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Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation

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Abstract

Stature (adult height) is one of the most heritable human traits, yet few genes, if any, have been convincingly associated with adult height variation in the general population. Here, we selected 150 tag SNPs from eight candidate genes in the growth hormone (GH)/insulin-like growth factor-1 (IGF1) axis (GHR, GHRH, GHRHR, IGF1, IGFALS, IGFBP3, JAK2, STAT5B), and genotyped them in ∼2,200 individuals ascertained for short or tall stature. Nominally significant tag SNPs were then tested in three additional replication cohorts, including a family-based panel to rule out spurious associations owing to population stratification. Across the four height cohorts (N = 6,075 individuals), we did not observe any consistent associations between stature and common variants (≥5% minor allele frequency) in these eight genes, including a common deletion of the growth hormone receptor gene exon 3. Tests of epistatic interactions between these genes did not yield any results beyond those expected by chance. Although we have not tested all genes in the GH/IGF1 axis, our results indicate that common variation in these GH/IGF1 axis genes is not a major determinant of stature, and suggest that if common variation contributes to adult height variation in the general population, the variants are in other, possibly unanticipated genes.

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Acknowledgments

We thank all participants to this study, as well as members of our laboratory for helpful discussions. J.N.H. is a recipient of a March of Dimes grant #6-FY04-61, which supported this work. We thank the Framingham Heart Study (NHLBI) for providing DNA samples. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) (Contract No. N01-25195) in collaboration with Boston University. This manuscript has been reviewed by Boston University and NHLBI for scientific content and consistency of data interpretation with previous Framingham publications and significant comments have been incorporated prior to submission for publication.

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Authors and Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, MA, 02142, USA

    Guillaume Lettre, Johannah L. Butler & Joel N. Hirschhorn

  2. Divisions of Endocrinology and Genetics, Program in Genomics, Children’s Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA

    Guillaume Lettre, Johannah L. Butler & Joel N. Hirschhorn

  3. Genomics Collaborative/Seracare LifeSciences, Cambridge, MA, USA

    Kristin G. Ardlie

  4. Biological Samples Platform, Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, MA, 02142, USA

    Kristin G. Ardlie

  5. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA

    Joel N. Hirschhorn

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  1. Guillaume Lettre
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Correspondence to Joel N. Hirschhorn.

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. Summary of tagSNP strategy and coverage (DOC 31.5 kb)

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. Resequencing results (DOC 32 kb)

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Lettre, G., Butler, J.L., Ardlie, K.G. et al. Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation. Hum Genet 122, 129–139 (2007). https://doi.org/10.1007/s00439-007-0385-4

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