Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies


  • A. Dempfle
  • S.A. Wudy
  • K. Saar
  • S. Hagemann
  • S. Friedel
  • A. Scherag
  • L.D. Berthold
  • G. Alzen
  • L. Gortner
  • W.F. Blum
  • A. Hinney
  • P. Nuernberg
  • H. Schaefer
  • J. Hebebrand


  • Human Molecular Genetics


  • Hum Mol Genet 15 (18): 2772-2783


  • Stature is a highly heritable trait under both polygenic and major gene control. We aimed to identify genetic regions linked to idiopathic short stature (ISS) in childhood, through a whole genome scan in 92 families each with two affected children with ISS, including constitutional delay of growth and puberty and familial short stature. Linkage analysis was performed for ISS, height and bone age retardation. Chromosome 12q11 showed significant evidence of linkage to ISS and height (maximum non-parametric multipoint LOD scores 3.18 and 2.31 at 55-58 cM, between D12S1301 and D12S1048), especially in sister-sister pairs (LOD score of 1.9 for ISS in 22 pairs). These traits were also linked to chromosomes 1q12 and 2q36. The region on chromosome 12q11 had previously shown significant linkage to adult stature in several genome scans and harbors the vitamin D receptor gene, which has been associated with variation in height. A single nucleotide polymorphism (SNP) (rs10735810, FokI), which leads to a functionally relevant alteration at the protein level, showed preferential transmission of the transcriptionally more active G-allele to affected children (P=0.04) and seems to be responsible for the observed linkage (P=0.05, GIST test). Bone age retardation showed moderate linkage to chromosomes 19p11-q11 and 7p14 (LOD scores 1.69 at 57 cM and 1.42 at 50 cM), but there was no clear overlap with linkage regions for stature. In conclusion, we identified significant linkage, which might be due to a functional SNP in the vitamin D receptor (VDR) gene and could be responsible for up to 34% of ISS cases in the population.