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Rare and low-frequency coding variants alter human adult height
Nature (London), 2017-02, Vol.542 (7640), p.186-190
2017
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Autor(en) / Beteiligte
Titel
Rare and low-frequency coding variants alter human adult height
Ist Teil von
  • Nature (London), 2017-02, Vol.542 (7640), p.186-190
Ort / Verlag
England: Nature Publishing Group
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0028-0836, 1476-4687
eISSN: 1476-4687
DOI: 10.1038/nature21039
Titel-ID: cdi_swepub_primary_oai_lup_lub_lu_se_3afab246_fd00_4522_a319_c310adf7315f
Format
–
Schlagworte
ADAMTS Proteins - genetics, Adult, Alleles, Basic Medicine, Body height, Body Height - genetics, Cell Adhesion Molecules - genetics, Datasets, Deoxyribonucleic acid, Disease, DNA, Female, Gene Frequency - genetics, Genes, Genetic aspects, Genetic variation, Genetic Variation - genetics, Genome, Human - genetics, Glycoproteins - genetics, Glycoproteins - metabolism, Glycosaminoglycans - biosynthesis, Hedgehog Proteins - genetics, Humans, Intercellular Signaling Peptides and Proteins - genetics, Intercellular Signaling Peptides and Proteins - metabolism, Interferon Regulatory Factors - genetics, Interleukin-11 Receptor alpha Subunit - genetics, Male, Medical and Health Sciences, Medical Genetics, Medicin och hälsovetenskap, Medicinsk genetik, Medicinska och farmaceutiska grundvetenskaper, Multifactorial Inheritance - genetics, NADPH Oxidase 4, NADPH Oxidases - genetics, Observations, Phenotype, Pregnancy-Associated Plasma Protein-A - metabolism, Procollagen N-Endopeptidase - genetics, Proteoglycans - biosynthesis, Proteolysis, Receptors, Androgen - genetics, Somatomedins - metabolism, Studies

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