FAM210A is a novel determinant of bone and muscle structure and strength

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a−/−), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus−/−). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a−/− mice. BMD of male TFam210aMus−/− mice was also reduced, and osteoclast numbers and surface in TFam210aMus−/− mice increased. Microarray analysis of muscle cells from TFam210aMus−/− mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms.

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Genome-Wide Association Studies Based on Equine Joint Angle Measurements Reveal New QTL Affecting the Conformation of Horses

Genes ◽

10.3390/genes10050370 ◽

2019 ◽

Vol 10 (5) ◽

pp. 370 ◽

Cited By ~ 5

Author(s):

Annik Imogen Gmel ◽

Thomas Druml ◽

Rudolf von Niederhäusern ◽

Tosso Leeb ◽

Markus Neuditschko

Keyword(s):

Joint Angle ◽

Association Studies ◽

Genome Wide Association ◽

Cranial Morphology ◽

Genome Wide Association Studies ◽

Joint Angles ◽

Mineral Density ◽

Mixed Effect ◽

Stifle Joint ◽

Genome Wide

The evaluation of conformation traits is an important part of selection for breeding stallions and mares. Some of these judged conformation traits involve joint angles that are associated with performance, health, and longevity. To improve our understanding of the genetic background of joint angles in horses, we have objectively measured the angles of the poll, elbow, carpal, fetlock (front and hind), hip, stifle, and hock joints based on one photograph of each of the 300 Franches-Montagnes (FM) and 224 Lipizzan (LIP) horses. After quality control, genome-wide association studies (GWASs) for these traits were performed on 495 horses, using 374,070 genome-wide single nucleotide polymorphisms (SNPs) in a mixed-effect model. We identified two significant quantitative trait loci (QTL) for the poll angle on ECA28 (p = 1.36 × 10−7), 50 kb downstream of the ALX1 gene, involved in cranial morphology, and for the elbow joint on ECA29 (p = 1.69 × 10−7), 49 kb downstream of the RSU1 gene, and 75 kb upstream of the PTER gene. Both genes are associated with bone mineral density in humans. Furthermore, we identified other suggestive QTL associated with the stifle joint on ECA8 (p = 3.10 × 10−7); the poll on ECA1 (p = 6.83 × 10−7); the fetlock joint of the hind limb on ECA27 (p = 5.42 × 10−7); and the carpal joint angle on ECA3 (p = 6.24 × 10−7), ECA4 (p = 6.07 × 10−7), and ECA7 (p = 8.83 × 10−7). The application of angular measurements in genetic studies may increase our understanding of the underlying genetic effects of important traits in equine breeding.

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Replication of previous genome-wide association studies of bone mineral density in premenopausal American women

Journal of Bone and Mineral Research ◽

10.1002/jbmr.62 ◽

2010 ◽

Vol 25 (8) ◽

pp. 1821-1829 ◽

Cited By ~ 16

Author(s):

Shoji Ichikawa ◽

Daniel L Koller ◽

Leah R Padgett ◽

Dongbing Lai ◽

Siu L Hui ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Mineral Density ◽

American Women ◽

Genome Wide

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Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

10.1101/828525 ◽

2019 ◽

Author(s):

Madison L. Doolittle ◽

Gina M Calabrese ◽

Larry D. Mesner ◽

Dana A. Godfrey ◽

Robert D. Maynard ◽

...

Keyword(s):

Bone Formation ◽

Genetic Basis ◽

Association Studies ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Mineral Density ◽

Osteoblast Activity ◽

Genome Wide ◽

Increased Risk

ABSTRACTOsteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

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Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab862 ◽

2021 ◽

Author(s):

Shunsuke Katsuhara ◽

Maki Yokomoto-Umakoshi ◽

Hironobu Umakoshi ◽

Yayoi Matsuda ◽

Norifusa Iwahashi ◽

...

Keyword(s):

Muscle Strength ◽

Grip Strength ◽

Lean Mass ◽

Bayesian Model Averaging ◽

Mendelian Randomization ◽

Association Studies ◽

Whole Body ◽

Genome Wide Association Studies ◽

Mass Estimate ◽

The Impact

Abstract Purpose Prolonged exposure to pathological cortisol, as in Cushing’s syndrome causes various age-related disorders including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. We performed a Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. Methods Three single nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12,597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. Results One standard deviation (SD) increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% confidence interval [CI] -0.044 ~ -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95%CI, -0.046 ~ -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95%CI, -0.049 ~ -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR-Bayesian model averaging analysis. Conclusion This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

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Genome-wide association studies of brain structure and function in the UK Biobank

10.1101/178806 ◽

2017 ◽

Cited By ~ 9

Author(s):

Lloyd T. Elliott ◽

Kevin Sharp ◽

Fidel Alfaro-Almagro ◽

Sinan Shi ◽

Karla Miller ◽

...

Keyword(s):

Brain Imaging ◽

Brain Structure ◽

Association Studies ◽

Structure And Function ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Genome Wide ◽

Brain Structure And Function ◽

And Function

SummaryThe genetic basis of brain structure and function is largely unknown. We carried out genome-wide association studies of 3,144 distinct functional and structural brain imaging derived phenotypes in UK Biobank (discovery dataset 8,428 subjects). We show that many of these phenotypes are heritable. We identify 148 clusters of SNP-imaging associations with lead SNPs that replicate at p<0.05, when we would expect 21 to replicate by chance. Notable significant and interpretable associations include: iron transport and storage genes, related to changes in T2* in subcortical regions; extracellular matrix and the epidermal growth factor genes, associated with white matter micro-structure and lesion volume; genes regulating mid-line axon guidance development associated with pontine crossing tract organisation; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide new insight into the genetic architecture of the brain with relevance to complex neurological and psychiatric disorders, as well as brain development and aging. The full set of results is available on the interactive Oxford Brain Imaging Genetics (BIG) web browser.

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The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1905489116 ◽

2019 ◽

Vol 116 (36) ◽

pp. 17980-17989 ◽

Cited By ~ 11

Author(s):

Qian Zhang ◽

Ryan C. Riddle ◽

Qian Yang ◽

Clifford R. Rosen ◽

Denis C. Guttridge ◽

...

Keyword(s):

Dna Damage ◽

Association Studies ◽

Metabolic Stress ◽

Genome Wide Association Studies ◽

Mineral Density ◽

Rna Profiling ◽

Genotoxic Damage ◽

Age Related ◽

Genome Wide ◽

The Stability

The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (FtoKO) or selectively in osteoblasts (FtoOcKO). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H2O2) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-κB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of FtoOc KO mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a–NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.

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The Genetics of Bone Loss: Challenges and Prospects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2865 ◽

2011 ◽

Vol 96 (5) ◽

pp. 1258-1268 ◽

Cited By ~ 22

Author(s):

Braxton D. Mitchell ◽

Laura M. Yerges-Armstrong

Keyword(s):

Bone Mineral Density ◽

Bone Loss ◽

Bone Mineral ◽

Association Studies ◽

Evidence Synthesis ◽

Susceptibility Genes ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Mineral Density ◽

Genome Wide

Context: A strong genetic influence on bone mineral density has been long established, and modern genotyping technologies have generated a flurry of new discoveries about the genetic determinants of bone mineral density (BMD) measured at a single time point. However, much less is known about the genetics of age-related bone loss. Identifying bone loss-related genes may provide new routes for therapeutic intervention and osteoporosis prevention. Evidence Acquisition: A review of published peer-reviewed literature on the genetics of bone loss was performed. Relevant studies were summarized, most of which were drawn from the period 1990–2010. Evidence Synthesis: Although bone loss is a challenging phenotype, available evidence supports a substantial genetic contribution. Some of the genes identified from recent genome-wide association studies of cross-sectional BMD are attractive candidate genes for bone loss, most notably genes in the nuclear factor κB and estrogen endocrine pathways. New insights into the biology of skeletal development and regulation of bone turnover have inspired new hypotheses about genetic regulation of bone loss and may provide new directions for identifying genes associated with bone loss. Conclusions: Although recent genome-wide association and candidate gene studies have begun to identify genes that influence BMD, efforts to identify susceptibility genes specific for bone loss have proceeded more slowly. Nevertheless, clues are beginning to emerge on where to look, and as population studies accumulate, there is hope that important bone loss susceptibility genes will soon be identified.

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