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Rare and low-frequency coding variants alter human adult height
Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England..
Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA..
Erasmus Sch Ctr, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;Erasmus Sch Ctr, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..ORCID iD: 0000-0001-7999-5538
Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
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2017 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7640, 186-190 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 542, no 7640, 186-190 p.
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Genetics
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URN: urn:nbn:se:uu:diva-317947DOI: 10.1038/nature21039ISI: 000393737500031PubMedID: 28146470OAI: oai:DiVA.org:uu-317947DiVA: diva2:1086349
Available from: 2017-04-01 Created: 2017-04-01 Last updated: 2017-04-01Bibliographically approved

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