9",
doi = "10.1038/nature21039",
language = "English",
volume = "542",
pages = "186--190",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7640",
}