Cytogenetic location: 12q14.3 Genomic coordinates (GRCh38): 12:64,700,001-67,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q14.3 | {Stature QTL 9} | 611547 | 2 |
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255).
Human height is a classic, highly heritable quantitative trait. To identify genetic variants influencing height, Weedon et al. (2007) examined genomewide association data from 4,921 individuals. Common variants in the HMGA2 (600698) oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 was considered a strong biologic candidate for influencing height as homozygous deletion of the orthologous gene in the mouse produces the 'pygmy' phenotype, while mice expressing the truncated gene develop gigantism and lipomatosis; in humans, an individual with a severe overgrowth syndrome carried a chromosomal inversion that truncated the HMGA2 gene product (Ligon et al., 2005). Weedon et al. (2007) confirmed the association in 19,064 adults from 4 further studies. They also observed the association in children and in a tall/short case-control study. They estimated that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). The authors stated that this was one of the few examples of a common genetic variant reproducibly associated with a human quantitative trait, and the first consistently replicated association with adult and childhood height.
In separate genomewide association studies involving approximately 63,000 individuals, Weedon et al. (2008), Lettre et al. (2008), and Gudbjartsson et al. (2008) confirmed the HMGA2 gene as a locus associated with stature as a quantitative trait. In a study using genomewide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples, Weedon et al. (2008) found association with the SNP rs1042725 (P = 2.5 x 10(-18)). Each of the 20 robustly associated variants identified in the study altered height by between approximately 0.2 and 0.6 centimeters per allele. Lettre et al. (2008) also found association with this SNP (P = 2.7 x 10(-20)) in a metaanalysis of genomewide association study data of height for 15,821 individuals at 2.2 million SNPs, with follow-up of the strongest findings in greater than 10,000 subjects. Gudbjartsson et al. (2008) found significant association with the SNP rs8756 (P = 1.8 x 10(-16)), which was a surrogate for rs1042725 (r(2) = 0.87).
Soranzo et al. (2009) performed a genomewide scan in 12,611 participants followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with genomewide significant association with height. All subjects were of European descent, including 1,430 British individuals from the British 1958 Birth Cohort, 2,224 individuals from the TwinsUK Cohort, and 5,746 individuals from a Dutch cohort. Soranzo et al. (2009) confirmed association of the HMGA2 gene with stature as a quantitative trait. The strongest association found in their study was achieved by the SNP rs8756 (combined P = 5.0 x 10(-14)).
Hodge et al. (2009) found a significant association between a TC repeat allele of the HMGA2 gene, TC227, corresponding to 27 TC repeats, and height (corrected p = 0.016) in 248 white families with sister-pairs affected with uterine leiomyomata (UL; 150699). The same TC227 repeat was also associated with development of UL.
Gudbjartsson, D. F., Walters, G. B., Thorleifsson, G., Stefansson, H., Halldorsson, B. V., Zusmanovich, P., Sulem, P., Thorlacius, S., Gylfason, A., Steinberg, S., Helgadottir, A., Ingason, A., and 25 others. Many sequence variants affecting diversity of adult human height. Nature Genet. 40: 609-615, 2008. [PubMed: 18391951] [Full Text: https://doi.org/10.1038/ng.122]
Hodge, J. C., Cuenco, K. T., Huyck, K. L., Somasundaram, P., Panhuysen, C. I. M., Stewart, E. A., Morton, C. C. Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele. Hum. Genet. 125: 257-263, 2009. [PubMed: 19132395] [Full Text: https://doi.org/10.1007/s00439-008-0621-6]
Lettre, G., Jackson, A. U., Gieger, C., Schumacher, F. R., Berndt, S. I., Sanna, S., Eyheramendy, S., Voight, B. F., Butler, J. L., Guiducci, C., Illig, T., Hackett, R., and 25 others. Identification of ten loci associated with height highlights new biological pathways in human growth. Nature Genet. 40: 584-591, 2008. [PubMed: 18391950] [Full Text: https://doi.org/10.1038/ng.125]
Ligon, A. H., Moore, S. D. P., Parisi, M. A., Mealiffe, M. E., Harris, D. J., Ferguson, H. L., Quade, B. J., Morton, C. C. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am. J. Hum. Genet. 76: 340-348, 2005. [PubMed: 15593017] [Full Text: https://doi.org/10.1086/427565]
Soranzo, N., Rivadeneira, F., Chinappen-Horsley, U., Malkina, I., Richards, J. B., Hammond, N., Stolk, L., Nica, A., Inouye, M., Hofman, A., Stephens, J., Wheeler, E., and 26 others. Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size. PLoS Genet. 5: e1000445, 2009. Note: Electronic Article. [PubMed: 19343178] [Full Text: https://doi.org/10.1371/journal.pgen.1000445]
Weedon, M. N., Lango, H., Lindgren, C. M., Wallace, C., Evans, D. M., Mangino, M., Freathy, R. M., Perry, J. R. B., Stevens, S., Hall, A. S., Samani, N. J., Shields, B., and 20 others. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40: 575-583, 2008. [PubMed: 18391952] [Full Text: https://doi.org/10.1038/ng.121]
Weedon, M. N., Lettre, G., Freathy, R. M., Lindgren, C. M., Voight, B. F., Perry, J. R. B., Elliott, K. S., Hackett, R., Guiducci, C., Shields, B., Zeggini, E., Lango, H., and 21 others. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genet. 39: 1245-1250, 2007. [PubMed: 17767157] [Full Text: https://doi.org/10.1038/ng2121]