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.

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    ABSTRACT: Osteoporosis is a common disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and in susceptibility to fractures. The genetic basis of osteoporosis is complex and involves multiple genes and environmental factors. Here we introduce a family-based study of the genetics of osteoporosis - the Genetic Analysis of Osteoporosis (GAO) Project - to discover genetic variants affecting osteoporosis-related phenotypes. The GAO Project involved 11 extended families from Barcelona, Spain selected through a proband with osteoporosis (N=367). We performed spine, femur and whole body densitometry for all participants and also analyzed strength and geometrical properties of the hip. Our study focused on 23 densitometric phenotypes that we considered of high clinical relevance and four definitions of low bone mass and fracture status. Pedigree validation was carried out through microsatellite genotyping. The same microsatellites were used to interrogate our data (i) for the replication of previous linkage signals and (ii) for the potential discovery of new linkage signals. The linkage analysis identified one region marked by microsatellite D17S787 showing a strong and significant signal of linkage with femoral shaft cross-sectional moment of inertia (CSMI; LOD=3.18; p=6.5×10(-5)). The chromosomal location marked by microsatellite D17S787 includes several genes, among which two of particular interest: COL1A1 and SOST, coding for collagen alpha-1 (I) chain and sclerostin, respectively. Follow-up association analysis resulted in only one significant result for rs4792909 from the SOST genomic region (p=0.00248). As a result, we provide strong and significant evidence from both linkage and association analyses that the SOST gene may affect the strength of the femoral shaft. Future investigations should study the relationship between bone mass formation and strength properties of the bones.
    Bone 12/2013; DOI:10.1016/j.bone.2013.12.010 · 4.46 Impact Factor
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    ABSTRACT: Rationale and objectives: Genetic factors play an important role in regulating bone mineral density and in the development of osteoporosis. In order to identify the gene(s) contributing to bone mineral density, we have performed a linkage ap- proach in the largest primary osteoporosis family in the literature. Methods: This family was tested for a linkage to eight candidate genes: Bone gam- ma-carboxyglutamate protein, Chloride channel , Collagen type 1 alpha 1, Colla- gen type 1 alpha 2, Estrogen receptor alpha, Insulin like growth factor 1/somatome- din C, Low density lipoprotein receptor related protein 5 and Vitamine D receptor. The computations were performed with SuperLink v1.3. Results: The LOD score calculation and haplotype results of our study showed that none of these genes are responsible for low bone mineral density in this family. Conclusions: This study presents the largest primary osteoporosis family in the lit- erature and suggests that Bone gamma-carboxyglutamate protein, Chloride chan- nel 7 , Collagen type 1 alpha 1, Collagen type 1 alpha 2, Estrogen receptor alpha, In- sulin like growth factor 1/somatomedin C, Low density lipoprotein receptor related protein 5 and Vitamine D receptor genes are not responsible for low bone mineral density in this family.
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    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

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