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Marouli, E.* ; Graff, M.* ; Medina-Gomez, C.* ; Lo, K.S.* ; Wood, A.R.* ; Kjaer, T.R.* ; Fine, R.S.* ; Lu, Y.* ; Schurmann, C.* ; Highland, H.M.* ; Rüeger, S.* ; Thorleifsson, G.* ; Justice, A.E.* ; Lamparter, D.* ; Stirrups, K.E.* ; Turcot, V.* ; Young, K.L.* ; Winkler, T.W.* ; Esko, T.* ; Karaderi, T.* ; Locke, A.E.* ; Masca, N.G.D.* ; Ng, M.C.Y.* ; Mudgal, P.* ; Rivas, M.A.* ; Vedantam, S.* ; Mahajan, A.* ; Guo, X.* ; Abecasis, G.* ; Aben, K.K.* ; Adair, L.S.* ; Alam, D.S.* ; Albrecht, E. ; Allin, K.H.* ; Allison, M.A.* ; Amouyel, P.* ; Appel, E.V.* ; Arveiler, D.* ; Asselbergs, F.W.* ; Auer, P.L.* ; Balkau, B.* ; Heid, I.M. ; Kriebel, J. ; Müller-Nurasyid, M. ; Bergmann, S.* ; Bielak, L.F.* ; Blüher, M.* ; Boeing, H.* ; Boerwinkle, E.* ; Böger, C.A.* ; Bonnycastle, L.L.* ; Bork-Jensen, J.* ; Bots, M.L.* ; Bottinger, E.P.* ; Bowden, D.W.* ; Brandslund, I.* ; Breen, G.* ; Brilliant, M.H.* ; Broer, L.* ; Burt, A.A.* ; Butterworth, A.S.* ; Carey, D.J.* ; Caulfield, M.J.* ; Chambers, J.C.* ; Chasman, D.I.*

Rare and low-frequency coding variants alter human adult height.

Nature 542, 186-190 (2017)
Postprint Research data DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Missing Heritability; Genetic Architecture; Interleukin-11; Mutations; Mice
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 542, Issue: 7640, Pages: 186-190 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
G-504000-007
G-504091-002
G-501900-402
G-504091-001
DOI 10.1038/nature21039
WOS ID WOS:000393737500031
Scopus ID 85012918562
PubMed ID 28146470
Erfassungsdatum 2017-02-27
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