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Additionally, richer phenotyping of endophenotypes may yield more insight. One of the underlying reasons is that it generates two-dimensional scans and does not sufficiently appreciate bone microarchitecture, an important determinant of bone strength Areal BMD does appreciate bone size and in part the internal architecture; the trabecular bone score TBS which can also be derived from DXA data will be worth further investigations Further improvements require more advanced imaging than dual energy X-ray absorptiometry, principally by direct three-dimensional radiological imaging investigations, such as computed tomography or magnetic resonance imaging, to directly visualize microstructure, differentiate cortical and trabecular bone, and model bone strength biomechanically Novel imaging techniques that can quantify this bone composition are coming up 78 , and genetic studies into these endophenotypes are yet to come.

Finally, it could be argued that bone geometry and its genetics should be studied. Intriguingly, taller persons are at increased risk of fractures in spite of having larger bones with more mass 79 , This may be caused by a different distribution of bone mass by periosteal apposition Further, loci implicated in the GWAS of human stature are enriched for genes important for skeletal growth And more specifically, a GWAS meta-analysis for hip shape was published very recently and found 17q However, some of the measurement methods with respect to both genotyping and phenotyping currently available are simply too expensive or invasive to apply on a population level at present.

Yet, current limits are being challenged, with the very first successful large-scale applications of whole-genome sequencing and deep imputation using sequencing-based reference panels in the osteoporosis research field Further studies of copy number and structural variations should be performed. However, the genome may be too distant in the cascade from the disease of interest to detect clinically relevant patterns, therefore, screening the transcriptome, epigenome, metabolome, proteome and even microbiome at perhaps multiple time points may prove necessary.

This may be applied to clinical fracture patient studies as well as population-based cohorts, where subgroups could be studied including for example individuals with multiple fractures, persons with fractures at young age, and elderly individuals free of fractures. The osteoporosis field has started to explore epigenetic regulation for instance: microRNA 84 , 85 , long non-coding RNA 86 , gene expression 87 , and DNA methylation Oftentimes the function of genes contained in the associated loci are not completely known.

Functional follow-up studies are needed, yet, the development of animal knock-out-models may take years. Establishment of multi-disciplinary research consortia worldwide may be beneficial to efficiently take GWAS discoveries to functional follow-up in a harmonized research pipeline.

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Also, publicly available databases are being launched to enhance interpretation of genomic sequence information, promoting mutual data sharing between expert consortia, professional organizations, health care providers, and patients. The Encyclopedia of DNA Elements ENCODE project, aiming to identify all functional elements in the human genome, has drastically enriched our comprehension about regions outside of the exome and showed that many GWAS SNPs overlap transcription-factor-occupied regions or DNase I hypersensitive sites and are particularly enriched in the segmentation classes associated with enhancers and transcription start sites A striking finding is that obesity-associated noncoding sequences within the FTO locus are associated with expression of the homeobox gene IRX3 at megabase distances, but not with expression of FTO itself; 91 this association seems to be driven by a topologically associated domain TAD structure encompassing the FTO and IRXB genes cluster Such genomic explorations remain to be performed for osteoporosis-related traits.

So far, therapies used to increase bone strength in individuals with osteoporosis are mainly based on antiresorptives Bisphosphonates are the most widely used first-line because of their effectiveness, reasonable safety, and a low cost price However, in practice, no single antiresorptive therapy is currently appropriate for all patients, as a subgroup of patients on anti-fracture medication responds suboptimally, e. To our knowledge no large-scale pharmacogenetic GWAS studies examining these phenomena in osteoporosis have been published to date, though initial case studies on the genetics of AFF and an accompanying systematic review have been published In the future, results from pharmacogenomic studies may aid in assigning the most effective therapy to specific patient groups and it has been hypothesized that genetic biomarkers can be identified to pinpoint those patients most vulnerable to side-effects of certain agents.

Until now in genetic osteoporosis research, solely candidate gene studies have been performed investigating genetically-based variation in treatment response to raloxifene, teriparatide, and bisphosphonates One of the reasons for this is that the coverage of pharmacogenomics variants was limited on GWAS genotyping platforms , , but this is improving with novel microarrays becoming available. GWAS is the study design necessary to further investigate the complex phenotypic and genetic architecture of osteoporotic fracture risk. Although fractures can be considered a complex trait, so far, the majority of susceptibility loci for fractures are also associated with bone mineral density.

Hopefully, novel discoveries in the genetics of fracture risk will increasingly be translated clinical practice, with genotyping increasingly being successfully applied providing access to previously unknown information that may change the diagnostics and treatment of patients with bone diseases including osteoporosis with increased fracture risk in the future.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RP declared a past co-authorship with the authors to the handling editor. Fall risk: the clinical relevance of falls and how to integrate fall risk with fracture risk.

Best Pract Res Clin Rheumatol. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Impact of genetics on low bone mass in adults. J Bone Miner Res. Genetic liability to fractures in the elderly. Arch Intern Med. A family history of fracture and fracture risk: a meta-analysis.

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Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta. PubMed Abstract Google Scholar. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. PLS3 mutations in X-linked osteoporosis with fractures. EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta.

Eur J Hum Genet. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. Consortium A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF Nat Genet. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites.

Hum Mol Gen. N Eng J Med. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Osteoprotegerin deficiency and juvenile Paget's disease. Activating mutations affecting the Dbl homology domain of SOS2 cause noonan syndrome.

Hum Mutat. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. CYP3A4 mutation causes vitamin D-dependent rickets type 3.


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Multiple genetic loci for bone mineral density and fractures. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. New sequence variants associated with bone mineral density. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. PLoS Genet. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. Collaborative meta-analysis: associations of candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Identification of new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Five years of GWAS discovery.

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Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus.

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J Med Genet. A genome-wide copy number association study of osteoporotic fractures points to the 6p A genome-wide association study meta-analysis of clinical fracture in 10, African American women. Bone Rep. Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

Ann Rheum Dis. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.


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Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures. Nat Commun. Mendelian randomization in the bone field. Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study. Osteoporos Int. Trajanoska K, Rivadeneira F. Using mendelian randomization to decipher mechanisms of bone disease. Curr Osteoporos Rep. An atlas of genetic influences on osteoporosis in humans and mice.

Evidence of a causal effect of estradiol on fracture risk in men. J Clin Endocrinol Metab. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Disentangling the genetics of lean mass. Am J Clin Nutr. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. Servick K.

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Can 23andMe have it all? Thompson SG, Willeit P. UK Biobank comes of age. Performance of genotype imputation for low frequency and rare variants from the genomes. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Gibson G. Rare and common variants: twenty arguments.

Nat Rev Genet. Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.


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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Fracture incidence and secular trends between and in a population based cohort: the Rotterdam Study. Dalle Carbonare L, Giannini S. Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest. Quantitative imaging methods in osteoporosis. Quant Imaging Med Surg. Burr DB. The contribution of the organic matrix to bone's material properties.

Quantification of human cortical bone bound and free water in vivo with ultrashort echo time MR imaging: a model-based approach. Risk factors for hip fracture in middle-aged Norwegian women and men. Am J Epidemiol. Type of fall and risk of hip and wrist fractures: the study of osteoporotic fractures.

Zentralblatt MATH identifier Liang, Yulan; Kelemen, Arpad. Statistical advances and challenges for analyzing correlated high dimensional SNP data in genomic study for complex diseases. Abstract Article info and citation First page References Abstract Recent advances of information technology in biomedical sciences and other applied areas have created numerous large diverse data sets with a high dimensional feature space, which provide us a tremendous amount of information and new opportunities for improving the quality of human life.

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Export Cancel. References [1] Anderson, E. Finding haplotype block boundaries by using the minimum-description-length principle. Selection of minimum subsets of single nucleotide polymorphisms to capture haplotype block diversity.