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Genome-wide association analysis identifies 20 loci that influence adult height

Abstract

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reaching P < 1 × 10−10). Combined, the 20 SNPs explain 3% of height variation, with a 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

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Figure 1: Quantile-quantile plots for the 402,951 SNPs from the genome-wide association meta-analysis as more studies are added in.
Figure 2: Manhattan plot for the 402,951 SNPs from the stage 1 genome-wide association meta-analysis of the WTCCC-T2D, DGI, WTCCC-HT, WTCCC-CAD, EPIC-Obesity and WTCCC-UKBS studies.
Figure 3: The combined impact of the 20 SNPs with a P < 5 × 10−7.
Figure 4: Power estimates.
Figure 5: Comparison of results across independent meta-analyses.

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Acknowledgements

M.N.W. is a Vandervell Foundation Research Fellow. C.L. is a Nuffield Department of Medicine Scientific Leadership Fellow. R.M.F. is funded by a Diabetes UK research studentship. S.B. is supported by the Giorgi-Cavaglieri Foundation and the Swiss National Science Foundation (grant 3100AO-116323/1), which also supports J.S.B. (grant 310000-112552/1). We would like to thank M. Bochud, Z. Kutalik, G. Waeber, K. Song and X. Yuan for their contribution to the Lausanne study. The WTCCC CAD cohort collection was supported by grants from the British Heart Foundation, Medical Research Council and National Health Service Research & Development. N.J.S. holds a chair supported by the British Heart Foundation. We thank the Wellcome Trust for funding. C.W. is funded by the British Heart Foundation (grant number FS/05/061/19501). The BRIGHT study is supported by the Medical Research Council (grant number G9521010D) and the British Heart Foundation (grant number PG02/128).

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M.N.W., H.L., C.M.L., C.W., D.M.E., M.M., J.R.B.P., S.S., I.P., members of the DGI, WTCCC, the GEM consortium, S.B., T.J. and D.M.W. were responsible for analyzing, quality control checking and cleaning the data from the individual GWA studies. C.W., R.M.F., B.S., M.N.W. and H.L. were responsible for analysis of the stage 2 samples. M.N.W. performed the meta-analyses. A.S.H. and N.J.S. are principal investigators from the WTCCC-CAD study. M.C. and M.F. are principal investigators from the WTCCC-HT study. W.H.O. is principal investigator of the WTCCC-UKBS study. A.T.H. and M.I.M. are principal investigators for the WTCCC-T2D study. J.S.B., P.V. and V.M. are principal investigators of the CoLaus study. M.C., M.F., A.D. and P.B.M. are principal investigators on the BRIGHT study. A.T.H. is principal investigator of the EFSOCH study. C.N.A.P. and A.D.M. are principal investigators of the Tayside UKT2D-GCC study. M.N.W., H.L., A.T.H., M.I.M. and T.M.F. wrote the manuscript. A.T.H., M.I.M., M.N.W. and T.M.F. designed and led the study. All authors read and approved the final manuscript.

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Correspondence to Timothy M Frayling.

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A full list of authors is provided in the Supplementary Note

A full list of authors is provided in the Supplementary Note

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Supplementary Tables 1–5, Supplementary Figures 1–3, Supplementary Note (PDF 4393 kb)

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Weedon, M., Lango, H., Lindgren, C. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40, 575–583 (2008). https://doi.org/10.1038/ng.121

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