GEFOS
GEFOS: The Genetic Factors for Osteoporosis (GEFOS) Consortium
The Genetic Factors for Osteoporosis (GEFOS) Consortium is a large-scale, international research collaboration focused on uncovering the genetic basis of osteoporosis, bone mineral density (BMD), and fracture risk. Osteoporosis is a major public health concern, characterized by decreased bone strength and an increased susceptibility to fractures, particularly in aging populations. By integrating expertise from geneticists, epidemiologists, bioinformaticians, and clinicians, GEFOS aims to enhance our understanding of the molecular mechanisms driving bone fragility, ultimately paving the way for improved diagnostic tools, prevention strategies, and therapeutic approaches.
Objectives and Research Approach
GEFOS operates through a genome-wide association study (GWAS) framework, leveraging data from large population-based cohorts across multiple countries. By conducting meta-analyses of extensive datasets, researchers identify genetic loci associated with bone health and explore their biological significance. The consortium’s work focuses on:
- Identifying genetic variants that influence bone mineral density (BMD) and susceptibility to osteoporosis.
- Developing genetic risk scores to predict individuals at higher risk of fractures.
- Investigating gene-environment interactions, such as the role of lifestyle factors (e.g., diet, exercise, and medication) in modifying genetic predisposition.
- Examining biological pathways related to bone metabolism to uncover potential drug targets.
- Validating findings across diverse populations to ensure the robustness and generalizability of genetic associations.
Major Contributions and Findings
Since its inception, GEFOS has made significant contributions to osteoporosis research, including the discovery of multiple genetic loci that play a role in BMD regulation and fracture susceptibility. Some of the consortium’s key achievements include:
- Identification of over 500 genetic variants associated with BMD, providing new insights into bone biology.
- Confirmation that genetic factors explain a substantial proportion of BMD variation and fracture risk in the general population.
- Discovery of shared genetic pathways between osteoporosis and other metabolic diseases, such as type 2 diabetes.
- Development of polygenic risk scores (PRS) to improve fracture prediction and guide personalized medicine approaches.
Impact and Future Directions
The discoveries made by GEFOS have had a profound impact on bone disease research and clinical practice. By pinpointing genetic markers associated with osteoporosis, researchers and healthcare professionals can improve early detection strategies, identify high-risk individuals, and refine treatment approaches. Furthermore, integrating genomic data with functional studies may lead to the development of novel therapeutic interventions targeting specific biological pathways involved in bone metabolism.
Moving forward, GEFOS aims to expand its research efforts by incorporating multi-omics approaches, including epigenetics, transcriptomics, and proteomics, to gain a more comprehensive understanding of bone health at the molecular level. Additionally, with the rise of machine learning and artificial intelligence, researchers within the consortium are exploring new ways to analyze complex genetic and clinical data to enhance osteoporosis risk prediction.
By fostering global collaborations and leveraging cutting-edge genomic technologies, GEFOS continues to drive progress in osteoporosis research, with the ultimate goal of reducing the burden of fractures and bone-related disorders worldwide.
Publications
Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies
Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies
- DOI: 10.1038/ng.446
Abstract
Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.
For more information on this article in Pure, click here.
Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.
Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture
Abstract
Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.
Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.
Design: Large-scale meta-analysis of genome-wide association data.
Setting: 5 international, multicenter, population-based studies.
Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.
Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.
Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.
Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.
Conclusion: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
For more information on this article in Pure, click here.
A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
Abstract
Background: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.
Aim: To identify CNVs associated with osteoporotic bone fracture risk.
Method: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.
Results: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.
Conclusions: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
Keywords: Calcium and Bone; Copy-Number; Genetic Epidemiology; Genome-Wide; Osteoporosis.
For more information on this article in Pure, click here.
