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Rare and low-frequency coding variants alter human adult height

Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R; Kjaer, Troels R.; Fine, Rebecca S.; Lu, Yingchang; Schurmann, Claudia and Highland, Heather M, et al. (2017) In Nature 542(7640). p.186-190
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... (More)

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.

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542
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7640
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186 - 190
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Nature Publishing Group
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  • scopus:85012918562
  • wos:000393737500031
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0028-0836
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10.1038/nature21039
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@article{3afab246-fd00-4522-a319-c310adf7315f,
  abstract     = {<p>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.</p>},
  author       = {Marouli, Eirini and Graff, Mariaelisa and Medina-Gomez, Carolina and Lo, Ken Sin and Wood, Andrew R and Kjaer, Troels R. and Fine, Rebecca S. and Lu, Yingchang and Schurmann, Claudia and Highland, Heather M and Rüeger, Sina and Thorleifsson, Gudmar and Justice, Anne E and Lamparter, David and Stirrups, Kathleen E. and Turcot, Valérie and Young, Kristin L. and Winkler, Thomas W and Esko, Tõnu and Karaderi, Tugce and Locke, Adam E. and Masca, Nicholas G D and Ng, Maggie C. 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  issn         = {0028-0836},
  language     = {eng},
  month        = {02},
  number       = {7640},
  pages        = {186--190},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Rare and low-frequency coding variants alter human adult height},
  url          = {http://dx.doi.org/10.1038/nature21039},
  volume       = {542},
  year         = {2017},
}