Assessing the genetic correlations between early growth parameters and bone mineral density: A polygenic risk score analysis.
ABSTRACT: OBJECTIVE:The relationships between early growth parameters and bone mineral density (BMD) remain elusive now. In this study, we performed a large scale polygenic risk score (PRS) analysis to evaluate the potential impact of early growth parameters on the variations of BMD. METHODS:We used 2286 Caucasian subjects as cohort 1 and 3404 Framingham Heart Study (FHS) subjects as cohort 2 in this study. BMD at ulna & radius, hip and spine were measured using dual energy X-ray absorptiometry. BMD values were adjusted for age, sex, height and weight as covariates. Genome-wide single-nucleotide polymorphism (SNP) genotyping of the 2286 Caucasian subjects was performed using Affymetrix Human SNP Array 6.0. The GWAS datasets of early growth parameters were driven from the Early Growth Genetics Consortium, including birth weight (BW), birth head circumference (BHC), childhood body mass index (CBMI), pubertal height growth related indexes and tanner stage. Polygenic Risk Score (PRSice) and linkage disequilibrium (LD) score regression analysis were conducted to assess the genetic correlation between early growth parameters and BMD. RESULTS:We detected significant genetic correlations in cohort 1, such as total spine BMD vs. CBMI (p value?=?1.51?×?10-4, rg?=?0.4525), right ulna and radius BMD vs. CBMI (p value?=?1.51?×?10-4, rg?=?0.4399) and total body BMD vs. tanner stage (p value?=?7.00?×?10-4, rg?=?-0.0721). For cohort 2, significant correlations were observed for total spine BMD vs. height change standard deviation score (SDS) between 8?years and adult (denoted as PGF?+?PGM) (p value?=?3.97?×?10-4, rg?=?-0.1425), femoral neck BMD vs. the timing of peak height velocity by looking at the height change SDS between age 14?years and adult (denoted as PTF?+?PTM) (p value?=?7.04?×?10-4, rg?=?-0.2185), and total spine BMD vs. PTF?+?PTM (p value?=?6.86?×?10-4, rg?=?-0.2180). CONCLUSION:Our study results suggest that some early growth parameters could affect the variations of BMD.
Project description:BACKGROUNDS:To explore the genetic correlation between schizophrenia (SCZ) and osteoporosis (OP). DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS:We conducted a trans-ethnic two-stage genetic correlation analysis of OP and SCZ, totally invoking 2286 Caucasia subjects in discovery stage and 4124 Chinese subjects in replication stage. The bone mineral density (BMD) and bone area values of ulna & radius, hip and spine were measured using Hologic 4500W dual energy X-ray absorptiometry machine. SCZ was diagnosed according to DSM-IV criteria. For the genome-wide association study (GWAS) of Caucasian OP, Chinese OP and Chinese SCZ, SNP genotyping was performed using Affymetrix SNP 6.0 array. For the GWAS of Caucasian SCZ, SNP genotyping was conducted using the Affymetrix 5.0 array, Affymetrix 6.0 array and Illumina 550 K array. Polygenetic risk scoring (PRS) analysis was conducted by PRSice software. Also, Linkage disequilibrium score regression (LD Score regression) analysis was performed to evaluate the genetic correlation between OP and SCZ. Multi-trait analysis of GWAS (MTAG) was performed to detect novel candidate genes for osteoporosis and SCZ. RESULTS:In the Caucasia discovery samples, significant genetic correlations were observed for ulna & radius BMD vs. SCZ (P value?=?0.010), ulna & radius area vs. SCZ (P value?=?0.031). In the Chinese replication samples, we observed significant correlation for ulna & radius area vs. SCZ (P value?=?0.019). In addition, LD Score regression also identified significant genetic correlations between SCZ and bone phenotypes in Caucasian and Chinese sample respectively. MTAG analysis identified several novel candidate genes, such as CTNNA2 (MTAG P value?=?2.24?×?10-6) for SCZ and FADS2 (MTAG P value?=?2.66?×?10-7) for osteoporosis. CONCLUSIONS:Our study results support the overlapped genetic basis for osteoporosis and SCZ, and provide novel clues for elucidating the biological mechanism of increased osteoporosis risk in SCZ patients.
Project description:Mitochondrial DNA (mtDNA) variants are involved in the pathogenesis of human complex diseases, especially for age-related disorders, including osteoporosis. However, the role of mtDNA variants in osteoporosis is largely unknown. In this study, we performed a mitochondria-wide association study for osteoporosis in a large sample of 2286 unrelated Caucasian subjects. A total of 445 mtSNPs were genotyped and 72 mtSNPs survived the quality control. We first examined association between mtSNPs and bone mineral density (BMD), and identified that an mtSNP, mt4823 within the ND2 gene, was strongly associated with hip BMD (P= 2.05 × 10(-4)), even after Bonferroni correction. The C allele of mt4823 was associated with reduced hip BMD and the effect size (?) was ?0.044. Another SNP mt15885 within the MT-CYB gene was associated both with spine (P= 1.66 × 10(-3)) and hip BMD (P= 0.023). The T allele of mt15885 had a protective effect on spine (?= 0.064) and hip BMD (?= 0.038). Next, we classified subjects into the nine common European haplogroups and conducted association analyses. Subjects classified as haplogroup X had significantly lower hip BMD values than others (P= 0.040). Our results highlighted the importance of mtDNA variants in osteoporosis.
Project description:Purpose:The current analysis evaluates cumulative benefits after year two (Y2) of a school-based resistance training intervention. Methods:Adolescent girls were enrolled and measured at the beginning of 6th grade (baseline, BL) and again at 1st follow-up (FU1: Y1 end) and 2nd follow-up (FU2: Y2 end). School gym classes met alternate school days. Site 1 had standard gym classes (CON). Site 2 gym classes included 8-12 minutes of resistance training (INT); INT girls were categorized based on observed participation effort and time (LO, HI). Measurements included: 1) height and weight; 2) questionnaires to assess extracurricular exercise and diet (calcium, vitamin D); 3) dual-energy X-ray absorptiometry (DXA, Lunar Prodigy). Whole body less head (SUB) scans yielded bone mineral content (BMC) and body composition. Lumbar spine (L1-L4) and femoral neck (FN) scans yielded BMC and areal bone mineral density (BMD); radius scans yielded ultradistal and 1/3 BMD. ANCOVA compared group means for percent gains from BL to FU2, accounting for biological maturity, BL height, height change, inter-scan interval, organized activity, calcium and vitamin D. Results:In 62 girls (21 CON, 41 INT), intention to treat analyses detected INT vs. CON advantages for L1-L4 BMC and BMD (4.1%, 5.6%: p<0.05). HI effort participants (n=19) demonstrated advantages for BMC and BMD at L1-L4 and FN (5.7% to 8.2%, p<0.01) vs. CON. Conclusions:Over two school years, this resistance intervention yielded lumbar spine advantages; enthusiastic participation (HI) yielded lumbar spine and femoral neck advantages. Further work is warranted to evaluate benefit persistence after intervention cessation.
Project description:<h4>Background/aims</h4>Untreated girls with Turner syndrome (TS) have growth failure, and adult height is, on average, 20 cm less than predicted height. Treatment with growth hormone (GH) is now standard of care. The objective of this study was to investigate the benefit of adding oxandrolone (Ox) to GH in a long-term, randomized, placebo (Pl)-controlled prospective trial to near adult height in TS.<h4>Methods</h4>prospective, randomized, Pl-controlled study: 76 girls with TS (ages 10-14.9 years) were randomized to receive Ox (0.06 mg/kg/day) or Pl in combination with GH (0.35 mg/kg/week, daily) over 2 years. Auxologic data, breast and pubic hair Tanner stages, and hormone and lipid levels were measured. Subjects who chose to continue were followed in a 2-year double-blind extension, also received estrogen therapy (years 3, 4), and had dual-energy X-ray absorptiometry evaluation of bone density (years 3, 4).<h4>Results</h4>at year 4, the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [26.2 ± 6.7 vs. 22.2 ± 5.1 cm, analysis of covariance (ANCOVA) p < 0.001; 1.8 ± 0.9 vs. 1.2 ± 0.7 standard deviation scores, ANCOVA p < 0.001]. Bone mineral density (BMD) of the wrist (0.51 ± 0.17 vs. 0.54 ± 0.05 g/cm(2)) and spine (0.91 ± 0.34 vs. 0.96 ± 0.13 g/cm(2)) in the GH/Ox versus GH/Pl groups was similar after 4 years. Breast development was slower in the GH/Ox versus GH/Pl group [year 4: Tanner stage 2.9 ± 1.3 (Ox) vs. 4.1 ± 1.3 (Pl), p = 0.003], and menarche was approximately 1 year later.<h4>Conclusions</h4>the addition of Ox to GH at mean age 12.0 ± 1.7 year augmented height gain after 4 years of treatment, slowed breast development and did not affect BMD in girls with TS. Whether initiation of Ox prior to initiation of pubertal development would optimize height gain without impeding breast development will require further study.
Project description:Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
Project description:To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) DESIGN: Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) SETTING: Outpatient clinics in the United States, Australia, and Spain.Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy.Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT).Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated.The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores -0.5 total hip, -0.7 spine DXA, -0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6-2.3; P = 0.002], 1.3% (spine DXA; 95% CI 0.1-2.4, P = 0.03), and 3.0% (spine qCT; 95% CI 0.8-5.2, P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1-22.5; P = 0.04).Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.
Project description:BACKGROUND: A Moroccan model for the FRAX tool to determine the absolute risk of osteoporotic fracture at 10 years has been established recently. The study aimed to assess the discriminative capacity of FRAX in identifying women with prevalent asymptomatic vertebral fractures (VFs). METHODS: We enrolled in this cross-sectional study 908 post-menopausal women with a mean age of 60.9 years ± 7.7 (50 to 91) with no prior known diagnosis of osteoporosis. Subjects were recruited from asymptomatic women selected from the general population. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genantsemiquantitative (SQ) approach and morphometry. We calculated the absolute risk of major fracture and hip fracture with and without bone mineral density (BMD)using the FRAX website.The overall discriminative value of the different risk scores was assessed by calculating the areas under the ROC curve (AUC). RESULTS: VFA images showed that 179 of the participants (19.7%) had at least one grade 2/3 VF. The group of women with VFs had a statistically significant higher FRAX scores for major and hip fractures with and without BMD, and lower weight, height, and lumbar spine and hip BMD and T-scores than those without a VFA-identified VF. The AUC ROC of FRAX for major fracture without BMD was 0.757 (CI 95%; 0.718-0.797) and 0.736 (CI 95%; 0.695-0.777) with BMD, being 0.756 (CI 95%; 0.716-0.796) and 0.747 (CI 95%; 0.709-0.785), respectively for FRAX hip fracture without and with BMD. The AUC ROC of lumbar spine T-score and femoral neck T-score were 0.660 (CI 95%; 0.611-0.708) and 0.707 (CI 95%; 0.664-0.751) respectively. CONCLUSION: In asymptomatic post-menopausal women, the FRAX risk for major fracture without BMD had a better discriminative capacity in identifying the women with prevalent VFs than lumbar spine and femoral neck T-scores suggesting its usefulness in identifying women in whom VFA could be indicated.
Project description:To assess factors associated with bone mineral density (BMD) in postmenopausal women in a longitudinal study, and to examine the relative contribution of lean mass, fat mass, dietary patterns, and years since menopause to BMD.Two hundred and eighty-two postmenopausal women were randomly selected from Hongqi Community Health Center, in Harbin City, China. All participants were followed up from 2009 to 2011. Dietary data were collected using a Food Frequency Questionnaire. BMD of the left hip, the lumbar spine, and the total body, and the body composition were measured by dual-energy X-ray absorptiometry at baseline and follow-up.Lean mass and fat mass were positively associated with BMD of the spine, hip, and the total body at both baseline and follow-up. The association between fat mass and BMD at the spine at baseline (P = 0.210) and at the spine (P = 0.116) and hip (P = 0.073) in the second year was not statistically significant when height was adjusted. Six dietary patterns were identified but only cereal grains-fruits pattern (P = 0.001 in the spine, P = 0.037 in hip) and milk-root vegetables pattern (P = 0.010 in hip) were associated with BMD of the spine and hip. The linear mixed model of follow-up data showed that lean mass, years since menopause, and age of menophania were the significant determinants of BMD of all sites. Moreover, lean mass was the best determinant of BMD (VIP = 1.936).Lean mass, years since menopause, age of menophania and dietary patterns are the important determinants of BMD of the spine, hip, and the total body. Lean mass is the best determinant of BMD.
Project description:This study examined the association between bone mineral density (BMD) and the rs7975232 (ApaI) polymorphism of the vitamin receptor D (VDR) gene. The polymorphism was detected using the real-time PCR TaqMan method. The rs7975232 genotype was determined in 274 postmenopausal osteoporotic Spanish women who were 60.53±8.02 years old. The observed genotype frequencies were in agreement with Hardy-Weinberg equilibrium (?(2)=1.85, P=0.1736). There were no significant differences in the rs7975232 genotype groups in our total sample of osteoporotic women regarding age, years since menopause, height, weight, and BMD at femoral neck, femoral trochanter and lumbar spine. Significant differences were found in menarche age (aa vs Aa; P=0.008) and BMI (aa vs AA; P=0.029). We conclude that the VDR gene rs7975232 polymorphism is not related to figures of bone mineral density in postmenopausal osteoporotic Spanish women.
Project description:Low bone mineral density (BMD) is a risk factor for osteoporosis. Osteoporosis is more prevalent in females than in males. So far, the pathophysiological mechanisms underlying osteoporosis are unclear. Peripheral blood monocytes (PBMs) are precursors of bone-resorbing osteoclasts. This study aims to identify PBM-expressed proteins (genes) influencing hip BMD in humans. We utilized three independent study cohorts (N=34, 29, 40), including premenopausal Caucasians with discordant hip BMD. We studied PBM proteome-wide protein expression profiles in cohort 1 and identified 57 differentially expressed proteins (DEPs) between low vs. high BMD subjects. One protein gelsolin (GSN), after validation by Western blotting, was subject to follow-up. We compared GSN mRNA level in PBM between low vs. high BMD subjects in cohorts 2 and 3. We genotyped SNPs across GSN in 2286 unrelated Caucasians (cohort 4) and 1627 Chinese (cohort 5) and tested their association with hip BMD in females and males, respectively. We discovered and validated that GSN protein expression level in PBM was down-regulated 3.0-fold in low vs. high BMD subjects (P<0.05). Down-regulation of GSN in PBM in low BMD subjects was also observed at mRNA level in both cohort 2 and cohort 3. We identified that SNP rs767770 was significantly associated with hip BMD in female Caucasians (P=0.0003) only. Integrating analyses of the datasets at DNA, RNA, and protein levels from female Caucasians substantiated that GSN is highly significant for hip BMD (P=0.0001). We conclude that GSN is a significant gene influencing hip BMD in female Caucasians.