Osteoporosis from genes to phenotypes

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is a systemic skeletal disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Family and twin studies have shown that osteoporosis and its associated phenotypes are under strong genetic control. In addition, it has been shown than not one major locus is responsible of the susceptibility to develop osteoporosis; instead, diverse genetic and environmental factors involved with the disease have confi rmed its complex multifactorial nature

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders

Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical interventions and treatments tailored to the characteristics of patients. As genomic research progresses, novel insights into the molecular mechanisms are starting to provide support to clinical decision-making; now offering ample opportunities for disease screening, diagnosis, prognosis and treatment. Drug targets holding mechanisms with genetic support are more likely to be successful. Therefore, implementing genetic information to the drug development process and a molecular redefinition of skeletal disease can help overcoming current shortcomings in pharmaceutical research, including failed attempts and appalling costs. This review summarizes the achievements of genetic studies in the bone field and their application to clinical care, illustrating the imminent advent of the genomic medicine era

Using Mendelian Randomization to Decipher Mechanisms of Bone Disease

Purpose of Review: This review summarizes the basic principles of Mendelian randomization (MR) and provides evidence for the causal effect of multiple modifiable factors on bone outcomes. Recent Findings: Several studies using MR approach have provided support for the causal effect of obesity on bone mineral density (BMD). Strikingly, studies have failed to prove a causal association between elevated 25(OH) D concentrations and higher BMD in community-dwelling individuals. Summary: The MR approach has been successfully used to evaluate multiple factors related to bone mineral density variation and/or fracture risk. The MR approach avoids some of the classical observational study limitations and provides more robust causal evidence, ensuring bigger success of the clinical trials. The selection of interventions based on genetic evidence could have a substantial impact on clinical practice

Recent advances in the genetics of fractures in osteoporosis

Genetic susceptibility, together with old age, female sex, and low bone mineral density (BMD) are amongst the strongest determinants of fracture risk. Tmost recent large-scale genome-wide association study (GWAS) meta-analysis has yielded fifteen loci. This review focuses on the advances in the research of genetic determinants of fracture risk. We first discuss the genetic architecture of fracture risk, touching upon different methods and overall findings. We then discuss in a second paragraph the most recent advances in the field and focus on the genetics of fracture risk and also of other endophenotypes closely related to fracture risk such as bone mineral density (BMD). Application of state-of-the-art methodology such as Mendelian randzation in fracture GWAS are reviewed. The final part of this review touches upon potential future directions in genetic research of osteoporotic fractures

Genetics of Bone and Muscle Interactions in Humans

Purpose of Review To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. Recent Findings Genome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models. Summary It is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understandin

Diabetes, Diabetic Complications, and Fracture Risk

Diabetes and osteoporosis are both common diseases with increasing prevalences in the aging population. There is increasing evidence corroborating an association between diabetes mellitus and bone. This review will discuss the disease complications of diabetes on the skeleton, highlighting findings from epidemiological, molecular, and imaging studies in animal models and humans. Compared to control subjects, decreased bone mineral dens

Genome-wide association studies in economics and entrepreneurship research: promises and limitations

The recently developed genome-wide association study (GWAS) design enables the identification of genes specifically associated with economic outcomes such as occupational and other choices. This is a promising new approach for economics research which we aim to apply to the choice for entrepreneurship. However, due to multiple testing issues, very large sample sizes are needed to differentiate between true and false positives. For a GWAS on entrepreneurship, we expect that a sample size of at least 30,000 observations is required

Skeletal maturation in relation to ethnic background in children of school age: The Generation R Study

Ethnicity is a well-established determinant of pediatric maturity, but the underlying genetic and environmental contributions to these ethnic differences are poorly comprehended. We aimed to evaluate the influence of ethnicity on skeletal age (SA), an assessment of pediatric maturation widely used in clinical settings. We included children from the Generation R Study, a multiethnic population-based pregnancy cohort, assessed at a mean age of 9.78 (±0.33) years. SA was evaluated by a trained observer on hand DXA scans using the Greulich and Pyle method. Ethnic background was defined as geographic ancestry (questionnaire-based assessment) (N = 5325) and genetic ancestry (based on admixture analysis) (N = 3413). Associations between the ethnic background and SA were investigated separately in boys and girls, using linear regression models adjusted for age, height and BMI. Based on geographic ancestry, 84% of the children were classified as European, 6% as Asian and 10% as African. Children of European background had on average younger SA than those of Asian or African descent. Asian boys had 0.46 (95% CI 0.26–0.66, p-value < 0.0001) and African boys 0.36 years (95% CI 0.20–0.53, p-value < 0.0001) older SA as compared to European boys. Similarly, Asian girls showed 0.64 (95% CI 0.51–0.77, p-value < 0.0001) and African girls 0.38 years (95% CI 0.27–0.48, p-value < 0.0001) older SA as compared to European girls. A similar pattern was observed in the analysis with genetically-defined ancestry. Furthermore, an increase in the proportion of Asian or African component was associated with older SA in both boys (log[Non-European/European]proportion = 0.10, 95% CI 0.06–0.13, p-value < 0.0001) and girls (log[Non-European/European]proportion = 0.06, 95% CI 0.04–0.08, p-value < 0.0001). In summary, children of Asian and African backgrounds have on average older SA as compared to children of European descent, partially explained by a genetic com

Heritability of fasting glucose levels in a young genetically isolated population

Aims/hypothesis: The heritability of fasting glucose levels in Northern European populations has been examined previously in twins and samples of small pedigrees. In this study the heritability of fasting plasma glucose (FPG) was estimated in participants in the Erasmus Rucphen Family study, who were members of a single pedigree from a young genetic isolate. We also studied the relationship between FPG and components of the metabolic syndrome. Methods: FPG, lipid, blood pressure and body composition measurements were completed for 852 participants without diabetic medication. The most significant predictors of FPG were used as covariates in heritability estimation. The sibship effect, which is a composite of genetic dominance and shared early-life environmental effects, was included as a random effect. Results: The age- and sex-adjusted heritability of log normal-transformed FPG was 36.6%. When further adjusted for metabolic risk factors, namely body composition parameters, systolic blood pressure, triglycerides and cholesterol:HDL ratio, the heritability estimate rose to 42.8%. After adjustment for the sibship effect, the additive component of heritability was estimated to be 28.3% (age-and sex-adjusted) and 24.9% (full model). Conclusions/ interpretation: Genes control a significant proportion of the variance in FPG levels. Adjustment for other metabolic risk factors did not substantially change the heritability estimate, which suggests that a large part of the variance in FPG levels is due to genes that act through pathways that are independent of those controlling body composition, blood pressure and lipid levels