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Rare and low-frequency coding variants alter human adult height
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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.
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-132627DOI: 10.1038/nature21039ISI: 000393737500031PubMedID: 28146470OAI: oai:DiVA.org:umu-132627DiVA: diva2:1083150
Available from: 2017-03-20 Created: 2017-03-20 Last updated: 2017-03-20Bibliographically approved

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Franks, Paul W.Jansson, Jan-HåkanRenstrom, FridaRolandsson, Olov
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MedicineDepartment of Public Health and Clinical MedicineDepartment of Biobank ResearchFamily Medicine
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CiteExportLink to record
Permanent link

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Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
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  • asciidoc
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