title: 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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: Johannah L
authors.initials: JL
authors.lastname: Butler
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D001483:Base Sequence; D001827:Body Height / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D019295:Computational Biology; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D014481:United States; D044465:White People
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C048250:somatotropin releasing hormone receptor; C051815:somatotropin-binding protein