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Genetics of Stature« Back to Volume 24, Issue 1, May 2008 - Table of Contents Variation in adult height is a classic polygenic trait, ie, it is determined by many genes each having a small effect. The identity of these genes has been elusive despite delineating many genes that have a major impact on height based on detection of mutations that cause severe growth deficiency. Although linkage studies have pointed to several genomic regions that influence height, there have not been any examples of gene variants that are reproducibly associated with height variation in the general population. However, from analysis of genome-wide association data, Weedon et al now showed that common variants in the HMGA2 oncogene are associated with height. The investigators began by analyzing data from 4,921 individuals including 1,896 UK individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium and 3,025 Swedish or Finnish participants from the Diabetes Genetics Initiative. More specifically, they performed a meta-analysis of sex- and age-adjusted height z–scores for 364,301 autosomal single nucleotide polymorphisms (SNPs) common across data sets. These SNPs provide 64% coverage of the Utah-based Haplotype Map.
Two SNPs most associated with height were mapped in and 12 kb downstream of the 3’ UTR (3’ untranslated region) of the high mobility group-A2 (HMGA2) gene. HMGA2 is a strong biological candidate for influencing height because its homozygous deletion produces the dwarf Pygmy mutant in mice. In replication studies of adults sampled from across the height distribution, each copy of the C allele of the SNP was associated with an increase of 0.07 in the adult height z–score, which is equivalent to ~0.4 cm in height. The authors discussed the fact that HMG proteins are DNA-binding proteins and often serve an architectural function with regard to chromatin structure and modeling, but they did not suggest possible mechanisms through which the polymorphism might alter bone growth. First Editor’s CommentIt is ironic that although normal height is probably one of the most studied polygenic traits in humans, the first gene to show a strong effect in the general population is only now coming to the fore. It will be interesting to see how this story unfolds and what other genes are identified with new genomics analysis technology. The genetics of height variation assessed by linkage studies were reviewed in GGH.1 These identified proteins, whose genes map to chromosomes 2q21 and 6q21 with locus interacting on an epistatic model, account for approximately 20% of height variation. These gene loci contain RUNX2 transcription factors with known functions on linear skeletal growth. William A. Horton, MD Second Editor’s CommentHMGA2 encodes “High Mobility Group AT-Hook 2” and is sited on chromosome 12q14.3. It is expressed in undifferentiated mesenchyme. HMG proteins alter chromatin configuration and thereby gene expression. They do so by the binding of their “AT hook domains” to AT-rich DNA; this alters conformation of the double helix and permits transcription complexes to either promote or inhibit transcription of targeted genes. Microdeletions or mutations of HMGA2 have been associated with benign neoplasia (lipoma, salivary adenoma, uterine leiomyoma). Truncation of HMGA2 secondary to a pericentric inversion of chromosome 12 with breakpoints at 12p11.22-12q14.3 has been associated with a syndrome of somatic overgrowth, advanced bone and dental ages, multiple lipomas and a cerebellar tumor.2 Truncations of mouse ortholog Hmga2 (Hmg1c) result in somatic overgrowth, lipomas, and increase in body fat.3 Homozygous deletion of mouse Hmga2 results in decrease in growth.4 Allen W. Root, MD References - (linked to
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Volume 25 Number 1
June 2009
www.GGHjournal.com
ISSN 1932-9032
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