Skip to main content
Top
Published in: Current Osteoporosis Reports 6/2023

16-11-2023 | Osteoporosis

Zebrafish as a Model for Osteoporosis: Functional Validations of Genome-Wide Association Studies

Authors: Inbar Ben-Zvi, David Karasik, Cheryl L. Ackert-Bicknell

Published in: Current Osteoporosis Reports | Issue 6/2023

Login to get access

Abstract

Purpose of Review

GWAS, as a largely correlational analysis, requires in vitro or in vivo validation. Zebrafish (Danio rerio) have many advantages for studying the genetics of human diseases. Since gene editing in zebrafish has been highly valuable for studying embryonic skeletal developmental processes that are prenatally or perinatally lethal in mammalian models, we are reviewing pros and cons of this model.

Recent Findings

The true power for the use of zebrafish is the ease by which the genome can be edited, especially using the CRISPR/Cas9 system. Gene editing, followed by phenotyping, for complex traits such as BMD, is beneficial, but the major physiological differences between the fish and mammals must be considered. Like mammals, zebrafish do have main bone cells; thus, both in vivo stem cell analyses and in vivo imaging are doable. Yet, the “long” bones of fish are peculiar, and their bone cavities do not contain bone marrow. Partial duplication of the zebrafish genome should be taken into account.

Summary

Overall, small fish toolkit can provide unmatched opportunities for genetic modifications and morphological investigation as a follow-up to human-first discovery.
Literature
1.
go back to reference Watson JD, Jordan E. The Human Genome Program at the National Institutes of Health. Genomics. 1989;5(3):654–6.PubMedCrossRef Watson JD, Jordan E. The Human Genome Program at the National Institutes of Health. Genomics. 1989;5(3):654–6.PubMedCrossRef
3.
go back to reference Wade N. Scientists complete rough draft of human genome. The New York Times. 2000, 26. Wade N. Scientists complete rough draft of human genome. The New York Times. 2000, 26.
4.
go back to reference Tsujimoto G. ‘Millennium Project’ of MHLW. Nihon Rinsho. 2001;59(10):1884–8.PubMed Tsujimoto G. ‘Millennium Project’ of MHLW. Nihon Rinsho. 2001;59(10):1884–8.PubMed
5.•
go back to reference Sollis E, et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2023; 51(D1): D977–D985. This resource is constantly updated as new GWAS are published. As it is not single disease or single phenotype focused, substantial information about cross-phenome associations can quickly be found. The catalog reports based on the information published in manuscripts or provided by the authors, so associations between and gene and a phenotype may not yet be proven. Sollis E, et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2023; 51(D1): D977–D985. This resource is constantly updated as new GWAS are published. As it is not single disease or single phenotype focused, substantial information about cross-phenome associations can quickly be found. The catalog reports based on the information published in manuscripts or provided by the authors, so associations between and gene and a phenotype may not yet be proven.
7.
8.
go back to reference Styrkarsdottir U, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008;358(22):2355–65.PubMedCrossRef Styrkarsdottir U, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008;358(22):2355–65.PubMedCrossRef
10.
go back to reference Rivadeneira F, et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009;41(11):1199–206.PubMedPubMedCentralCrossRef Rivadeneira F, et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009;41(11):1199–206.PubMedPubMedCentralCrossRef
11.
go back to reference Cho YS, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41(5):527–34.PubMedCrossRef Cho YS, et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41(5):527–34.PubMedCrossRef
12.
go back to reference Ackert-Bicknell CL, et al. Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map. J Bone Miner Res. 2010;25(8):1808–20.PubMedPubMedCentralCrossRef Ackert-Bicknell CL, et al. Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map. J Bone Miner Res. 2010;25(8):1808–20.PubMedPubMedCentralCrossRef
13.
14.
go back to reference Kheirallah AK, et al. Translating lung function genome-wide association study (GWAS) findings: new insights for lung biology. Adv Genet. 2016;93:57–145.PubMedCrossRef Kheirallah AK, et al. Translating lung function genome-wide association study (GWAS) findings: new insights for lung biology. Adv Genet. 2016;93:57–145.PubMedCrossRef
15.
go back to reference von Scheidt M, et al. Applications and limitations of mouse models for understanding human atherosclerosis. Cell Metab. 2017;25(2):248–61.CrossRef von Scheidt M, et al. Applications and limitations of mouse models for understanding human atherosclerosis. Cell Metab. 2017;25(2):248–61.CrossRef
16.
go back to reference Xiao SM, et al. Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density. Hum Mol Genet. 2012;21(7):1648–57.PubMedCrossRef Xiao SM, et al. Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density. Hum Mol Genet. 2012;21(7):1648–57.PubMedCrossRef
17.
go back to reference •• Morris JA, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019; 51(2): 258–266. The largest published GWAS for bone traits and the first study to replicate loci for fracture. This study did not use X-ray-based techniques such as dual X-ray Absorptiometry (DXA), however. This study used data from the UK Biobank and therefore the BMD data is estimated BMD, which is derived from ultrasound measures. •• Morris JA, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019; 51(2): 258–266. The largest published GWAS for bone traits and the first study to replicate loci for fracture. This study did not use X-ray-based techniques such as dual X-ray Absorptiometry (DXA), however. This study used data from the UK Biobank and therefore the BMD data is estimated BMD, which is derived from ultrasound measures.
18.
go back to reference Kague E, Karasik D. Functional validation of osteoporosis genetic findings using small fish models. Genes (Basel). 2022;13(2):279–308.PubMedCrossRef Kague E, Karasik D. Functional validation of osteoporosis genetic findings using small fish models. Genes (Basel). 2022;13(2):279–308.PubMedCrossRef
19.
go back to reference • Khrystoforova I, et al. Zebrafish mutants reveal unexpected role of Lrp5 in osteoclast regulation. Front Endocrinol (Lausanne). 2022; 13: 985304. In this paper, we showed that in-depth phenotyping in zebrafish can yield information about a gene’s function that could not, or was not, identified using a higher organism. The Lrp5 gene is well studied in bone in humans and in mice. • Khrystoforova I, et al. Zebrafish mutants reveal unexpected role of Lrp5 in osteoclast regulation. Front Endocrinol (Lausanne). 2022; 13: 985304. In this paper, we showed that in-depth phenotyping in zebrafish can yield information about a gene’s function that could not, or was not, identified using a higher organism. The Lrp5 gene is well studied in bone in humans and in mice.
22.
go back to reference Brommage R, Ohlsson C. High fidelity of mouse models mimicking human genetic skeletal disorders. Front Endocrinol (Lausanne). 2019;10:934.PubMedCrossRef Brommage R, Ohlsson C. High fidelity of mouse models mimicking human genetic skeletal disorders. Front Endocrinol (Lausanne). 2019;10:934.PubMedCrossRef
24.
go back to reference Kemmler CL, et al. Conserved enhancer logic controls the notochord expression of vertebrate Brachyury. Nat Commun. 2023;14(1):6594. Kemmler CL, et al. Conserved enhancer logic controls the notochord expression of vertebrate Brachyury. Nat Commun. 2023;14(1):6594.
25.
go back to reference Drickamer LC. Seasonal variation in fertility, fecundity and litter sex ratio in laboratory and wild stocks of house mice (Mus domesticus). Lab Anim Sci. 1990;40(3):284–8.PubMed Drickamer LC. Seasonal variation in fertility, fecundity and litter sex ratio in laboratory and wild stocks of house mice (Mus domesticus). Lab Anim Sci. 1990;40(3):284–8.PubMed
26.
go back to reference Veldman MB, Lin S. Zebrafish as a developmental model organism for pediatric research. Pediatr Res. 2008;64(5):470–6.PubMedCrossRef Veldman MB, Lin S. Zebrafish as a developmental model organism for pediatric research. Pediatr Res. 2008;64(5):470–6.PubMedCrossRef
28.
go back to reference Rauner M, et al. Perspective of the GEMSTONE Consortium on current and future approaches to functional validation for skeletal genetic disease using cellular, molecular and animal-modeling techniques. Front Endocrinol. 2021;12: 731217.CrossRef Rauner M, et al. Perspective of the GEMSTONE Consortium on current and future approaches to functional validation for skeletal genetic disease using cellular, molecular and animal-modeling techniques. Front Endocrinol. 2021;12: 731217.CrossRef
29.
go back to reference Furuya M, et al. Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo. Nat Commun. 2018;9(1):300.PubMedPubMedCentralCrossRef Furuya M, et al. Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo. Nat Commun. 2018;9(1):300.PubMedPubMedCentralCrossRef
30.
go back to reference Fleming A, Sato M, Goldsmith P. High-throughput in vivo screening for bone anabolic compounds with zebrafish. J Biomol Screen. 2005;10(8):823–31.PubMedCrossRef Fleming A, Sato M, Goldsmith P. High-throughput in vivo screening for bone anabolic compounds with zebrafish. J Biomol Screen. 2005;10(8):823–31.PubMedCrossRef
31.
go back to reference Richardson L, et al. EMAGE mouse embryo spatial gene expression database: 2014 update. Nucleic Acids Res. 2014;42(Database issue):D835-44.PubMedCrossRef Richardson L, et al. EMAGE mouse embryo spatial gene expression database: 2014 update. Nucleic Acids Res. 2014;42(Database issue):D835-44.PubMedCrossRef
32.
go back to reference Patton EE, Zon LI, Langenau DM. Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov. 2021;20(8):611–28.PubMedPubMedCentralCrossRef Patton EE, Zon LI, Langenau DM. Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov. 2021;20(8):611–28.PubMedPubMedCentralCrossRef
33.
go back to reference Lleras-Forero L, Winkler C, Schulte-Merker S. Zebrafish and medaka as models for biomedical research of bone diseases. Dev Biol. 2020;457(2):191–205.PubMedCrossRef Lleras-Forero L, Winkler C, Schulte-Merker S. Zebrafish and medaka as models for biomedical research of bone diseases. Dev Biol. 2020;457(2):191–205.PubMedCrossRef
34.
go back to reference Apschner A, Schulte-Merker S, Witten PE. Not all bones are created equal - using zebrafish and other teleost species in osteogenesis research. Methods Cell Biol. 2011;105:239–55.PubMedCrossRef Apschner A, Schulte-Merker S, Witten PE. Not all bones are created equal - using zebrafish and other teleost species in osteogenesis research. Methods Cell Biol. 2011;105:239–55.PubMedCrossRef
35.
go back to reference Harris MP, et al. Fish is fish: the use of experimental model species to reveal causes of skeletal diversity in evolution and disease. J Appl Ichthyol. 2014;30(4):616–29.PubMedPubMedCentralCrossRef Harris MP, et al. Fish is fish: the use of experimental model species to reveal causes of skeletal diversity in evolution and disease. J Appl Ichthyol. 2014;30(4):616–29.PubMedPubMedCentralCrossRef
37.
go back to reference Diamond KM, et al. Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases. J Anat. 2023;243(1):66–77.PubMedCrossRef Diamond KM, et al. Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases. J Anat. 2023;243(1):66–77.PubMedCrossRef
38.
go back to reference Diamond KM, et al. Computational anatomy and geometric shape analysis enables analysis of complex craniofacial phenotypes in zebrafish. Biol Open. 2022;11(2):bio058948.PubMedPubMedCentralCrossRef Diamond KM, et al. Computational anatomy and geometric shape analysis enables analysis of complex craniofacial phenotypes in zebrafish. Biol Open. 2022;11(2):bio058948.PubMedPubMedCentralCrossRef
41.
go back to reference Neuhauss SC, et al. Mutations affecting craniofacial development in zebrafish. Development. 1996;123:357–67.PubMedCrossRef Neuhauss SC, et al. Mutations affecting craniofacial development in zebrafish. Development. 1996;123:357–67.PubMedCrossRef
42.
go back to reference Reeck JC, Oxford JT. The shape of the jaw-zebrafish Col11a1a regulates Meckel’s cartilage morphogenesis and mineralization. J Dev Biol. 2022;10(4):40.PubMedPubMedCentralCrossRef Reeck JC, Oxford JT. The shape of the jaw-zebrafish Col11a1a regulates Meckel’s cartilage morphogenesis and mineralization. J Dev Biol. 2022;10(4):40.PubMedPubMedCentralCrossRef
43.
go back to reference Truong BT, Artinger KB. The power of zebrafish models for understanding the co-occurrence of craniofacial and limb disorders. Genesis. 2021;59(1–2): e23407.PubMedPubMedCentralCrossRef Truong BT, Artinger KB. The power of zebrafish models for understanding the co-occurrence of craniofacial and limb disorders. Genesis. 2021;59(1–2): e23407.PubMedPubMedCentralCrossRef
44.
go back to reference de Bruijn E, Cuppen E, Feitsma H. Highly efficient ENU mutagenesis in zebrafish. Methods Mol Biol. 2009;546:3–12.PubMedCrossRef de Bruijn E, Cuppen E, Feitsma H. Highly efficient ENU mutagenesis in zebrafish. Methods Mol Biol. 2009;546:3–12.PubMedCrossRef
45.
go back to reference Bergen DJM, Kague E, Hammond CL. Zebrafish as an emerging model for osteoporosis: a primary testing platform for screening new osteo-active compounds. Front Endocrinol (Lausanne). 2019;10:6.PubMedCrossRef Bergen DJM, Kague E, Hammond CL. Zebrafish as an emerging model for osteoporosis: a primary testing platform for screening new osteo-active compounds. Front Endocrinol (Lausanne). 2019;10:6.PubMedCrossRef
47.
49.
go back to reference Irion U, Krauss J, Nusslein-Volhard C. Precise and efficient genome editing in zebrafish using the CRISPR/Cas9 system. Development. 2014;141(24):4827–30.PubMedPubMedCentralCrossRef Irion U, Krauss J, Nusslein-Volhard C. Precise and efficient genome editing in zebrafish using the CRISPR/Cas9 system. Development. 2014;141(24):4827–30.PubMedPubMedCentralCrossRef
50.
go back to reference Kamachi Y, Kawahara A. CRISPR-Cas9-mediated genome modifications in zebrafish. Methods Mol Biol. 2023;2637:313–24.PubMedCrossRef Kamachi Y, Kawahara A. CRISPR-Cas9-mediated genome modifications in zebrafish. Methods Mol Biol. 2023;2637:313–24.PubMedCrossRef
53.
go back to reference • Watson CJ, et al. Phenomics-based quantification of CRISPR-induced mosaicism in zebrafish. Cell Syst. 2020;10(3): 275–286. In this paper, the concept of CRISPants is introduced for rapid generation of mosaic mutant fish for the bone-related phenotyping. • Watson CJ, et al. Phenomics-based quantification of CRISPR-induced mosaicism in zebrafish. Cell Syst. 2020;10(3): 275–286. In this paper, the concept of CRISPants is introduced for rapid generation of mosaic mutant fish for the bone-related phenotyping.
54.
go back to reference Bek JW, et al. Lrp5 mutant and crispant zebrafish faithfully model human osteoporosis, establishing the zebrafish as a platform for CRISPR-based functional screening of osteoporosis candidate genes. J Bone Miner Res. 2021;36(9):1749–64.PubMedCrossRef Bek JW, et al. Lrp5 mutant and crispant zebrafish faithfully model human osteoporosis, establishing the zebrafish as a platform for CRISPR-based functional screening of osteoporosis candidate genes. J Bone Miner Res. 2021;36(9):1749–64.PubMedCrossRef
55.
go back to reference Muñoz-Fuentes V, et al. The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation. Conserv Genet. 2018;19(4):995–1005.PubMedPubMedCentralCrossRef Muñoz-Fuentes V, et al. The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation. Conserv Genet. 2018;19(4):995–1005.PubMedPubMedCentralCrossRef
56.
go back to reference Gistelinck C, et al. Loss of type I collagen telopeptide lysyl hydroxylation causes musculoskeletal abnormalities in a zebrafish model of Bruck syndrome. J Bone Miner Res. 2016;31(11):1930–42.PubMedCrossRef Gistelinck C, et al. Loss of type I collagen telopeptide lysyl hydroxylation causes musculoskeletal abnormalities in a zebrafish model of Bruck syndrome. J Bone Miner Res. 2016;31(11):1930–42.PubMedCrossRef
57.
59.
go back to reference Phan QT, et al. Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model. Proc Natl Acad Sci U S A. 2020;117(32):19276–86.PubMedPubMedCentralCrossRef Phan QT, et al. Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model. Proc Natl Acad Sci U S A. 2020;117(32):19276–86.PubMedPubMedCentralCrossRef
60.
go back to reference Butylina M, et al. Nothobranchius furzeri, the turquoise killifish: a model of age-related osteoporosis? Gerontology. 2022;68(12):1415–27.PubMedCrossRef Butylina M, et al. Nothobranchius furzeri, the turquoise killifish: a model of age-related osteoporosis? Gerontology. 2022;68(12):1415–27.PubMedCrossRef
62.
go back to reference Dubale NM, Kapron CM, West SL. Commentary: zebrafish as a model for osteoporosis-an approach to accelerating progress in drug and exercise-based treatment. Int J Environ Res Public Health. 2022;19(23):15866.PubMedPubMedCentralCrossRef Dubale NM, Kapron CM, West SL. Commentary: zebrafish as a model for osteoporosis-an approach to accelerating progress in drug and exercise-based treatment. Int J Environ Res Public Health. 2022;19(23):15866.PubMedPubMedCentralCrossRef
63.
go back to reference Rajpurohit SK, et al. Development of Tg(UAS:SEC-Hsa.ANXA5-YFP, myl7:RFP); casper(roy(-/-), nacre(-/-)) transparent transgenic in vivo zebrafish model to study the cardiomyocyte function. Cells. 2021;10(8):1963.PubMedPubMedCentralCrossRef Rajpurohit SK, et al. Development of Tg(UAS:SEC-Hsa.ANXA5-YFP, myl7:RFP); casper(roy(-/-), nacre(-/-)) transparent transgenic in vivo zebrafish model to study the cardiomyocyte function. Cells. 2021;10(8):1963.PubMedPubMedCentralCrossRef
67.
go back to reference Charles JF, et al. Utility of quantitative micro-computed tomographic analysis in zebrafish to define gene function during skeletogenesis. Bone. 2017;101:162–71.PubMedPubMedCentralCrossRef Charles JF, et al. Utility of quantitative micro-computed tomographic analysis in zebrafish to define gene function during skeletogenesis. Bone. 2017;101:162–71.PubMedPubMedCentralCrossRef
68.
70.
go back to reference Bachrach LK, et al. Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab. 1999;84(12):4702–12.PubMed Bachrach LK, et al. Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab. 1999;84(12):4702–12.PubMed
72.
go back to reference Beamer WG, et al. Genetic variability in adult bone density among inbred strains of mice. Bone. 1996;18(5):397–403.PubMedCrossRef Beamer WG, et al. Genetic variability in adult bone density among inbred strains of mice. Bone. 1996;18(5):397–403.PubMedCrossRef
73.
74.
go back to reference Liao W-N, et al. Micro-CT analysis reveals the changes in bone mineral density in zebrafish craniofacial skeleton with age. J Anat. 2023;242(3):544–51.PubMedCrossRef Liao W-N, et al. Micro-CT analysis reveals the changes in bone mineral density in zebrafish craniofacial skeleton with age. J Anat. 2023;242(3):544–51.PubMedCrossRef
75.
go back to reference Kague E, et al. 3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease. Bone Res. 2021;9(1):39.PubMedPubMedCentralCrossRef Kague E, et al. 3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease. Bone Res. 2021;9(1):39.PubMedPubMedCentralCrossRef
77.
go back to reference Buniello A, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005–12.PubMedCrossRef Buniello A, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005–12.PubMedCrossRef
78.
go back to reference Watson CJ, et al. wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome. PLoS Genet. 2022;18(11): e1010496.PubMedPubMedCentralCrossRef Watson CJ, et al. wnt16 regulates spine and muscle morphogenesis through parallel signals from notochord and dermomyotome. PLoS Genet. 2022;18(11): e1010496.PubMedPubMedCentralCrossRef
80.
go back to reference Lasconi C, et al. Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits. Sleep. 2022;45(8):zsac109.PubMedPubMedCentralCrossRef Lasconi C, et al. Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits. Sleep. 2022;45(8):zsac109.PubMedPubMedCentralCrossRef
81.
82.
go back to reference Chesi A, et al. Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density. Nat Commun. 2019;10(1):1260.PubMedPubMedCentralCrossRef Chesi A, et al. Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density. Nat Commun. 2019;10(1):1260.PubMedPubMedCentralCrossRef
83.
go back to reference Zhong W, et al. Understanding the function of regulatory DNA interactions in the interpretation of non-coding GWAS variants. Front Cell Dev Biol. 2022;10: 957292.PubMedPubMedCentralCrossRef Zhong W, et al. Understanding the function of regulatory DNA interactions in the interpretation of non-coding GWAS variants. Front Cell Dev Biol. 2022;10: 957292.PubMedPubMedCentralCrossRef
84.
go back to reference Kikuta H, et al. Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. Genome Res. 2007;17(5):545–55.PubMedPubMedCentralCrossRef Kikuta H, et al. Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates. Genome Res. 2007;17(5):545–55.PubMedPubMedCentralCrossRef
85.
86.
go back to reference Xue Z, et al. Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank. eBioMedicine. 2022;82:104161.PubMedPubMedCentralCrossRef Xue Z, et al. Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank. eBioMedicine. 2022;82:104161.PubMedPubMedCentralCrossRef
87.
go back to reference Madelaine R, et al. A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human. Nucleic Acids Res. 2018;46(7):3517–31.PubMedPubMedCentralCrossRef Madelaine R, et al. A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human. Nucleic Acids Res. 2018;46(7):3517–31.PubMedPubMedCentralCrossRef
88.
go back to reference Kichaev G, et al. Leveraging polygenic functional enrichment to improve GWAS power. Am J Hum Genet. 2019;104(1):65–75.PubMedCrossRef Kichaev G, et al. Leveraging polygenic functional enrichment to improve GWAS power. Am J Hum Genet. 2019;104(1):65–75.PubMedCrossRef
90.
go back to reference Styrkarsdottir U, et al. Two rare mutations in the COL1A2 gene associate with low bone mineral density and fractures in Iceland. J Bone Miner Res. 2016;31(1):173–9.PubMedCrossRef Styrkarsdottir U, et al. Two rare mutations in the COL1A2 gene associate with low bone mineral density and fractures in Iceland. J Bone Miner Res. 2016;31(1):173–9.PubMedCrossRef
91.
go back to reference Henke K, et al. Genetic screen for postembryonic development in the zebrafish (Danio rerio): dominant mutations affecting adult form. Genetics. 2017;207(2):609–23.PubMedPubMedCentralCrossRef Henke K, et al. Genetic screen for postembryonic development in the zebrafish (Danio rerio): dominant mutations affecting adult form. Genetics. 2017;207(2):609–23.PubMedPubMedCentralCrossRef
92.
go back to reference Medina-Gomez C, et al. Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet. 2018;102(1):88–102.PubMedPubMedCentralCrossRef Medina-Gomez C, et al. Life-course genome-wide association study meta-analysis of total body BMD and assessment of age-specific effects. Am J Hum Genet. 2018;102(1):88–102.PubMedPubMedCentralCrossRef
93.
go back to reference Zheng HF, et al. WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet. 2012;8(7): e1002745.PubMedPubMedCentralCrossRef Zheng HF, et al. WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet. 2012;8(7): e1002745.PubMedPubMedCentralCrossRef
94.
go back to reference Laue K, et al. Restriction of retinoic acid activity by Cyp26b1 is required for proper timing and patterning of osteogenesis during zebrafish development. Development. 2008;135(22):3775–87.PubMedCrossRef Laue K, et al. Restriction of retinoic acid activity by Cyp26b1 is required for proper timing and patterning of osteogenesis during zebrafish development. Development. 2008;135(22):3775–87.PubMedCrossRef
95.
go back to reference Trajanoska K, et al. Assessment of the genetic and clinical determinants of fracture risk: genome wide association and Mendelian randomisation study. BMJ. 2018;362: k3225.PubMedPubMedCentralCrossRef Trajanoska K, et al. Assessment of the genetic and clinical determinants of fracture risk: genome wide association and Mendelian randomisation study. BMJ. 2018;362: k3225.PubMedPubMedCentralCrossRef
96.
97.
98.
go back to reference Kemp JP, et al. 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. PLoS Genet. 2014;10(6): e1004423.PubMedPubMedCentralCrossRef Kemp JP, et al. 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. PLoS Genet. 2014;10(6): e1004423.PubMedPubMedCentralCrossRef
99.
go back to reference Stevenson NL, et al. Giantin-knockout models reveal a feedback loop between Golgi function and glycosyltransferase expression. J Cell Sci. 2017;130(24):4132–43.PubMedPubMedCentral Stevenson NL, et al. Giantin-knockout models reveal a feedback loop between Golgi function and glycosyltransferase expression. J Cell Sci. 2017;130(24):4132–43.PubMedPubMedCentral
100.
go back to reference Yao Y, et al. Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene-environment interaction analysis in UK Biobank cohort. Endocrine. 2021;73(3):702–11.PubMedCrossRef Yao Y, et al. Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene-environment interaction analysis in UK Biobank cohort. Endocrine. 2021;73(3):702–11.PubMedCrossRef
101.
go back to reference Estrada K, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491–501.PubMedPubMedCentralCrossRef Estrada K, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491–501.PubMedPubMedCentralCrossRef
102.
go back to reference Han Y, et al. Zebrafish mafbb mutants display osteoclast over-activation and bone deformity resembling osteolysis in MCTO patients. Biomolecules. 2021;11(3):480.PubMedPubMedCentralCrossRef Han Y, et al. Zebrafish mafbb mutants display osteoclast over-activation and bone deformity resembling osteolysis in MCTO patients. Biomolecules. 2021;11(3):480.PubMedPubMedCentralCrossRef
103.
go back to reference Zheng HF, et al. Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm. J Med Genet. 2013;50(7):473–8.PubMedCrossRef Zheng HF, et al. Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm. J Med Genet. 2013;50(7):473–8.PubMedCrossRef
104.
go back to reference DeLaurier A, et al. Role of mef2ca in developmental buffering of the zebrafish larval hyoid dermal skeleton. Dev Biol. 2014;385(2):189–99.PubMedCrossRef DeLaurier A, et al. Role of mef2ca in developmental buffering of the zebrafish larval hyoid dermal skeleton. Dev Biol. 2014;385(2):189–99.PubMedCrossRef
105.
go back to reference Nichols JT, et al. Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development. 2016;143(23):4430–40.PubMedPubMedCentral Nichols JT, et al. Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development. 2016;143(23):4430–40.PubMedPubMedCentral
106.
go back to reference Dauer MVP, Currie PD, Berger J. Skeletal malformations of Meox1-deficient zebrafish resemble human Klippel-Feil syndrome. J Anat. 2018;233(6):687–95.PubMedPubMedCentralCrossRef Dauer MVP, Currie PD, Berger J. Skeletal malformations of Meox1-deficient zebrafish resemble human Klippel-Feil syndrome. J Anat. 2018;233(6):687–95.PubMedPubMedCentralCrossRef
107.
go back to reference Kemp JP, et al. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. 2017;49(10):1468–75.PubMedPubMedCentralCrossRef Kemp JP, et al. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. 2017;49(10):1468–75.PubMedPubMedCentralCrossRef
108.
go back to reference de Vos I, et al. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Hum Mol Genet. 2018;27(16):2775–88.PubMedPubMedCentralCrossRef de Vos I, et al. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Hum Mol Genet. 2018;27(16):2775–88.PubMedPubMedCentralCrossRef
110.
go back to reference Medina-Gomez C, et al. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. Nat Commun. 2017;8(1):121.PubMedPubMedCentralCrossRef Medina-Gomez C, et al. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. Nat Commun. 2017;8(1):121.PubMedPubMedCentralCrossRef
111.
go back to reference Shochat C, et al. Deletion of SREBF1, a functional bone-muscle pleiotropic gene, alters bone density and lipid signaling in zebrafish. Endocrinology. 2020;162(1):bqaa189.PubMedCentralCrossRef Shochat C, et al. Deletion of SREBF1, a functional bone-muscle pleiotropic gene, alters bone density and lipid signaling in zebrafish. Endocrinology. 2020;162(1):bqaa189.PubMedCentralCrossRef
112.
go back to reference Qu X, et al. Loss of Wnt16 leads to skeletal deformities and downregulation of bone developmental pathway in zebrafish. Int J Mol Sci. 2021;22(13):6673.PubMedPubMedCentralCrossRef Qu X, et al. Loss of Wnt16 leads to skeletal deformities and downregulation of bone developmental pathway in zebrafish. Int J Mol Sci. 2021;22(13):6673.PubMedPubMedCentralCrossRef
113.
go back to reference Medina-Gomez C, et al. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Commun Biol. 2023;6(1):691.PubMedPubMedCentralCrossRef Medina-Gomez C, et al. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Commun Biol. 2023;6(1):691.PubMedPubMedCentralCrossRef
Metadata
Title
Zebrafish as a Model for Osteoporosis: Functional Validations of Genome-Wide Association Studies
Authors
Inbar Ben-Zvi
David Karasik
Cheryl L. Ackert-Bicknell
Publication date
16-11-2023
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 6/2023
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-023-00831-5

Other articles of this Issue 6/2023

Current Osteoporosis Reports 6/2023 Go to the issue