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. 2007 Oct;39(10):1245-50.
doi: 10.1038/ng2121. Epub 2007 Sep 2.

A common variant of HMGA2 is associated with adult and childhood height in the general population

Michael N Weedon  1 , Guillaume Lettre, Rachel M Freathy, Cecilia M Lindgren, Benjamin F Voight, John R B Perry, Katherine S Elliott, Rachel Hackett, Candace Guiducci, Beverley Shields, Eleftheria Zeggini, Hana Lango, Valeriya Lyssenko, Nicholas J Timpson, Noel P Burtt, Nigel W Rayner, Richa Saxena, Kristin Ardlie, Jonathan H Tobias, Andrew R Ness, Susan M Ring, Colin N A Palmer, Andrew D Morris, Leena Peltonen, Veikko Salomaa; Diabetes Genetics Initiative; Wellcome Trust Case Control Consortium; George Davey Smith, Leif C Groop, Andrew T Hattersley, Mark I McCarthy, Joel N Hirschhorn, Timothy M Frayling
Affiliations

A common variant of HMGA2 is associated with adult and childhood height in the general population

Michael N Weedon et al. Nat Genet. 2007 Oct.

Abstract

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 x 10(-11), overall P = 4 x 10(-16), including the genome-wide association data). We also observed the association in children (P = 1 x 10(-6), N = 6,827) and a tall/short case-control study (P = 4 x 10(-6), N = 3,207). We estimate that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

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Figures

Figure 1
Figure 1
Quantile-quantile plot of 364,301 SNPs from the meta-analysis of DGI and WTCCC genome-wide association statistics. Blue dots represent observed statistics, and black line represents expected statistics.
Figure 2
Figure 2
Association, gene structure, conservation and linkage disequilibium of the HMGA2 gene region. (a) Plot of −log(P) versus chromosome position for the WTCCC and DGI meta-analysis. (b) Genomic location of genes showing intron and exon structure (NCBI build 35). (c) Multi-Z vertebrate alignment of 17 species showing evolutionary conservation. (d) Recombination rate given as cM/Mb. Red boxes represent recombination hotspots. (e) GOLDsurfer plot of linkage disequilibrium in HapMap CEU samples (expressed as pairwise r2).
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