Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: The FAMOS study

Rheumatic Diseases Unit, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.
Human Molecular Genetics (Impact Factor: 6.68). 05/2005; 14(7):943-51. DOI: 10.1093/hmg/ddi088
Source: PubMed

ABSTRACT 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, Aug 18, 2015
  • Source
    • "Considering that Inpp4b modulates bone mass in mice and that INPP4B maps to chromosome 4q (Ferron and Vacher, 2006) where quantitative trait loci for bone mineral density (BMD) have been localized (Deng et al., 2002; Ralston et al., 2005), we hypothesized that INPP4B could be a candidate gene for association with this trait in humans. Screening of the Utah residents with ancestry from Northern and Western Europe population from HapMap detected 493 single nucleotide variant (SNP) within the INPP4B genomic locus. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a regulator of osteoclastogenesis, the murine homolog of inositol polyphosphate 4-phosphatase type IIα (Inpp4bα). Expression of Inpp4bα is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4bα ex vivo repressed whereas phosphatase-inactive Inpp4bα stimulated osteoclast differentiation. Inpp4bα acts on intracellular calcium level that modulates NFATc1 nuclear translocation and activation. In vivo mice deficient in Inpp4b displayed increased osteoclast differentiation rate and potential resulting in decreased bone mass and osteoporosis. Importantly, INPP4B in human was identified as a susceptibility locus for osteoporosis. This study defined Inpp4b as a major modulator of the osteoclast differentiation and as a gene linked to variability of bone mineral density in mice and humans.
    Cell metabolism 10/2011; 14(4):466-77. DOI:10.1016/j.cmet.2011.08.013 · 16.75 Impact Factor
  • Source
    • "The whole-genome linkage scanning approach has identified many quantitative trait loci (QTL) for bone mineral density (BMD) [11] [12] [13] [14] [15] [16] [17] [18] [19] [20], strongly suggesting that the genetic effect for common variation of the phenotype is under polygenic control. The 3p14-p21 region of the human genome has been identified as one of the most replicated QTLs for BMD in multiple studies, including our own [19] and a metaanalysis [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P=0.001-0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P=0.002-0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.
    Bone 06/2009; 45(2):387-91. DOI:10.1016/j.bone.2009.04.254 · 4.46 Impact Factor
  • Source
    • "The 5 longitudinal cohorts are the Aberdeen Prospective Osteoporosis Study (APOSS) [25], the Longitudinal Aging Study Amsterdam (LASA) [26], the Danish Osteoporosis Prevention Study (DOPS) [27], the European Prospective Osteoporosis Study (EPOS) [28], including data from the European Polish Osteoporosis Study (EPOLOS), and the Rotterdam study (ERGO) [29]. The 5 cross-sectional studies included are the Aarhus Osteoporosis Study (AROS) [30], the Barcelona Cross-sectional Study (BARCOS) [31], the Florence Cross-sectional Study (FLOS), the Graz Crosssectional Study (AUSTRIOS) [32], and the Familial Osteoporosis Study (FAMOS) [33]. Only the clinic-based studies (AROS, AUSTRIOS, BARCOS, DOPS and FLOS) excluded patients with chronic steroid use, hyperthyroidism and hyperparathyroidism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results. We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05. This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.
    Bone 06/2008; 42(5):969-81. DOI:10.1016/j.bone.2007.11.007 · 4.46 Impact Factor
Show more