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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
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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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    • "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. "
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    Cell metabolism 10/2011; 14(4):466-77. DOI:10.1016/j.cmet.2011.08.013 · 16.75 Impact Factor
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    • "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]. "
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    Bone 06/2009; 45(2):387-91. DOI:10.1016/j.bone.2009.04.254 · 4.46 Impact Factor
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    • "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. "
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