Ralston, S. H. et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum. Mol. Genet. 14, 943-951

Rheumatic Diseases Unit, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.
Human Molecular Genetics (Impact Factor: 6.39). 05/2005; 14(7):943-51. DOI: 10.1093/hmg/ddi088
Source: PubMed


Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.

Download full-text


Available from: Ian J Mackay,

Click to see the full-text of:

Article: Ralston, S. H. et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study. Hum. Mol. Genet. 14, 943-951

318.74 KB

See full-text
  • Source
    • "The DKK1 gene is able to modulate canonical Wnt signaling, and because of the established role of this pathway in the regulation of bone strength, this study aimed at understanding the influence of common genetic variations in DKK1 and CER1 genes on BMD, bone markers, and age of menopause. In a large genome-wide linkage scan, Ralston et al. [36] already suggested that the chromosomal region 10q21 containing the DKK1 gene was specifically associated with the regulation of BMD in men. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporosis has a multifactorial pathogenesis characterized by a combination of low bone mass and increased fragility. In our study, we focused on the effects of polymorphisms in CER1 and DKK1 genes, recently reported as important susceptibility genes for osteoporosis, on bone mineral density (BMD) and bone markers in osteoporotic women. Our objective was to evaluate the effect of CER1 and DKK1 variations in 607 postmenopausal women. The entire DKK1 gene sequence and five selected CER1 SNPs were amplified and resequenced to assess whether there is a correlation between these genes and BMD, early menopause, and bone turnover markers in osteoporotic patients. Osteoporotic women seem to suffer menopause 2 years earlier than the control group. The entire DKK1 gene sequence analysis revealed six variations. There was no correlation between the six DKK1 variations and osteoporosis, in contrast to the five common CER1 variations that were significantly associated with BMD. Additionally, osteoporotic patients with rs3747532 and rs7022304 CER1 variations had significantly higher serum levels of parathyroid hormone and calcitonin and lower serum levels of osteocalcin and IGF-1. No significant association between the studied DKK1 variations and osteoporosis was found, while CER1 variations seem to play a significant role in the determination of osteoporosis and a potential predictive role, combined with bone markers, in postmenopausal osteoporotic women.
    Human genomics 10/2013; 7(1):21. DOI:10.1186/1479-7364-7-21 · 2.15 Impact Factor
  • Source
    • "Both mentioned polymorphisms are found in the same haplotype block of the VDR gene and are linked to each other. A paper by Ralston et al. [30], who also did not show such relationship, is more in line with our work. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The goal of the study was to investigate the possibility of an association between polymorphisms and single alleles of BsmI, ApaI, TaqI of the vitamin D receptor (VDR) gene with bone mineral density (BMD) and prevalence of vertebral/non-vertebral fractures in a group of postmenopausal Polish women with osteoporosis. The study group comprised of 501 postmenopausal females with osteoporosis (mean age 66.4 ± 8.9), who were diagnosed on the basis of either the WHO criteria or self-reported history of low-energy fractures. The three polymorphisms were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). BMD at the lumbar spine and femoral neck was assessed by dual energy X-ray absorptiometry (DXA). 285 fractures were reported in the whole group (168 vertebral and 117 non-vertebral). Incidence of non-vertebral fractures was significantly higher in the carriers of single alleles a of ApaI, b of BsmI and T of TaqI VDR gene polymorphisms (p = 0.021, 0.032, 0.020, respectively). No significant associations between allelic variants of the studied polymorphisms and BMD or fracture incidence were found. (1).The presence of single alleles a,b and T of ApaI, BsmI, TaqI VDR gene polymorphisms respectively, might serve as an indicator of non-vertebral fractures. (2). Lack of association between the VDR gene polymorphisms and BMD suggests that VDR contributes to low-energy fractures also through other ways.
    Molecular Biology Reports 10/2012; 40(1). DOI:10.1007/s11033-012-2072-3 · 2.02 Impact Factor
  • Source
    • "Both genes encode different pre-mature miRNAs but generate the same mature miR-133a sequence. Interestingly, human genetic studies also found the association of 18q11.2 to osteoporosis-related traits [35] and linkage of 20q13 to bone phenotypes [36]–[38]. In humans, there are two types of miR-133 miRNA isoforms, miR-133a and miR-133b, with one base difference (g-a) in the last nucleotide at the 3′ end (miRBase: http://www.mirbase.org/). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporosis mainly occurs in postmenopausal women, which is characterized by low bone mineral density (BMD) due to unbalanced bone resorption by osteoclasts and formation by osteoblasts. Circulating monocytes play important roles in osteoclastogenesis by acting as osteoclast precursors and secreting osteoclastogenic factors, such as IL-1, IL-6 and TNF-α. MicroRNAs (miRNAs) have been implicated as important biomarkers in various diseases. The present study aimed to find significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. We used ABI TaqMan® miRNA array followed by qRT-PCR validation in circulating monocytes to identify miRNA biomarkers in 10 high and 10 low BMD postmenopausal Caucasian women. MiR-133a was upregulated (P=0.007) in the low compared with the high BMD groups in the array analyses, which was also validated by qRT-PCR (P=0.044). We performed bioinformatic target gene analysis and found three potential osteoclast-related target genes, CXCL11, CXCR3 and SLC39A1. In addition, we performed Pearson correlation analyses between the expression levels of miR-133a and the three potential target genes in the 20 postmenopausal women. We did find negative correlations between miR-133a and all the three genes though not significant. This is the first in vivo miRNA expression analysis in human circulating monocytes to identify novel miRNA biomarkers underlying postmenopausal osteoporosis. Our results suggest that miR-133a in circulating monocytes is a potential biomarker for postmenopausal osteoporosis.
    PLoS ONE 04/2012; 7(4):e34641. DOI:10.1371/journal.pone.0034641 · 3.23 Impact Factor
Show more