Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density

Abstract

Bone mineral content (BMC) and\or bone mineral density (BMD, i.e. BMC scaled by bone size) are major determinants for osteoporosis, which is a serious health problem. The major determinant of variation in BMD\BMC is genetic. The few studies now available are inconsistent in the identification and\or even in the existence of major gene(s) for BMD\BMC. In 51 human pedigrees with 941 individuals (526 measured for phenotypes) identified via probands with extreme BMD values, we performed complex segregation analyses to test the existence of a genetic locus with a major effect on BMD\BMC variation. We analyzed BMD and BMC at the spine, hip and wrist jointly by employing, as the study phenotype, factor scores (FS) of the principle component that explains " 75 % of the total BMD\BMC variation at the three sites. The results indicate that a major gene exists with a codominant effect that is responsible for " 16 % of the FS variation when adjusted for significant effects of sex, body weight and age. A significant genotype-i-sex-i-age interaction was found, which may explain " 14 % of the FS variation after adjusting for body weight. Testing of various models did not provide support for shared familial environmental effects but suggested the existence of residual polygenic effects, which may explain " 50 % of the FS variation when adjusting for sex, body weight and age. This study indicates a promising aspect of studies to identify a major gene for BMD\BMC variation in our pedigrees identified via extreme probands. Bone mineral density (BMD) and bone mineral content (BMC) are quantitative traits that are measured on continuous scales by methods such as dual X-ray absorptiometry (DEXA). BMD is BMC scaled by bone size (silhouette size). Low BMD and BMC are major risk factors for fracture, and osteoporosis is mainly characterized by low BMD (Cummings et al. 1985 ;Melton et al. 1989). Osteoporosis results in more

Transmission Disequilibrium Test for Hand Bone Mineral Density and 11q12-13 Chromosomal Segment

“…On the other hand, there are a number of studies exploring the normal and abnormal variation of BMD, both in human pedigrees and in laboratory animals, which have provided substantial evidence in support of linkage to the 11q12-13 chromosome (Table 1). There are also several investigations employing segregation analysis on a number of ethnically different samples, including the Chuvasha studied here, which suggest that a single gene may have a major effect on BMD variation [6,[8][9][10][11]24]. In the present study, we therefore attempted to ascertain whether this putative gene may be located in the 11q12-13 chromosomal area.…”

“…It has also been demonstrated recently in a number of ethnic samples that major gene effects may be involved in the determination of interindividual variation in BMD and some geometric properties of bone such as cortical index [6][7][8][9][10][11]. Since BMD/C is the principal risk factor for the development of osteoporosis and bone fracture, it is not surprising that much energy has been expended in identifying the possible chromosomal location of the corresponding gene(s) [5,12,13].…”

Contribution of Gender‐Specific Genetic Factors to Osteoporosis Risk

“…The majority of the studies focused on areal BMD, which has been shown to be highly heritable (Slemenda et al, 1991;Deng et al, 2002a;Peacock et al, 2002). However the susceptibility to fractures depends on many factors, including non-skeletal factors, such as propensity to fall, diminished soft tissue cushion etc.…”

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

“…Adult bone mass, primarily measured as bone mineral density (BMD), has typically been the focal phenotype in genetic studies of bone regulation in humans [6,8,9,18,29,[38][39][40]. With the growing awareness of the importance of childhood bone accrual in determining adult bone health status, however, genetic studies are emerging that incorporate children into the study design.…”