Pedigree samples were collected from five ethnically and geographically different populations : Kirghizians, Turkmenians, Chuvashians, Israelis and Mexicans. All studied individuals were assessed for body height, weight and BMI. The sample size in the studied pedigrees ranged from 381 to 1811 individuals. Segregation analysis of these traits preliminarily adjusted for sex and age was performed by means of program package  that provides parameter estimates for the major gene effects, for the residual within the genotype correlations between relatives and for the assortative mating. By the usual transmission probability tests, the ' environmental ' model was strongly rejected for all measured traits in all 5 populations. The major gene mode of inheritance, however, was accepted for all traits. The results of analysis in 5 populations were remarkably similar, and showed that except for Mexican sample, the proportion of variance attributable to major gene effect ranged between 37 and 53 % for body weight and height. In the Mexican sample it explained only about 14 % of the body weight variation. The proportion of inter-individual variation in BMI attributable to major gene effect was consistently lower in all populations in comparison with height and weight and ranged between 17 and 40 %. Strong assortive mating in body height, as estimated by correlation between putative major gene genotypes in spouses, was found in four populations, not including Mexican pedigrees. In spite of the fact that human body height, weight and other anthropometric characteristics became the subject of quantitative genetics almost from the beginning of the present century, very little is known regarding the involvement of large-effect genes in their mode of inheritance, except for body mass index (BMI) and various measures of obesity (e.g. Comuzzie et al. 1995 ; Lecomte et al. 1997).The heritability estimates obtained in standard genetic investigations, utilizing variance

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

Genetic factors substantially influence inter-individual differences in body shape and configuration in two studied samples. However, further studies are needed to clarify the extent of pleiotropy and epigenetic effects on various facets of the human physique.

BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors.Introduction: BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors Materials and Methods: A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. Results and Conclusions:The genetic correlation between BMD measures ranged between 0.50 Ϯ 0.09 and 0.79 Ϯ 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 Ϯ 0.07 to 0.66 Ϯ 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.

This study was designed to test the hypothesis of a major gene influence on the variation in bone mineral density (BMD). BMD and bone mineral content at the lumbar spine and femoral neck were measured in 330 men and 413 women, aged 18-90 yr, from 107 nuclear and complex families (including 5 large pedigrees with 194 individuals who were identified through an index case with moderately high BMD at the femoral neck (z-score, >or=1.28)). After adjusting for age and body weight, familial factors accounted for up to 72% of the total variation in BMD. In complex segregation analysis, for all variables examined the best-fitting most parsimonious model consistently suggested the Mendelian transmission of a major gene locus with significant residual correlations among siblings. This genetic model suggested that the proportion of a total variance (adjusted for significant covariates) attributable to a putative major gene effect ranged between 0.30 +/- 0.09 for femoral neck BMD and 0.53 +/- 0.07 for the principal component obtained on BMD and corresponding bone mineral content measures. These findings clearly support the hypothesis that a large component of the variance in BMD is under genetic control, with strong evidence for a major gene locus influencing BMD transmission.