Defining the role of common variation in the genomic and biological architecture of adult human height

Andrew R. Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H. Pers, Stefan Gustafsson, Audrey Y. Chun, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L. Buchkovich, Damien C. Croteau-Chonka, Felix R. Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U. Jackson, Juha KarjalainenKen Sin Lo, Adam E. Locke, Reedik Maegi, Evelin Mihailov, Eleonora Porcu, Joshua C. Randall, Andre Scherag, Anna A. E. Vinkhuyzen, Harm-Jan Westra, Irene Mateo Leach, Sander W. van der Laan, Jana V. Van Vliet-Ostaptchouk, Marcel Bruinenberg, Catharina A. Hartman, Hans L. Hillege, Ilja M. Nolte, Salome Scholtens, Joanna Smolonska, Morris A. Swertz, Niek Verweij, Judith M. Vonk, Stephan J. L. Bakker, Ron T. Gansevoort, Meena Kumari, Albertine J. Oldehinkel, Ronald P. Stolk, Folkert W. Asselbergs, Harold Snieder, Pim van der Harst, Lude Franke, Elect Med Records & Genom eMERGE C, MIGen Consortium, PAGE Consortium, Lifelines Cohort Study

Research output: Contribution to journalArticleAcademicpeer-review

999 Citations (Scopus)

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Original languageEnglish
Pages (from-to)1173-1186
Number of pages14
JournalNature Genetics
Volume46
Issue number11
DOIs
Publication statusPublished - Nov-2014

Keywords

  • GENETIC-VARIATION
  • COMPLEX TRAITS
  • HERITABILITY
  • MUTATIONS
  • SNPS

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