Heritability and Genetic Correlations for Bone Microarchitecture: The Framingham Study Families

Karasik, David; Demissie, Serkalem; Zhou, Yanhua; Lu, Darlene; Broe, Kerry E; Bouxsein, Mary L.; Cupples, L. Adrienne; Kiel, Douglas P.

doi:10.1002/jbmr.2915

Cited by 32 publications

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“…Thus, our finding of substantial heritabilities of height‐ and other covariate‐adjusted failure load—from 47% to 52% (radius) and 50% (tibia)—is significant. This h 2 estimate is comparable with the heritability for covariate‐adjusted ultradistal radius aBMD (41.7%) and femoral neck aBMD (54.3%) in the Framingham sample.…”

Section: Discussionsupporting

confidence: 63%

“…Scans were qualitatively graded according to a 5‐point progressive movement scale (1 = perfect, 5 = severe motion artifact). For the micro‐finite element analysis, scans with extreme movement (a movement grade > 3) were excluded . Data capture was supported by REDCap .…”

Section: Methodsmentioning

confidence: 99%

“…A significance level for the difference between estimated genetic correlation and ρG = 0 (no genetic correlation), as well as ρG = 1.0 (absolute genetic correlation) was calculated. For additional details regarding the bivariate extensions to VCA, see the following articles …”

Section: Methodsmentioning

confidence: 99%

“…Several recent studies supported the hypothesis that HR-pQCT-derived bone microarchitecture and volumetric BMD (vBMD) traits are heritable (reviewed in Karasik and colleagues (17) ). However, there are less data on genetic regulation of HR-pQCT-derived bone strength estimates.…”

Section: Introductionmentioning

confidence: 92%

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Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study

Karasik

Demissie

et al. 2017

Journal of Bone and Mineral Research

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Genetic factors contribute to the risk of bone fractures, partly due to effects on bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) estimates bone strength using micro finite element analysis (μFEA). The goal of this study was to investigate if the bone failure load estimated by HR-pQCT-based μFEA is heritable and to what extent it shares genetic regulation with areal BMD (aBMD). Bone microarchitecture was measured by HR-pQCT at the ultradistal tibia and ultradistal radius in adults from the Framingham Heart Study (n=1,087, mean age 72 ys old; 57% women). Radial and tibial failure load in compression were estimated by μFEA. Femoral neck (FN) and ultradistal forearm (UD) aBMD were measured by DXA. Heritability (h2) of failure load and aBMD and genetic correlations between them was estimated adjusting for covariates (age and sex). Failure load values at the non-weight-bearing ultradistal radius and at the weight-bearing ultradistal tibia were highly correlated (r=0.906; P<0.001). Estimates of h2 adjusted for covariates were 0.522 for the radius and 0.497 for the tibia. Additional adjustment for height did not impact on the h2 results but adjustment for aBMD at the UD and FN somewhat decreased h2 point estimates: 0.222 and 0.380 for radius and tibia, respectively. In bivariate analysis, there was a high phenotypic and genetic correlation between covariate-adjusted failure load at the radius and UD aBMD (ρP =0.826, ρG =0.954, respectively), while environmental correlations were lower (ρE=0.696), all highly significant (p<0.001). Similar correlations were observed between tibial failure load and femoral neck aBMD (ρP = 0.577, ρG = 0.703, both p<0.001;ρE= 0.432, p<0.05). These data from adult members of families from a population-based cohort suggest that bone strength of distal extremities estimated by micro finite element analysis is heritable and shares some genetic composition with areal BMD, regardless of the skeletal site.

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Section: Discussionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study

Karasik

Demissie

et al. 2017

Journal of Bone and Mineral Research

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“…Another study examining HR‐pQCT microstructure of monozygotic and dizygotic middle‐aged white female twin pairs indicated that genetic factors accounted for 72% to 81% of the variance of microstructure, suggesting genetics plays a stronger role than environmental factors in bone microarchitecture . Furthermore, data from the Framingham Offspring cohort found high heritability of HR‐pQCT traits ranging from 19.3% for radial trabecular number to 98.3% for tibial cortical cross‐sectional area . Future studies are needed to assess the genes associated with these microstructural characteristics, as differences in allele frequencies between the white and Chinese populations in genes associated with microstructure may contribute to the microstructural skeletal advantages observed here among Asian individuals.…”

Section: Discussionmentioning

confidence: 99%

Chinese Women in Both the United States and Hong Kong Have Cortical Microstructural Advantages and More Trabecular Plates Compared With White Women

et al. 2018

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We cross‐sectionally compared racial differences in bone quality between Chinese women in the United States (US) and Hong Kong (HK) with white women. A total of 514 women were included. We measured bone geometry, mass, microstructure, and stiffness by high‐resolution peripheral quantitative computed tomography (HR‐pQCT), individual trabecula segmentation (ITS), and microfinite element analysis (μFEA). After adjustment for age and body mass index (BMI), premenopausal Chinese women in the US and HK had smaller bone area but greater radial cortical (Ct.) thickness and Ct. and trabecular (Tb.) volumetric bone mineral density (vBMD) versus white women but did not differ from each other. At the radius, Tb. number was lower and spacing greater in Chinese women from HK and the US versus white women, whereas Chinese women did not differ from each other. Tb. thickness was highest in Chinese women from HK, intermediate in Chinese‐Americans, and lowest in white women. Chinese women had more trabecular plates versus white women, leading to greater age‐ and BMI‐adjusted stiffness for premenopausal Chinese women in HK and the US (both p < 0.05) versus white women. Tibial differences were similar in premenopausal women; analogous trends in microstructure were present in postmenopausal women at the tibia, although stiffness did not differ. In contrast, at the radius, cortical, plate‐to‐rod ratio, and stiffness were similar between postmenopausal HK and white women. Adjusting for age, weight, and height rather than age and BMI tended to reduce differences in bone size and Tb. parameters but accentuate cortical differences such that Chinese premenopausal women in both locations and postmenopausal women from HK had higher stiffness at both skeletal sites compared with white women. Compared with white women, Chinese women in the US and HK have vBMD and microstructural advantages leading to higher or similar mechanical competence in pre‐ and postmenopausal women, respectively, despite smaller bone size. © 2018 American Society for Bone and Mineral Research.

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Scrutinizing the Genetic Underpinnings of Bone Strength

Rivadeneira

Uitterlinden

2017

Journal of Bone and Mineral Research

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E very year, osteoporosis causes millions of fractures worldwide, with the lifetime risk of suffering a wrist, hip, or vertebral fracture estimated to be about 30% in developed countries. (1) Osteoporosis has been operationally defined for diagnostic and treatment purposes on the basis of the bone mineral density (BMD) assessment performed at the skeletal sites where fracture is most common. Nevertheless, BMD measurement alone is not optimal for the detection of individuals at high risk of fracture. Despite high specificity (ie, risk of fracture is high when BMD is low), BMD measurement also holds low sensitivity (ie, risk is still substantial when BMD levels do not indicate the presence of osteoporosis). This has to do with the multifactorial etiology of osteoporosis and its associated fractures, involving significant environmental influences together with a very large set of genetic factors acting across numerous biological processes. Multiple underlying factors, apart from bone strength, influence the risk of fracture, including age, sex, menopausal status, diet, physical activity, smoking, falls risk, coexisting diseases, and medications. Among the established risk factors, the predictive ability of family history of fracture has led researchers to start looking for the molecular genetic determinants of fracture. Such enterprises usually start by determining how much of the phenotypic variance is explained by genetic factors, ie, determining the "heritability" of the traits of interest. Theoretically, identifying the factors that together constitute the genetic contribution to fracture risk will expand the understanding of the underlying biologic mechanisms, lead to development of novel interventions (treatments), and will enable the application of molecular definitions to reclassify disease and improve risk prediction. Until 2005, the identification of genetic factors for complex diseases such as osteoporosis was plagued with underpowered and irreproducible studies of suspected (well-known) candidate genes in human studies (eg, cases/controls, families, sib pairs, and populations). It was, however, realized that collaboration could overcome several of these hurdles, and this concept proved successful when hypothesis-free interrogations of the complete genome were made possible by novel massively parallel genotyping techniques that analyzed millions of DNA polymorphisms simultaneously. As in other human complex diseases, the field of genetics of osteoporosis has been revolutionized by the advent of the so-called genome-wide association study (GWAS) approach, (2) very rapidly bringing the number of identified BMD loci from none (3) to dozens (4) and currently hundreds (5) in less than a decade of GWAS research. This has resulted in an unprecedented leap in the number of factors and pathways being linked to skeletal biology, some of which have been shown to constitute in retrospect solid leads for pharmacological treatment, (6,7) whereas others revealed clear translational potential of a GWAS discovery. (8,9) ...

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Heritability and Genetic Correlations for Bone Microarchitecture: The Framingham Study Families

Cited by 32 publications

References 32 publications

Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study

Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study

Chinese Women in Both the United States and Hong Kong Have Cortical Microstructural Advantages and More Trabecular Plates Compared With White Women

Scrutinizing the Genetic Underpinnings of Bone Strength

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