A significant association exists between receptor tyrosine kinase-like orphan receptor 2 gene variants and the OPG/RANKL ratio in human plasma.

SUMMARY: There is a paucity of studies investigating association between ROR2 gene variants and osteoporosis and osteoarthritis-related phenotypes. The published literature suggests that osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) are essential for bone metabolism and correlate with osteoarthritis manifestation and progression. The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma. The present results also suggest significant association between ROR2 polymorphisms and severity of radiographic hand osteoarthritis. INTRODUCTION: Despite the importance of the ROR-2 in skeletal physiology, there is a paucity of studies investigating the potential association of ROR2 gene variants with phenotypes relevant to osteoporosis and osteoarthritis. On the other hand, there is a considerable body of literature suggesting that OPG and RANKL and their ratio (OPG/RANKL) are essential for regulating bone resorption. This is also correlated with osteoarthritis manifestation and progression. The present study therefore examines whether ROR2 polymorphisms may be associated with the OPG/RANKL ratio and hand osteoarthritis (HOA). METHODS: The study was conducted in a family-based sample of 1,515 Caucasian individuals, assessed for radiographic hand osteoarthritis, using the Kellgren/Lawrence score. Of these, 865 individuals were genotyped for 19 SNPs, relatively equally covering the ROR2 locus, and their plasma levels of OPG and RANKL were assayed. The association between the selected SNPs and OPG, along with the OPG/RANKL ratio and HOA, was explored using the pedigree disequilibrium test. RESULTS: Of the total of 57 tests, 16 nominally significant results (p < 0.05) were obtained, which is considerably more than the three normally expected for type I error. The significant association signals for all three phenotypes were mapped to the intron 1 region. The most significant results were detected between OPG/RANKL and rs7048756 (p < 0.0005) and between adjacent rs4744107 and Kellgren/Lawrence score (p = 0.006). CONCLUSIONS: The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma and also suggests ROR2 association with HOA.

Inheritance of finger pattern types in MZ and DZ twins.

Digital patterns of a sample on twins were analyzed to estimate the resemblance between monozygotic (MZ) and dizygotic (DZ) twins and to evaluate the mode of inheritance by the use of maximum likelihood based variance decomposition analysis. MZ twin resemblance of finger pattern types appears to be more pronounced than in DZ twins, which suggests the presence of genetic factors in the forming of fingertip patterns. The most parsimonious model shows twin resemblance in count of all three basic finger patterns on 10 fingers. It has significant dominant genetic variance component across all fingers. In the general model, the dominant genetic variance component proportion is similar for all fingertips (about 60%) and the sibling environmental variance is significantly nonzero, but the proportion between additive and dominant variance components was different. Application of genetic model fitting technique of segregation analyses clearly shows mode of inheritance. A dominant genetic variance component or a specific genetic system modifies the phenotypic expression of the fingertip patterns. The present study provided evidence of strong genetic component in finger pattern types and seems more informative compared to the earlier traditional method of correlation analysis.

Quantitative genetic study of the circulating osteopontin in community-selected families.

UNLABELLED: The study assessed contribution of genetic factors to variability of osteopontin (OPN) levels. Evidence of association of OPN levels with polymorphisms in its structural gene and integrin-binding sialoprotein gene loci was obtained. The results motivate research of OPN-related proteins and genes with respect to biomineralization and other biological processes. INTRODUCTION: OPN is a major phosphoprotein in bone, which plays key role in regulation of bone mineralization process. It is considered as a promising biomarker for osteoarthritis and osteoporosis, and various other pathological conditions. However, the contribution of genetics and other confounding factors to OPN circulating levels variation in general population has never been specifically determined. The main aims of the present study included (1) evaluation of the putative genetic and familial factors' effect on OPN variability and (2) testing the hypothesis that OPN plasma levels are associated with the genetic polymorphisms in its structural gene locus (SPP1) and in integrin-binding sialoprotein gene locus (IBSP). METHODS: To address these questions, we used a family-based sample of 925 apparently healthy Caucasian individuals. Association of OPN levels with three SNPs in each of the two selected gene loci was explored using pedigree disequilibrium tests. RESULTS: Some 58% and 13% of the OPN levels variability were attributable to genetic factors and common spouse environment, respectively. Three SNPs showed nominally significant association with OPN (p < 0.05). Of these, rs2616262 linked to IBSP promoter region remained significant after correction for multiple testing (p = 0.003). Significant association of this SNP and rs10516799 (distal segment of SPP1) with OPN was confirmed in several statistical tests. Using a special modification of variance component analysis, we examined gene-gene and gene-sex interaction effects, but found non-significant confirmation for these hypotheses. CONCLUSIONS: Further studies are required to confirm the observed results and to explore the underlying molecular and physiological mechanisms.

Morphological and biochemical features of obesity are associated with mineralization genes' polymorphisms.

BACKGROUND: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. AIM: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. SUBJECTS AND METHODS: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. RESULTS: Associations were observed between ENPP1 polymorphisms and BMI (P=0.0037) and leptin (P=0.0068). ALPL markers were associated with WHR (P=0.0026) and EGFR (P=0.0001). The ANKH gene was associated with all four studied obesity-related traits (P<0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. CONCLUSION: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

Prevalence, pattern and determinants of radiographic hand osteoarthritis in five Russian community-based samples.

OBJECTIVE: The aim of the study was to evaluate the prevalence and pattern of radiographic hand osteoarthritis (OA) and its association with age, sex, body mass index (BMI), and place of residence in five Russian community-based samples. DESIGN: Cross-sectional observational study: The study population comprised ethnic Russians [821 males and 1076 females, aged 18-90 (mean 46.2+/-15.3)], living in five different geographic areas. OA was evaluated for 14 joints of the left hand according to the Kellgren and Lawrence grading scheme. Statistical analyses included prevalence estimation, logistic and generalized model regressions, and chi(2) tests. RESULTS: We present extensive data on the prevalence of radiographic hand OA in a total Russian sample. After the age of 65, 98.5% of males and 96.8% of females had at least one affected joint. In individuals younger than 50, OA was most prevalent in the metacarpophalangeal joints, and after age 50, was most prevalent in the distal interphalangeal joints. Prevalence of hand OA was significantly higher in males than in females in ages 35-50. After adjustment for age, age(2) and place of residence, there were no associations between prevalence or severity of hand OA and BMI. CONCLUSIONS: Significant differences in prevalence and severity of hand OA were found between the Russian samples living in different geographic areas. Additional studies are needed to discover the mechanism defining the association between places of residence and development of hand OA.

Climatic factors in the development of radiographic hand osteoarthritis.

A study was undertaken to evaluate whether various ethno-territorial samples have different characteristics of radiographic hand osteoarthritis (OA) and to evaluate whether climate is associated with differences in hand OA characteristics. The total sample included 4775 individuals (2220 males and 2555 females), belonging to 12 sub-samples, including 9 ethnic groups, from 10 geographic locations in the former USSR. Ethnicity, latitude, longitude, and climatic parameters (mean temperatures, humidity, and day length of January and July) were collected for each sample. X-rays of the left hand were obtained from each individual. Prevalence of hand OA was evaluated in four age groups (36-40, 41-45, 46-50, and 51-55 years). Using maximum likelihood estimation, the following characters were determined: the mean age of persons having 1 and 5 affected joints--A(m1) and A(m5), and the mean time in which one additional joint was affected--T(m). The difference between samples was evaluated using the chi(2)-test. The associations between hand OA, and climate were evaluated using Pearson's correlations. Significant differences in OA characteristics among samples were found. Prevalence of hand OA in the age-group 46-50 showed significant association with longitude (r=0.57, p=0.05) and inter-seasonal temperature amplitude (r=0.77, p=0.0035) and significant negative association with mean temperature of January (r=-0.72, p=0.0089). Significant associations were found between longitude, the mean temperature of January, and inter-seasonal temperature amplitude and age-related hand OA parameters (A(m1) and A(m5)). The present study indicates that the differences in characteristics of radiographic hand OA among samples are most likely associated with climatic variation.

Age-related changes and secular trends in hand bone size.

The aim of the present study was to evaluate age- and sex-related changes in the size and shape of long hand bones in a large Chuvashian cohort using cross-sectional and longitudinal study designs. The data were gathered in 1994 (557 individuals) and 2002 (513 individuals). The latter sample included 260 individuals that were studied only during the second expedition, and 253 individuals who were previously investigated in 1994. Statistical analyses included a maximum likelihood-based model-fitting technique and a t-test comparison. We found evidence for secular trend of hand bone size in both males and females within the Chuvashian population. In males, the length and total area of the long hand bones were greater in younger individuals, but mid-shaft bone width remained almost the same in individuals born at different periods of the last century. In females, the length of the hand bones and total bone area remained unchanged in women born after 1937. However, bone mid-shaft width gradually decreased in women born after 1940. Therefore, we argue that, at least within the Chuvashian population, there is a secular trend towards a more gracile appendicular skeleton in both males and females.

Family-based association study of polymorphisms in the RUNX2 locus with hand bone length and hand BMD.

Osteoporosis is characterized by reduced bone strength. Bone size and bone mineral density (BMD) are major bone strength determinants. Identification of genes affecting the variability of these traits should improve prognosis and management of osteoporosis. This research was aimed to test the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in the RUNX2 locus. Four SNPs linked to the two RUNX2 promoters were genotyped in 212 nuclear Caucasian families. These SNPs and four pairwise haplotypes were tested for association with eight BL and BMD traits, adjusted for covariates. We observed significant associations between polymorphisms linked to the RUNX2 P1 promoter and BL mean values for three studied bone groups: all 18 bones, proximal and medial bones (p = 0.0118, 0.0085, and 0.0056, respectively). Mean BMD values for all 18 bones, proximal and medial bones were associated with polymorphisms linked to the RUNX2 P2 promoter (p = 0.0032, 0.0077, 0.0007, respectively). Associations with BL and BMD mean values for medial and proximal bones remained significant even after correction for multiple testing. This study provides evidence of the association between polymorphisms linked to the two RUNX2 promoters and variability of hand BL and BMD. The results suggest independent roles for the two RUNX2 promoters in the determination of the traits studied.

Epiphyseal expansion in hand bones: association with age, sex, and hand osteoarthritis.

OBJECTIVES: Previous studies showed increased femoral, neck, and tibial plateau with age in individuals with and without osteoarthritis (OA) at adjacent joints. However, the question whether epiphyseal bone enlargement is a natural phenomenon of aging or associated with OA remains open. The aim of the present study was to evaluate age- and sex-related changes in the relative size of epiphyses of long hand bones and their association with radiographic OA. DESIGN: The data were collected from a population-based European sample in 1994 (557 individuals) and in 2002 (513 individuals). The latter sample included 253 individuals who were previously investigated in 1994. The epiphyseal index (EI), reflecting the relative size of bone epiphyses and hand OA, was evaluated from hand radiographs. Statistical analyses included multiple regression analyses and a maximum likelihood-based model-fitting technique. RESULTS: Hand bone epiphyses increased with age and with OA. In males, the EI gradually increased during their entire life span. In females, the EI remained almost unchanged up to the age of 40, after which, it increased more rapidly than in males. Individuals with OA had higher values of EI at any age. In both sexes, epiphyseal enlargement is a predisposing factor for hand OA progression in adjacent joints. This was clearly seen in males, where old individuals with high EI values had much higher OA scores in comparison with age-matched individuals. CONCLUSIONS: Enlargement of long bone epiphyses with age appears to be a general tendency in the human skeleton. Our study shows that the enlargement of epiphyses may also be related to OA.

Search for hand osteoarthritis susceptibility locus on chromosome 6p12.3-p12.1.

The existence of osteoarthritis susceptibility loci on chromosome 6 for individuals suffering from hip and knee osteoarthritis has been suggested. We determined whether radiographic hand osteoarthritis in a demographically homogeneous population of European origin can be linked to loci on chromosome 6p12.3-p12.1. Nine single nucleotide polymorphisms (SNPs) were genotyped in 764 individuals (members of 189 nuclear and more complex two- or three-generation families). Radiographic hand osteoarthritis was characterized by two traits: (1) the total individual osteoarthritis score (PC1-OA) and (2) the osteophytes score (PC1-OS), obtained from the principal components analysis of sums of the Kellgren and Lawrence grade and of the osteophyte grades, respectively, for 14 joints on each hand. The contribution of genetic and environmental factors and of covariates such as age and body mass index to hand osteoarthritis was evaluated by variance components analysis. The association between the studied traits and selected DNA markers was evaluated by three types of transmission disequilibrium tests. The parent-offspring and sib-sib correlations were statistically significant for all studied traits. The additive genetic effects for PC1-OA and PC1-OS were estimated to be 43% and 37.9%, respectively. Transmission disequilibrium tests consistently revealed a statistically significant association (p values ranged from 0.017 to 0.030) between SNP rs1508632 and PC1-OS. In the tested cohort the putative genetic factors are influential enough to determine interindividual differences regarding the extent of hand osteoarthritis. SNP rs1508632 lies in immediate proximity to the TINAG gene, implicating it as a possible hand osteoarthritis susceptibility gene.

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes.

UNLABELLED: For the first time the study provides evidence of association of radiographic hand bone length (BL) and bone mineral density (BMD) with polymorphisms in ROR2 gene that plays important role in skeletal development. This contributes to better understanding of bone physiology and may have application in clinical practice. INTRODUCTION AND HYPOTHESIS: Bone size and bone mineral density (BMD) are major determinants of bone strength. Identification of genes affecting these traits' variability is important for better understanding of normal and pathological bone physiology and identification of the individuals at risk for bone fracture. This study tested the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in ROR2 gene that is important in skeletal development. METHODS: Nineteen ROR2 SNPs were genotyped in 705 individuals, belonging to 212 nuclear families. The four tagging SNPs (tSNPs) and the pairwise haplotypes between adjacent tSNPs were tested for association with series of hand BL and BMD measurements, adjusted for covariates, using family-based association tests. RESULTS: We observed significant associations with BL and BMD mean values for all 18 studied hand bones (p = 0.0080, 0.0030), mean BL and BMD for proximal phalanges (p = 0.0218, 0.0060) and metacarpal bones (p = 0.0014, 0.0004). In the latter, the association remained significant after correction for multiple testing. CONCLUSIONS: The region of the first through the second ROR2 introns is most likely to contain the functional polymorphism/s responsible for the observed associations. Further studies are required to identify the ROR2 functional polymorphism/s affecting bone size and BMD variation.

Hand bone midshaft enthesophytes: the influence of age, sex, and heritability.

OBJECTIVE: The aims of the present study were (1) to evaluate whether development of enthesophytes is an age- and/or sex-associated phenomenon; (2) to clarify whether enthesophyte development is controlled by genetics; (3) to evaluate the correlations between the enthesophytes and osteophytes of the hand joints. DESIGN: The studied cohort comprised 359 Chuvashian (Russian Federation) pedigrees (424 nuclear families) and included 786 males and 723 females aged 18-90 years. The enthesophyte score (ES) was constructed as the overall number of enthesophytes at the midshaft of the phalanges of the second to the fifth fingers of both hands. The osteophyte score (OS) was constructed similarly. We used variance component (VC) analysis to examine the age-related patterns and compare the contribution of the genetic and common environmental factors to ES and OS variations. RESULTS AND CONCLUSIONS: After age 25, ES increases with age (on average linearly). Age explains 45% of the ES variation in males but only 25% of the variation in females, in contrast to about 75% of the variation of OS in both sexes. At any age, males showed higher ES than females and the difference between sexes increased with age. Genetic components explained 20% of enthesophyte development variation. We did not find common additive genetic factors for ES and OS. The correlation coefficients between ES and OS were r=0.62 (P=0.0001) in males and r=0.50 (P=0.0001) in females. After age adjustment, the correlation decreased to r=0.087 (P=0.014) and r=0.14 (P=0.001) correspondingly. Most probably, enthesophytes and osteophytes are manifestations of different etiological processes.

Osteoprotegerin plasma levels are strongly associated with polymorphisms in human homologue of the mouse progressive ankylosis (ANKH) gene.

Osteoprotegerin inhibits osteoclastogenesis and plays an important role in the control of bone resorption. However, the genetic mechanisms underlying regulation of OPG levels are currently not fully elucidated. The aim of the present study was to determine whether the ANKH gene, which plays a central role in bone mineralization, contributes to the genetic regulation of OPG levels. A family-based association study used a sample of 159 ethnically homogeneous nuclear families, comprising 556 apparently healthy individuals. Statistical analyses included family aggregation analysis of OPG variation and four types of transmission disequilibrium tests. Each individual was genotyped for 11 SNPs in the ANKH gene. Four TDTs consistently showed a highly significant association between OPG levels and the intronic SNP rs875525 located between exons 6 and 7. The combined p-value for four tests to reject the null hypothesis of no association was 0.0003. Furthermore, haplotypes generated between rs875525 and two additional neighbouring SNPs (rs2291943 and rs2288474) also revealed a significant association with OPG plasma levels (p < 10(-4)-10(-3)). ANKH genetic polymorphisms in the area between SNP rs2291943 and rs2288474 are strongly associated with OPG plasma levels. The molecular mechanism underlying this association is not obvious, and therefore these results should be regarded cautiously until they are confirmed in independent studies.

Search for linkage between hand osteoarthritis and 11q 12-13 chromosomal segment.

OBJECTIVE: The aims of the present study were: (1) to evaluate the extent and mode of inheritance of hand osteoarthritis by using a large sample of ethnically homogeneous pedigrees of Caucasian origin; (2) to examine whether the synthetic measure of osteoarthritis according to Kellgren and Lawrence (K-L) and the more specific measure, namely, the extent of osteophytes development, have a similar putative genetic determination and pattern of biological inheritance and (3) to test the hypothesis that hand osteoarthritis dependent phenotypes are linked to the 11q 12-13 chromosomal region. METHODS: The population of the present study comprised 1190 Chuvashians (Russian Federation) belonging to 295 nuclear families. Segregation analysis was carried out on a total sample. Sub-sample of 571 individuals was used to conduct Transmission/disequilibrium test (TDT) and model-based linkage analysis. RESULTS: Adjusted for age, sex and other covariates, both OA phenotypes showed significant familial aggregation. The model fitting analysis strongly supported the hypothesis of a major gene effect on study traits. The inferred major gene explained about 52% of the osteophyte score (OPS) and 49% of the K-L score variation adjusted for confounding variables. The series of model-based linkage analyses and TDTs provided inconclusive evidence on possible linkage of both phenotypes to the 11q 12-13 chromosomal region. CONCLUSIONS: We support the hypothesis of a major gene effect in heritability of hand osteoarthritis in both phenotypes. Despite the fact that some DNA markers showed statistically significant association to studied primary phenotypes, we find only weak evidence of linkage disequilibrium between hand osteoarthritis and the proximal part of the 11q 12-13 chromosomal segment (D11S1983 for K-L score and D11S1313 for OPS). The subject, however, a merit requires further investigation.

Transmission disequilibrium test for hand bone mineral density and 11q12-13 chromosomal segment.

The main aim of the present study was to test the hypothesis that the bone mineral density (BMD) assessed from radiographs of the hand phalanges in a random sample of ethnically homogeneous pedigrees is linked to the 11q12-13 chromosomal segment. The data for the study were gathered from 574 Chuvasha individuals belonging to two- and three-generation pedigrees who live in small villages in the Bashkortostan autonomy, Russia. Preliminary statistical-genetic analysis of the BMD in the pedigrees studied showed that potential genetic effects were highly significant ( p<0.001, in comparison with the model assuming no genetic effect), and explained at least 36% of the BMD variation adjusted for sex and age differences. For the transmission/disequilibrium test (TDT) used in our study, a total of 163 nuclear families with two sibs on average were available. Seven DNA microsatellite markers ( D11S1313, D11S1765, D11S987, D11S913, D11S983, D11S1314, D11S916) with average spacing of 2 cM on the chromosomal area 11q12-13 were selected for the TDT. The nominal p values ( p<0.05-0.0015) obtained from three TDT-type tests used for random and extreme-threshold sampling designs pointed consistently to possible linkage disequilibrium between BMD and some of the DNA markers. There was evidence for possible linkage disequilibrium in the upper part of the chromosomal segment studied (markers D11S1313 and D11S1765), and also in the lower part (markers D11S1983 and D11S1314). The lowest nominal p values (0.0015-0.0067) were obtained from three TDT-type tests for marker D11S1313. However, our findings must still be treated with great caution.

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 beta(1s) in young age or a plateau (beta(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 beta(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.

Evidence on major gene control of cortical index in pedigree data from Middle Dalmatia, Croatia.

It was recently reported that the inheritance of the metacarpal cortical index (CI) in the Chuvashian population can be described in terms of a major gene (MG) model. By applying transmission probability tests, the hypothesis was accepted that not only baseline level of CI but also its sex-specific dependence on age were under control of the same putative large-effect gene. Using a pedigree sample from the population of the islands of Middle Dalmatia, Croatia (847 observed individuals in 278 pedigrees), data are presented to support the above findings. The following hypotheses were accepted: (i) inheritance of baseline CI in the Croatian population can be attributed to the effect of a MG responsible for about 42% of the variation; (ii) the same MG takes part in the control of the dependence of CI on age, particularly the age at onset of involutive bone changes (inflection point), and of the rate of decrease in CI with age (slope coefficient). Issues related to the assortative mating effect on CI and the determination of the most parsimonious model are discussed.