Axial quantitative ultrasound assessment of pediatric bone quality in eastern Nepal.

UNLABELLED: This study presents quantitative ultrasonography (QUS) bone quality data for an underrepresented, south Asian pediatric population from Nepal. Data were collected as part of a longitudinal study of growth and development. This study offers normative data and documents the effect of stunting, wasting, and underweight on the bone properties measured by QUS. INTRODUCTION: The purpose of this study was to (1) examine the bone quality of a rural, non-Western pediatric population using QUS, (2) explore variation in the trajectory of bone quality development between males and females, and (3) examine the impact of growth disruption(s) on bone quality. METHODS: A cross-sectional study of 860 children and adolescents aged 5-18 years from the Jirel ethnic group in eastern Nepal was performed. The Sunlight Omnisense 7000P was used to assess bone quality of the distal 1/3 radius and midshaft tibia. WHO reference standards were used to assess growth disruptions of height, weight, and BMI. RESULTS: QUS bone quality data for an underrepresented, non-Western pediatric population are presented for the radius and tibia. A sizable portion of the study participants were classified as stunted, wasted, and/or underweight. Despite this prevalence of growth disruption in the study sample, bone quality data conform to other documented populations with less growth disruption. Thus, this study offers normative data and documents the minimal effect of stunting, wasting, and underweight on the bone properties measured by QUS. CONCLUSIONS: Non-Western pediatric populations are significantly underserved with regard to simple, non-invasive screening tools that may help identify developmental disorders and assess bone health. The children and adolescents examined here represent normal growth and development for an underrepresented south Asian population. While this work demonstrates that stunting, wasting, or underweight status at time of QUS assessment is not associated with poor bone quality, we do suggest that further study is needed to examine possible cumulative effects of persistent disruptions that may lead to compromised bone quality in later adolescence.

Characterization of complex, co-adapted skeletal biomechanics phenotypes: a needed paradigm shift in the genetics of bone structure and function.

The genetic architecture of skeletal biomechanical performance has tremendous potential to advance our knowledge of the biological mechanisms that drive variation in skeletal fragility and osteoporosis risk. Research using traditional approaches that focus on specific gene pathways is increasing our understanding of how and to what degree those pathways may affect population-level variation in fracture susceptibility, and shows that known pathways may affect bone fragility through unsuspected mechanisms. Non-traditional approaches that incorporate a new appreciation for the degree to which bone traits co-adapt to functional loading environments, using a wide variety of redundant compensatory mechanisms to meet both physiological and mechanical demands, represent a radical departure from the dominant reductionist paradigm and have the potential to rapidly advance our understanding of bone fragility and identification of new targets for therapeutic intervention.

Waist circumference is genetically correlated with incident Type 2 diabetes in Mexican-American families.

AIMS: We aimed to determine the genetic and environmental correlation between various anthropometric indexes and incident Type 2 diabetes with a focus on waist circumference. METHODS: We used the data on extended Mexican-American families (808 subjects, 7617.92 person-years follow-up) from the San Antonio Family Heart Study and estimated the genetic and environmental correlations of 16 anthropometric indexes with the genetic liability of incident Type 2 diabetes. We performed bivariate trait analyses using the solar software package. RESULTS: All 16 anthropometric indexes were significantly heritable (range of heritabilities 0.24-0.99). Thirteen indexes were found to have significant environmental correlation with the liability of incident Type 2 diabetes. In contrast, only anthropometric indexes consisting of waist circumference (waist circumference, waist-hip ratio and waist-height ratio) were significantly genetically correlated (genetic correlation coefficients: 0.45, 0.55 and 0.44, respectively) with the liability of incident Type 2 diabetes. We did not observe such a correlation for BMI. CONCLUSIONS: Waist circumference as a predictor of future Type 2 diabetes is supported by the finding that they share common genetic influences.

Intracortical bone remodeling variation shows strong genetic effects.

Intracortical microstructure influences crack propagation and arrest within bone cortex. Genetic variation in intracortical remodeling may contribute to mechanical integrity and, therefore, fracture risk. Our aim was to determine the degree to which normal population-level variation in intracortical microstructure is due to genetic variation. We examined right femurs from 101 baboons (74 females, 27 males; aged 7-33 years) from a single, extended pedigree to determine osteon number, osteon area (On.Ar), haversian canal area, osteon population density, percent osteonal bone (%On.B), wall thickness (W.Th), and cortical porosity (Ct.Po). Through evaluation of the covariance in intracortical properties between pairs of relatives, we quantified the contribution of additive genetic effects (heritability [h (2)]) to variation in these traits using a variance decomposition approach. Significant age and sex effects account for 9 % (Ct.Po) to 21 % (W.Th) of intracortical microstructural variation. After accounting for age and sex, significant genetic effects are evident for On.Ar (h (2) = 0.79, p = 0.002), %On.B (h (2) = 0.82, p = 0.003), and W.Th (h (2) = 0.61, p = 0.013), indicating that 61-82 % of the residual variation (after accounting for age and sex effects) is due to additive genetic effects. This corresponds to 48-75 % of the total phenotypic variance. Our results demonstrate that normal, population-level variation in cortical microstructure is significantly influenced by genes. As a critical mediator of crack behavior in bone cortex, intracortical microstructural variation provides another mechanism through which genetic variation may affect fracture risk.

Genetical genomics of Th1 and Th2 immune response in a baboon model of atherosclerosis risk factors.

OBJECTIVE: CD4(+) T-cells mediate inflammation in atherosclerosis, but additive genetic effects on associated pathways of Th1 and Th2 immune response have not been described. We sought to characterize heritability, pleiotropy, and QTL effects on the expression of genes implicated in Th1 and Th2 immune response in a baboon model of risk factors for atherosclerosis. METHODS: We employed a maximum likelihood-based variance decomposition approach to estimate additive genetic effects on transcript levels generated from a gene expression profile of lymphocytes in 499 pedigreed baboons maintained on a basal diet. Transcript levels for 57 genes implicated in Th1 and Th2 immune response were selected for analysis based on significant heritability in this profile. Multipoint whole genome scans were conducted on heritable transcript levels to localize QTLs influencing these measures. To evaluate pleiotropic effects on transcript levels, we estimated genetic and phenotypic correlations among transcript measures, and assessed their correspondence using a Mantel test. Network analysis using GeneGo's MetaCore™ software was conducted to characterize known interaction among coded proteins. RESULTS: Heritabilities for candidate gene transcript levels ranged from 0.092-0.786 (median h(2)=0.278, P=4.72×10(-4)). Linkage analyses yielded significant evidence (LOD≥2.73) for 14 eQTLs (LOD score range 2.76-14.87, genome-wide P=4.9×10(-2)-1.03×10(-14)). Estimates of genetic correlation supported shared additive genetic effects incorporating all 57 transcripts (null hypothesis of ρ(G)=0 rejected at FDR≤0.05 for 522 of 1596 estimates), and accounted for most of the observed phenotypic correlation among transcripts (Mantel test, r([ρP],)([ρG])=0.781, P<0.0001). Network analysis revealed direct interactions among 54 of the 57 coded proteins. CONCLUSIONS: We conclude that major genetic effects influence expression levels of multiple genes implicated in Th1 and Th2 immune response. Additionally, we find that expression levels of these candidate genes are characterized by extensive pleiotropy, consistent with known interaction among their coded proteins, many of which are independently associated with atherosclerosis.

A quantitative trait locus on chromosome 5p influences d-dimer levels in the san antonio family heart study.

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

Heritability of lumbar trabecular bone mechanical properties in baboons.

Genetic effects on mechanical properties have been demonstrated in rodents, but not confirmed in primates. Our aim was to quantify the proportion of variation in vertebral trabecular bone mechanical properties that is due to the effects of genes. L3 vertebrae were collected from 110 females and 46 male baboons (6-32 years old) from a single extended pedigree. Cranio-caudally oriented trabecular bone cores were scanned with microCT then tested in monotonic compression to determine apparent ultimate stress, modulus, and toughness. Age and sex effects and heritability (h(2)) were assessed using maximum likelihood-based variance components methods. Additive effects of genes on residual trait variance were significant for ultimate stress (h(2)=0.58), toughness (h(2)=0.64), and BV/TV (h(2)=0.55). When BV/TV was accounted for, the residual variance in ultimate stress accounted for by the additive effects of genes was no longer significant. Toughness, however, showed evidence of a non-BV/TV-related genetic effect. Overall, maximum stress and modulus show strong genetic effects that are nearly entirely due to bone volume. Toughness shows strong genetic effects related to bone volume and shows additional genetic effects (accounting for 10% of the total trait variance) that are independent of bone volume. These results support continued use of bone volume as a focal trait to identify genes related to skeletal fragility, but also show that other focal traits related to toughness and variation in the organic component of bone matrix will enhance our ability to find additional genes that are particularly relevant to fatigue-related fractures.

Determinants of variation in human serum paraoxonase activity.

Paraoxonase-1 (PON1) is associated with high-density lipoprotein (HDL) particles and is believed to contribute to antiatherogenic properties of HDLs. We assessed the determinants of PON1 activity variation using different substrates of the enzyme. PON1 activity in serum samples from 922 participants in the San Antonio Family Heart Study was assayed using a reliable microplate format with three substrates: paraoxon, phenyl acetate and the lactone dihydrocoumarin. There were major differences among results from the three substrates in degree of effect by various environmental and genetic factors, suggesting that knowledge of one substrate activity alone may not provide a complete sense of PON1 metabolism. Three significant demographic covariates (age, smoking status and contraceptive usage) together explained 1-6% of phenotypic variance, whereas four metabolic covariates representing lipoprotein metabolism (apoAII, apoAI, triglycerides and non-HDL cholesterol) explained 4-19%. Genes explained 65-92% of phenotypic variance and the dominant genetic effect was exerted by a locus mapping at or near the protein structural locus (PON1) on chromosome 7. Additional genes influencing PON1 activity were localized to chromosomes 3 and 14. Our study identified environmental and genetic determinants of PON1 activity that accounted for 88-97% of total phenotypic variance, suggesting that few, if any, major biological determinants are unrepresented in the models.

Osteopenia and osteoporosis in adult baboons (Papio hamadryas).

BACKGROUND: Little is known about the degree to which baboons, an important animal model in skeletal research, spontaneously experience age-related osteopenia and osteoporosis. METHODS: We measured bone mineral density (BMD) in 667 baboons, assigned T-scores to older animals based on sex-specific young adult reference groups, and compared reproductive history in older females with low BMD to those with normal BMD. RESULTS: Approximately 25% of older baboon females were osteopenic. No females or males were osteoporotic. Neither parity nor interbirth interval spine clearly distinguished low vs. normal BMD groups. Intersite correspondence in low BMD was highest between sites in the same region rather than sites of the same bone type. CONCLUSION: As with humans, osteopenia is common among older females. The absence of osteoporotic animals may be due to colony maintenance resulting in truncation of the aged population and selection for healthier animals in the oldest ranges.

Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon.

Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.

Genetics of variation in adiponectin in pedigreed baboons: evidence for pleiotropic effects on adipocyte volume and serum adiponectin.

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h2=0.19+/-0.07, P=0.01) and protein levels (h2=0.28+/-0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (rho(G)=-0.51, P=0.03), cell volume (rho(G)=-0.73, P=0.04), serum triglycerides (rho(G)=-0.67, P=0.03), and between adiponectin mRNA and glucose (rho(G)=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.

A pleiotropic QTL on 2p influences serum Lp-PLA2 activity and LDL cholesterol concentration in a baboon model for the genetics of atherosclerosis risk factors.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), the major portion of which is bound to low-density lipoprotein, is an independent biomarker of cardiovascular disease risk. To search for common genetic determinants of variation in both Lp-PLA(2) activity and LDL cholesterol (LDL-C) concentration, we assayed these substances in serum from 679 pedigreed baboons. Using a maximum likelihood-based variance components approach, we detected significant evidence for a QTL affecting Lp-PLA(2) activity (LOD=2.79, genome-wide P=0.039) and suggestive evidence for a QTL affecting LDL-C levels (LOD=2.16) at the same location on the baboon ortholog of human chromosome 2p. Because we also found a significant genetic correlation between the two traits (rho(G)=0.50, P<0.00001), we conducted bivariate linkage analyses of Lp-PLA(2) activity and LDL-C concentration. These bivariate analyses improved the evidence (LOD=3.19, genome-wide P=0.015) for a QTL at the same location on 2p, corresponding to the human cytogenetic region 2p24.3-p23.2. The QTL-specific correlation between the traits (rho(Q)=0.62) was significantly different from both zero and 1 (P[rho(Q)=0]=0.047; P[rho(Q)=1]=0.022), rejecting the hypothesis of co-incident linkage and consistent with incomplete pleiotropy at this locus. We conclude that polymorphisms at the QTL described in this study exert some genetic effects that are shared between Lp-PLA(2) activity and LDL-C concentration.

Bivariate linkage study of proximal hip geometry and body size indices: the Framingham study.

Femoral geometry and body size are both characterized by substantial heritability. The purpose of this study was to discern whether hip geometry and body size (height and body mass index, BMI) share quantitative trait loci (QTL). Dual-energy X-ray absorptiometric scans of the proximal femur from 1,473 members in 323 pedigrees (ages 31-96 years) from the Framingham Osteoporosis Study were studied. We measured femoral neck length, neck-shaft angle, subperiosteal width (outer diameter), cross-sectional bone area, and section modulus, at the narrowest section of the femoral neck (NN), intertrochanteric (IT), and femoral shaft (S) regions. In variance component analyses, genetic correlations (rho ( G )) between hip geometry traits and height ranged 0.30-0.59 and between hip geometry and BMI ranged 0.11-0.47. In a genomewide linkage scan with 636 markers, we obtained nominally suggestive linkages (bivariate LOD scores > or =1.9) for geometric traits and either height or BMI at several chromosomes (4, 6, 9, 15, and 21). Two loci, on chr. 2 (80 cM, BMI/shaft section modulus) and chr. X (height/shaft outer diameter), yielded bivariate LOD scores > or =3.0; although these loci were linked in univariate analyses with a geometric trait, neither was linked with either height or BMI. In conclusion, substantial genetic correlations were found between the femoral geometric traits, height and BMI. Linkage signals from bivariate linkage analyses of bone geometric indices and body size were similar to those obtained in univariate linkage analyses of femoral geometric traits, suggesting that most of the detected QTL primarily influence geometry of the hip.

Quantitative trait locus on chromosome 12q14.1 influences variation in plasma plasminogen levels in the San Antonio Family Heart Study.

Plasminogen is a hemostasis-related phenotype and is commonly implicated in thrombotic and bleeding disorders. In the San Antonio Family Heart Study (SAFHS), we performed to our knowledge the first genomewide linkage scan for quantitative trait loci (QTLs) that influence the level of plasminogen. The subset of the SAFHS population used for this study consists of 629 individuals distributed across 26 extended Mexican American families. Pedigree-based variance component linkage analyses were performed using SOLAR. The mean plasminogen level was 114.94% +/- 17.8 (range, 42-195). The heritability (h2) of plasminogen was 0.43 +/- 0.08 (p < 6.3 x 10(-13)). One region on chromosome 12 (12q14.1) showed suggestive evidence of linkage (LOD = 2.73, nominal p < 0.0002, genomewide p = 0.0786) near marker D12S1609. Because plasminogen has important effects in many human health problems, such as cancer and atherosclerosis, the role of this putative QTL in the regulation of plasminogen variability needs to be studied further.

Bone ALP and OC reference standards in adult baboons (Papio hamadryas) by sex and age.

BACKGROUND: Serum bone-specific alkaline phosphatase (bone ALP) and intact osteocalcin (OC) are markers of bone formation of interest because of easy measurability and potential utility as identifiers of those at risk for fractures associated with bone metabolism disorders. The baboon (Papio hamadryas) exhibits extensive biological similarities to humans making it particularly well suited to studies of bone maintenance and turnover. METHODS: We measured serum bone ALP and OC in 591 baboons. RESULTS: We report significant sex and age effects and present reference ranges and percentile distributions for these markers. CONCLUSIONS: This study is the first to characterize normal variation in bone ALP and OC levels in baboons and to assess the age and sex effects on this variation. The results provide much-needed reference standards to allow researchers to evaluate the status of their animals in cross-sectional studies and assess the meaning of changes in bone ALP and OC levels in longitudinal studies.

Cross-species replication of a serum osteocalcin quantitative trait locus on human chromosome 16q in pedigreed baboons.

Osteocalcin (OC), a serum marker of bone formation, in its intact form reflects osteoblast activity. It is of interest to clinicians and bone biologists due to easy measurability and potential utility as an identifier of those at risk for fracture and other complications associated with bone metabolism disorders. The only published linkage study in humans shows significant evidence for a quantitative trait locus (QTL) affecting OC levels on 16q. We used the baboon, a primate model for skeletal maintenance and turnover, to detect and quantify the effects of genes on serum OC levels and to localize chromosomal regions harboring the responsible loci. We assayed OC levels in 591 pedigreed animals, assessed OC heritability, and conducted a genomewide linkage scan for evidence of QTLs affecting this phenotype. Heritability in these baboons is 0.24. Suggestive linkage is evident with markers in a region homologous to human chromosome 16q. This first genomewide linkage scan in a nonhuman primate for QTLs affecting bone formation as reflected by OC levels provides cross-species replication of the QTL on chromosome 16q previously localized in humans. Given the concordance of results of the only two genome scans for this trait in two primate species, further studies of this region are warranted.

A quantitative trait locus for normal variation in forearm bone mineral density in pedigreed baboons maps to the ortholog of human chromosome 11q.

Baboons share many anatomical, physiological, and developmental characteristics with humans that make them excellent models for human bone maintenance and turnover. We conducted statistical genetic analyses, including a whole-genome linkage screen, of dual-energy x-ray absorptiometry-acquired measures of areal bone mineral density (aBMD), currently the most reliable single predictor of susceptibility to osteoporotic fracture in humans, from three forearm sites on the radius and ulna of 667 pedigreed baboons. We used a maximum likelihood-based variance decomposition approach to detect and quantify the effects of genes on normal variation in aBMD in the forearm of these baboons and to localize these effects to chromosomal regions. We estimated significant heritability for aBMD at all three sites and found evidence for a quantitative trait locus (QTL) contributing significantly to the genetic effects on this trait in a region of the baboon genome homologous to human chromosome 11q12-13. This first reported genome-wide linkage screen in a nonhuman primate for QTLs affecting forearm aBMD provides important cross-species replication of a QTL found in humans. The concordance of our results in a nonhuman primate with those reported for humans provides strong evidence that a gene (or genes) in this region affects normal variation in BMD.

Genome-wide scan of resistin mRNA expression in omental adipose tissue of baboons.

INTRODUCTION: The hormone resistin was recently discovered in adipose tissue of mice. Functional tests suggest a role for resistin in the regulation of insulin sensitivity. However, human studies have reported controversial results on the metabolic function of this hormone. METHODS: A 1 g omental adipose tissue biopsy was obtained from 404 adult baboons. Resistin mRNA expression was assayed by real-time, quantitative RT-PCR, and univariate and bivariate quantitative genetic analyses were performed, via the variance decomposition approach. A genome scan analysis was conducted using resistin mRNA abundance in omental adipose tissue as a quantitative phenotype. RESULTS: A significant heritability of h2 = 0.23 (P = 0.003) was found for resistin mRNA abundance in omental adipose tissue. A genome scan detected a quantitative trait locus for resistin expression with an LOD score of 3.8, in the region between markers D19S431 and D19S714, corresponding to human chromosome 19 p13. This chromosomal region contains genes related to insulin resistance phenotypes, such as resistin, insulin receptor, angiopoietin-like 4 protein and LDL receptor. CONCLUSIONS: Individual variation in resistin mRNA expression has a significant genetic component, and a gene or genes on chromosome 19 p13 may regulate resistin mRNA levels in baboon omental adipose tissue.

White monkey syndrome in infant baboons (Papio species).

Over 23 months, zinc toxicosis was diagnosed in 35 baboons aged 5-12 months in one galvanized metal and concrete cage complex with conditions that led to excessive exposure to environmental zinc. Clinical signs included reduced pigmentation of hair, skin, and mucous membranes (whiteness), alopecia, dehydration, emaciation, cachexia, dermatitis, diarrhea and, in six cases, severe gangrenous dermatitis of extremities. The syndrome was characterized by pancytopenia, elevated zinc and low copper serum concentrations, low vitamin D and bone-specific alkaline phosphatase levels, and atypical myelomonocytic proliferation of bone marrow. This syndrome emphasizes the importance of proper husbandry and cage design and indicates the potential of infant baboons as a model to study the effects of excessive zinc on development. This is the first report describing the epidemiologic and clinical presentation of zinc toxicosis in infant baboons in captivity.

Genotype-by-sex and environment-by-sex interactions influence variation in serum levels of bone-specific alkaline phosphatase in adult baboons (Papio hamadryas).

While more than 77% of the people in the US with osteoporosis are women, the contributions of genotype-by-sex (G x S) and environment-by-sex interactions to sex differences in osteoporosis risk factors have not been studied. To address this issue, we conducted a statistical genetic analysis of serum concentrations of bone-specific alkaline phosphatase (Bone ALP), a highly specific marker of osteoblast function that is elevated in persons with conditions like osteoporosis characterized by excessive bone turnover or rapid bone loss. We assayed Bone ALP from 657 pedigreed baboons using a commercially available ELISA kit. Using a maximum likelihood variance decomposition approach, we treated sex as an environmental milieu in which genes influencing Bone ALP levels are expressed. We modeled the genetic covariance in Bone ALP between all relative pairs conditional on their sex so that the covariance is the product of the kinship, the genetic correlation between trait levels in the two sexes, and the genetic variances in the two sexes. Sex-specific maximum likelihood estimates (MLE) of residual heritability for Bone ALP were greater for females than for males (h2 = 0.44 vs. h2 = 0.26, respectively), but likelihood ratio tests revealed only a marginally significant difference in sex-specific genetic variances (P = 0.057). In contrast, the between-sex genetic correlation (rhoG = 0.43) was significantly less than 1.0 (P = 0.037), and the difference in sex-specific environmental variances was highly significant (P = 0.00006). We report the first evidence for G x S interactions influencing variation in an osteoporosis risk factor. The diminished between-sex genetic correlation implies that different genes influence Bone ALP levels in the two sexes. The significant differences between environmental variances suggest that unmeasured factors, including those from the internal, biological environments of the two sexes, account for a greater proportion of the Bone ALP variation in males.