Segregation analysis reveals a major gene effect in compact and cancellous bone mineral density in 2 populations

Abstract Involvement of genetic factors in determining bone mineral density (BMD) is doubtless. However, the exact nature of the genes governing BMD variation and sources for genetic determination of BMD of different parts of bone (compact and cancellous) have not been completely studied. The results of the complex segregation analyses performed in our previous study (Livshits et al. 1996) on a Turkmenian sample strongly support the hypothesis that a single Mendelian locus has a large effect on BMD. The parameter estimates for both types of bone tissue were so similar that we could assume a common gene effect for BMD variation of cancellous and compact bone. The objectives of the present study are to test again the possibility of major gene control of BMD in a different ethnic sample of pedigrees, namely, the Chuvasha. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both the Turkmenian and the Chuvasha samples of pedigrees. The results of the present study closely resemble the results obtained on the Turkmenian pedigrees. Likewise, the major finding of the present study is that there is a significant major gene effect on both compact and cancellous BMD; polygenic hypotheses were clearly rejected. Moreover, the results of the bivariate segregation analysis in both the Chuvasha and Turkmenian samples were similar. They lead to acceptance of the hypothesis that there is a single major locus with pleiotropy to both compact and cancellous bone.

KEY WORDS: BONE MINERAL DENSITY, OSTEOPOROSIS, GENETIC MODELING, BIVARIATE SEGREGATION ANALYSIS

Osteoporosis is a common age-dependent degenerative bone disease characterized by reduced bone mass and increased fracture risk. Involvement of genetic factors in determination of bone mass and, in particular, bone mineral density (BMD) is doubtless but not fully elucidated (Spotila et al.1996; Livshits et al. 1998; Rogers et al. 1997). A complete understanding of the genetic basis of variation in risk of osteoporosis should include information about the number of loci exerting influence, the magnitude and precise nature of these loci effects, and the patterns of interaction among genes and between genes and the environment (Livshits et al. 1998; Rogers et al. 1997).

Although twin and family studies are useful and important indicators of potential genetic control in the rate of bone loss, they do not attempt to answer several questions of critical importance. For example, it is not known whether bone mass and bone density are governed by a single or a few major genes and where they may be located. Do the potential loci controlling BMD at different skeletal sites have a pleiotropic effect and to what degree might the loci be linked? The family studies, which use segregation analysis, can and do provide much greater statistical power to assess the genotype-- phenotype relationships than do twin or association studies.

Several researchers who have used classical methods of genetic analysis concluded that different genes are probably responsible for BMD in the two types of bone, cancellous and compact (Mahaney et al.1995). The assumption of different sources of genetic determination of cancellous and compact BMD may stem from the difference in their structure, function, and rates of bone loss and from the fact that cancellous bone is more metabolically active and actively involved in bone turnover than compact bone (Dequeker 1976).

Livshits et al. (1996), using complex segregation analysis of nuclear pedigrees from rural Turkmenia, found similar patterns of inheritance in both cancellous and compact BMD variation. The conclusion was that the BMD of each type is determined by a putative major gene and not by a set of additive polygenes. The parameter estimates for both types of bone tissue were so similar that we can assume a common gene effect for BMD variation of cancellous and compact bone.

The objectives of the present study are to test again the possibility of major gene control of BMD in another sample of pedigrees. The new sample, from the Chuvasha, is drastically different from the previous sample of Turkmenians ethnically, culturally, and environmentally. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both samples (Turkmenians and Chuvasha). The main aim here is to determine and to compare the extent to which two primary characteristics of hand bone BMD, which are determined by major gene effects, are sharing a major gene effect.

We are well aware of potential sex- and age-genotype-specific interactions within BMD heritability. These interactions are due to possible incomplete expression of genes at certain ages or differences in gene action at different ages (Pocock et al. 1987; Sowers et al. 1992; Gueguen et al. 1995), but besides the attempt to determine the major gene effects and pleiotropy, we did not try in this study to investigate particular age and sex interactions in BMD gene expression.