Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation

Abstract

Stature (adult height) is one of the most heritable human traits, yet few genes, if any, have been convincingly associated with adult height variation in the general population. Here, we selected 150 tag SNPs from eight candidate genes in the growth hormone (GH)/insulin-like growth factor-1 (IGF1) axis (GHR, GHRH, GHRHR, IGF1, IGFALS, IGFBP3, JAK2, STAT5B), and genotyped them in approximately 2,200 individuals ascertained for short or tall stature. Nominally significant tag SNPs were then tested in three additional replication cohorts, including a family-based panel to rule out spurious associations owing to population stratification. Across the four height cohorts (N = 6,075 individuals), we did not observe any consistent associations between stature and common variants (> or =5% minor allele frequency) in these eight genes, including a common deletion of the growth hormone receptor gene exon 3. Tests of epistatic interactions between these genes did not yield any results beyond those expected by chance. Although we have not tested all genes in the GH/IGF1 axis, our results indicate that common variation in these GH/IGF1 axis genes is not a major determinant of stature, and suggest that if common variation contributes to adult height variation in the general population, the variants are in other, possibly unanticipated genes.

Genetic variants that affect length/height in infancy/early childhood in Vietnamese-Korean families

“…[12][13][14][15] GWAS on height have been reported since 2007 and our group also reported genetic variants for adult height in the Korean population and apparent ancestral differences between Koreans and Europeans. 16 Recently, 54 genetic variants were known to influence the height and all of them were results of studies conducted on adults.…”

Family-based association study of IGF1 microsatellites and height, weight, and body mass index

“…22 These results 28,29 A genome-wide association study from Korea reported a possible association between an IGF1 single-nucleotide polymorphism and height, which did not achieve genome-wide significance. An association of the same single-nucleotide polymorphism with height for children with idiopathic short stature was reported by the same study.…”

Heterozygous GHR gene mutation in a child with idiopathic short stature

“…Importantly, this fact must be analyzed by functional studies, but bearing in mind that in vitro results are not always predictive of a clinical effect (3).…”

“…Importantly, these various disorders need to be excluded before the diagnosis of ISS can be made. These mutations include defects in GH-1, growth hormone-releasing hormone receptor (GHRHR), GH receptor gene (GHR), as well as various other genes, such as signal transducer (STAT5B), IGF-I and IGF-acid labile subunit (ALS), and so on (3). With an increasing number of reports on these gene defects, it has become evident that there is no strict geno/phenotype correlation; furthermore, phenotypes are highly variable.…”