Eugene Kobyliansky

Complex Segregation Analysis of the Radiographic Phalanges Bone Mineral Density and Their Age‐Related Changes

The complex segregation analyses performed in our previous studies revealed a significant major gene (MG) effect on the age‐adjusted cortical and cancellous bone mineral density (BMD) in two ethnically different populations, Chuvasha and Turkmenians. The aim of the present study was to test the hypothesis of pleiotropic MG control of three components of bone aging, that is, the baseline level of BMD (μgs), the age at onset of the bone mass loss (Tgs), and the rate of this loss over the years (αgs). Nuclear and more complex pedigrees from the same two ethnic samples were assessed for hand phalangeal BMD (Chuvasha, 1208 individuals, and Turkmenians, 643 individuals), and complex segregational analysis incorporating age and sex effects directly into MG penetrance function was carried out. The results of the present analysis clearly confirmed the existence of the putative MG and showed that the proportion of BMD variation attributable to this MG effect within the sex was remarkably similar in both populations and ranged between 34.7% and 35.2%. The most parsimonious model for BMD transmission in Chuvasha pedigrees additionally indicated significant residual correlation between siblings and clear sex differences in the annual rates of bone loss αgs. The latter was more than twice as high in females than that in males (0.086 SD vs. 0.033 SD per year). In Turkmenian pedigrees the most parsimonious model presented obvious evidence of the MG control of BMD baseline levels in both sexes with significantly lower baseline levels and younger age at onset (Tgs) in females. No clear MG effects were inferred on Tgs and/or αgs in either sample, either in males or in females. That is, the present study does not suggest MG × SEX × AGE interaction. We suppose that if the rate of age‐related changes in phalangeal BMD is genetically determined, then these are not the same genes as those affecting the BMD baseline levels.

Major gene control of human body height, weight and BMI in five ethnically different populations

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 man 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.

Study of genetic variance in the fluctuating asymmetry of anthropometrical traits

We have studied the fluctuating asymmetry (FA) of 8 bilateral morphometric traits in two-parent families, comprising 216 families with one newborn baby, and 60 families with two children (age range 5-18 years). Heritability was assessed by: (1) multiple regression analyses of the childrens measurements on the mothers and fathers measurements; (2) midparent-child regressions; and (3) sibling correlations. The extent of genetic determination of individual FA measurements was generally low, albeit statistically significant in some cases. However, even these correlations were inconsistent between samples and relatives. However, the mean FA values for all 8 studied traits showed positive and significant correlation between parents and children in two samples and in total. Additive genetic variance, calculated from multiple regression analyses and midparent-child correlations, was estimated to be between 0.25-0.30. Three multiple regressions (two for the separate group and one for the total sample) yielded a statistically significant value (between 0.21-0.33) also for the non-additive genetic component.

Modelling of age-related bone loss using cross-sectional data

Background : Current applications of bone mineral density (BMD) data in age studies are not free of certain drawbacks. Since it is well established that age-related patterns of BMD changes involve three distinct periods (bone acquisition in youth, stabilization at maturity, and decrease with ageing), adjusting for age via an inappropriate mathematical function may lead to inconsistencies and wrong conclusions. Hypothesis : The piecewise model, which encompasses the above three periods, will accurately describe the BMD dependence on age. Objective : To examine age-related patterns of BMD changes using a number of possible mathematical functions and to find among them the best-fitting function. Next, to test whether the chosen function is universally applicable or if there are diverse population-specific functions. Material and methods : Thirteen ethnic samples from various regions of Europe and Asia, assigned into five ethnic-geographic groups, were examined. The total sample included 2430 males and 2515 females. Compact BMD of hand phalanges was measured by photodensitometry from plain radiographs of each individual studied. Statistical software was developed for the purposes of the present study; this software gave a maximum likelihood of the parameter estimates for various statistical models (functions). Results : In all samples of sufficient size and representative age range, a two-interval function was found as the best fitting and most parsimonious model to describe the BMD age-related changes. This two-interval function was characterized by age-related bone mass increase, positive slope g 1s in young age or a plateau ( g 1s = 0, i.e. no age-related changes) until a sex-specific age threshold, T 0, after which annual bone loss ensued with a slope coefficient g 2s. Threshold of BMD loss in women of different ethnic groups ranged between 37.85 and 47.77 years, and roughly coincided with perimenopausal age. In males, the age T 0 varied between 27.85 and 49.07 years. The ensuing cortical bone loss appeared to be linear in both sexes, averaging between 0.51% and 1.15% in men and between 0.74% and 1.77% per year of young age BMD value in females. Conclusions : The change of phalangeal BMD with age may be best described by a two-interval function, regardless of sex and ethnic background. However, specific parameter estimates depend both on gender and ethnic affiliation. This study has yielded a well-fitted model of BMD dependence on age suitable for further use in population studies.

Jewish populations of the world: genetic likeness and differences

In six Jewish populations from Eastern, Central and Southern Europe, the Middle East, North Africa and Yemen, the frequencies of 30 genes from 13 loci were determined. The calculation of genetic distances between these populations as well as a cluster analysis were done. The gene frequencies of these six populations were computed together with those of 19 other Jewish populations of diverse countries described in the literature. Of the 19 populations, 22 alleles from 10 loci were checked. Gene frequencies in autochthonous, non-Jewish populations from these countries were also computed. All Jewish populations except Yemenites are concentrated in the same cluster, being closer one to another than to any of the non-Jewish groups. A similar picture is obtained when Jewish and non-Jewish populations from 19 countries are subjected to cluster analysis. The differences between the Jewish populations generally tend to bring them closer to the corresponding non-Jewish groups. The present data suggest that these differences cannot always be explained by admixture; other factors such as the effect of convergent adaptive processes must be considered.

Quantitative genetic analysis of circulating levels of biochemical markers of bone formation

Carboxyterminal propeptide of type 1 collagen (PICP) and bone Gla-protein-osteocalcin (BGP) are the most important components of the organic bone matrix and play a key role in bone formation. To investigate whether and to what extent variation of the plasma levels of these indices of bone turnover depends on genetic factors, we studied 355 adults belonging to nuclear pedigrees. Genetic analysis was carried out in 2 steps: 1) variance decomposition analysis was performed using the FISHER statistical package; and 2) complex segregation analysis implemented in the program package MAN. The effect of age and gender differences, gender hormones, as well as PTH and vitamin-D (calcidiol) plasma levels were evaluated simultaneously with the parameters of variance analysis. The results showed that about 50% of PICP variation is attributable to genetic factors. The effect of age was significant among men and postmenopausal women, whereas calcidiol influenced variation of PICP in premenopausal women. The results of variance analysis showed that some 40% of BGP, adjusted for confounding variables, can be explained in genetic factors. Age and PTH were important covariates for osteocalcin in men and premenopausal women. Exploration of the maximum likelihood estimates of the various hypotheses concerning the mode of intergenerational transmission of PICP and BGP demonstrated a good correspondence to the Mendelian mode of inheritance (i.e., major gene effect).

Evidence of major gene control of cortical bone loss in humans.

Cortical index (CI) is the ratio of the combined cortical thickness to the total diameter of the bone. It serves for the assessment of the geometric properties of bone and for indirect evaluation of bone mass. CI is a useful predictor of osteoporosis. The aim of the present study was to test the hypothesis of major gene control of CI variation in a large sample of pedigrees from Chuvashia, Russia. Complex segregation analysis revealed that the major gene model of CI inheritance is the best fitting and most parsimonious for the present data. Parameters of the genotype‐gender specific dependence of CI variation on age were estimated simultaneously with other parameters in the segregation analysis. The results of analysis showed that not only the baseline level of CI but also the age at onset of the involutive bone changes (inflection point) and the rate of the CI decrease with age (slope coefficient) are under control of the same major gene. Non‐major gene effects shared by pedigree members (residual familial correlations) were found to be statistically insignificant. Approximately 73% of inter‐individual variation in CI was attributable to the effects explicitly included in the model. Genet. Epidemiol. 19:410–421, 2000.

Mode of Inheritance of Hand Osteoarthritis in Ethnically Homogeneous Pedigrees

The aim of the present study was to investigate the extent and mode of inheritance of hand osteoarthritis (OA) using a large sample of ethnically homogeneous pedigrees. Two types of segregation analysis (SA) models were examined. Type I models used the data adjusted for potential significant covariates, particularly age and sex, prior to genetic analysis. Type II models incorporated effects of the potential covariates into major gene penetrance functions, permitting an account of the genotype covariate-specific effect on study variables. The results of this study strongly supported the hypothesis of a major gene effect and additional multifactorial component. The best-fitting model was the Mendelian one with an additive type of inheritance. The estimates obtained using the standard three-factor variance decomposition analysis suggest that age (72.8%) and major gene (14.5%) are the main sources of interindividual differences in the development of hand OA. The contribution of the putative major gene on age- and sex-adjusted OA phenotype variation was 55% in the present study.

Genetics of human body size and shape: pleiotropic and independent genetic determinants of adiposity

The present study utilized pedigree data from three ethnically different populations of Kirghizstan, Turkmenia and Chuvasha. Principal component analysis was performed on a matrix of genetic correlations between 22 measures of adiposity, including skinfolds, circumferences and indices. Findings are summarized as follows: (1) All three genetic matrices were not positive definite and the first four factors retained even after exclusion RG > or = 1.0, explained from 88% to 97% of the total additive genetic variation in the 22 trials studied. This clearly emphasizes the massive involvement of pleiotropic gene effects in the variability of adiposity traits. (2) Despite the quite natural differences in pairwise correlations between the adiposity traits in the three ethnically different samples under study, factor analysis revealed a common basic pattern of covariability for the adiposity traits. In each of the three samples, four genetic factors were retained, namely, the amount of subcutaneous fat, the total body obesity, the pattern of distribution of subcutaneous fat and the central adiposity distribution. (3) Genetic correlations between the retained four factors were virtually non-existent, suggesting that several independent genetic sources may be governing the variation of adiposity traits. (4) Variance decomposition analysis on the obtained genetic factors leaves no doubt regarding the substantial familial and (most probably genetic) effects on variation of each factor in each studied population. The similarity of results in the three different samples indicates that the findings may be deemed valid and reliable descriptions of the genetic variation and covariation pattern of adiposity traits in the human species.

Fluctuating asymmetry and morphometric variation of hand bones

The major aim of this study was to test three hypotheses: 1) more complex traits of the hand are less prone to developmental insults and therefore show lower fluctuating asymmetry (FA) as compared with simple traits; 2) the manifestation of FA correlates with the variability of the trait (i.e., CV); and 3) FA is an organ-wide property, and therefore a concordance exists between the FA measures of different traits in hand bones. Seventy-two bilateral measurements of hand bones, were made from plain-film radiographs of 365 cadavers. A complex trait was considered as the total length of the three phalanges of a finger and their contiguous metacarpals. Simple traits were considered to be the lengths of individual bone that made up the complex trait. The following results were obtained: 1) on the average simple traits, composing the complex trait, show much higher FA than the corresponding complex trait, but this result is expected if there is no correlation (or low correlation) between FA of simple traits within the complex trait, due to random direction of right-left differences; 2) strong and highly significant correlation was observed between FA and CV of studied traits, regardless of sex and age of individuals; and 3) the majority of FA measurements of hand bones showed no correlation. However, correlations between some sets of FA traits were highly significant. They were interpreted, although not specifically tested, as the result of a tight relationship between traits related not only developmentally but also by active performance of the same function.