| 1. |
- Medina-Gomez, C., et al.
(författare)
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Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis
- 2023
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Ingår i: Communications Biology. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n similar to 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
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| 2. |
- Jones, G., et al.
(författare)
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Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p=4x10(-17)), arthritis (GDF5p=4x10(-13)), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
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| 3. |
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| 4. |
- Tobias, J. H., et al.
(författare)
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Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.
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| 5. |
- Foessl, Ines, et al.
(författare)
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Bone Phenotyping Approaches in Human, Mice and Zebrafish – Expert Overview of the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork”)
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Forskningsöversikt (refereegranskat)abstract
- A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal Traits translational Network”) Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals – including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing –omics data in order to advance musculoskeletal research and move towards “personalised medicine”.
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