Rare and low-frequency coding variants alter human adult height
Nature Publishing Group
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Stirrups, K., Butterworth, A., Chowdhury, R., Danesh, J., Di Angelantonio, E., Howson, J., Surendran, P., et al. (2017). Rare and low-frequency coding variants alter human adult height. Nature, 542 186-190. https://doi.org/10.1038/nature21039
Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome-wide association studies. Here, we report 83 new height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing variants of STC2 (+1-2 cm/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 mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/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.
genetic association study, development
Cancer Research UK, Wellcome Trust A full list of acknowledgments appears in the Supplementary Note. Part of this work was conducted using the UK Biobank resource.
British Heart Foundation (RG/08/014/24067)
External DOI: https://doi.org/10.1038/nature21039
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262031