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

Abstract

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.

Within-family outliers: segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs

“…Furthermore, a meta-analysis of published linkage studies on chromosome 12 has shown that there is significant evidence for the presence of a QTL on this chromosome. 38 In the present study, the LOD score for this region did not reach suggestive linkage, but a LOD score of 1.4 was observed. Power calculations suggest that the expected LOD scores for a QTL explaining 5 to 10% of the phenotypic variance are 0.9 and 2.8, respectively, so if the VDR has a moderate effect on height, the observed LOD scores in this region are not inconsistent with VDR being a candidate gene for height.…”

“…Among many genes that have been associated with height, the vitamin D receptor (VDR) has recently received much attention. As one of the intracellular hormone receptors, the main role of VDR is to bind the active form of vitamin D. This gene has been mapped to 12q12 -q14 40 and it has been associated with height (eg, 38,41 ). Furthermore, a meta-analysis of published linkage studies on chromosome 12 has shown that there is significant evidence for the presence of a QTL on this chromosome.…”

Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

“…Screening both obese diabetics and those with anorexia did not identify any pathological LEP mutations (27,28). A recent genome-wide association study in US and Chinese populations identified two SNPs within the only intron of the TRH receptor gene which showed significant association with lean body mass (29), while an association with the vitamin D receptor gene was identified in a cohort of children with idiopathic short stature/CDGP (30).…”

Relationship between vitamin D receptor (VDR) polymorphisms and the efficacy of recombinant human growth hormone (rhGH) treatment in children with idiopathic short stature

“…These studies have identified the BsmI, ApaI, TaqI, and FokI loci as the four enzyme loci that contribute to the development of multiple sclerosis, asthma, and cancer (Poon et al, 2013;Atoum and Tchoporyan, 2014;Kalman and Toldy, 2014). Dempfle et al (2006) reported that a functional SNP in the VDR gene may contribute to 34% of the ISS cases in a population. The more transcriptionally active allele of the functional FokI SNP (rs10735810) is overrepresented in children affected with ISS, and may contribute to short stature (Dempfle et al, 2006).…”

“…Dempfle et al (2006) reported that a functional SNP in the VDR gene may contribute to 34% of the ISS cases in a population. The more transcriptionally active allele of the functional FokI SNP (rs10735810) is overrepresented in children affected with ISS, and may contribute to short stature (Dempfle et al, 2006). The exon 2 polymorphism affecting the VDR mRNA and protein is one of the most important determinants of adult height, especially in female Japanese subjects (Minamitani et al, 1998).…”