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

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          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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          Most cited references 13

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          Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

          Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.
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            Demonstrating stratification in a European American population.

            Population stratification occurs in case-control association studies when allele frequencies differ between cases and controls because of ancestry. Stratification may lead to false positive associations, although this issue remains controversial. Empirical studies have found little evidence of stratification in European-derived populations, but potentially significant levels of stratification could not be ruled out. We studied a European American panel discordant for height, a heritable trait that varies widely across Europe. Genotyping 178 SNPs and applying standard analytical methods yielded no evidence of stratification. But a SNP in the gene LCT that varies widely in frequency across Europe was strongly associated with height (P < 10(-6)). This apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. The failure of standard methods to detect this stratification indicates that new methods may be required.
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              Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C.

              Growth is one of the fundamental aspects in the development of an organism. Classical genetic studies have isolated four viable, spontaneous mouse mutants disrupted in growth, leading to dwarfism. Pygmy is unique among these mutants because its phenotype cannot be explained by aberrations in the growth hormone-insulin-like growth factor endocrine pathway. Here we show that the pygmy phenotype arises from the inactivation of Hmgi-c (ref. 6), a member of the Hmgi family which function as architectural factors in the nuclear scaffold and are critical in the assembly of stereospecific transcriptional complexes. Hmgi-c and another Hmgi family member, Hmgi(gamma) (ref. 10), were found to be expressed predominantly during embryogenesis. The HMGI proteins are known to be regulated by cell cycle-dependent phosphorylation which alters their DNA binding affinity. These results demonstrate the important role of HMGI proteins in mammalian growth and development.
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                Author and article information

                Journal
                Nature Genetics
                Nat Genet
                Springer Science and Business Media LLC
                1061-4036
                1546-1718
                October 2007
                September 2 2007
                October 2007
                : 39
                : 10
                : 1245-1250
                Article
                10.1038/ng2121
                3086278
                17767157
                © 2007

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