Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques
The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:ab5cda7f24e346b4a98b3e682c5454072021-12-01T19:45:37ZPerspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques1664-239210.3389/fendo.2021.731217https://doaj.org/article/ab5cda7f24e346b4a98b3e682c5454072021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.731217/fullhttps://doaj.org/toc/1664-2392The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.Martina RaunerMartina RaunerInes FoesslMelissa M. FormosaMelissa M. FormosaErika KagueVid PrijateljVid PrijateljVid PrijateljNerea Alonso LopezBodhisattwa BanerjeeDylan BergenDylan BergenBjörn BusseÂngelo CaladoEleni DouniEleni DouniYankel GabetNatalia García GiraltDaniel GrinbergNika M. LovsinXavier Nogues SolanBarbara OstanekNathan J. PavlosFernando RivadeneiraIvan SoldatovicJeroen van de PeppelBram van der EerdenWim van HulSusanna BalcellsJanja MarcSjur ReppeSjur ReppeSjur ReppeKent SøeKent SøeKent SøeDavid KarasikDavid KarasikFrontiers Media S.A.articlegenome-wide association studymusculoskeletal diseasegene regulationanimal modelsdata integration analysisDiseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
genome-wide association study musculoskeletal disease gene regulation animal models data integration analysis Diseases of the endocrine glands. Clinical endocrinology RC648-665 |
| spellingShingle |
genome-wide association study musculoskeletal disease gene regulation animal models data integration analysis Diseases of the endocrine glands. Clinical endocrinology RC648-665 Martina Rauner Martina Rauner Ines Foessl Melissa M. Formosa Melissa M. Formosa Erika Kague Vid Prijatelj Vid Prijatelj Vid Prijatelj Nerea Alonso Lopez Bodhisattwa Banerjee Dylan Bergen Dylan Bergen Björn Busse Ângelo Calado Eleni Douni Eleni Douni Yankel Gabet Natalia García Giralt Daniel Grinberg Nika M. Lovsin Xavier Nogues Solan Barbara Ostanek Nathan J. Pavlos Fernando Rivadeneira Ivan Soldatovic Jeroen van de Peppel Bram van der Eerden Wim van Hul Susanna Balcells Janja Marc Sjur Reppe Sjur Reppe Sjur Reppe Kent Søe Kent Søe Kent Søe David Karasik David Karasik Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| description |
The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets. |
| format |
article |
| author |
Martina Rauner Martina Rauner Ines Foessl Melissa M. Formosa Melissa M. Formosa Erika Kague Vid Prijatelj Vid Prijatelj Vid Prijatelj Nerea Alonso Lopez Bodhisattwa Banerjee Dylan Bergen Dylan Bergen Björn Busse Ângelo Calado Eleni Douni Eleni Douni Yankel Gabet Natalia García Giralt Daniel Grinberg Nika M. Lovsin Xavier Nogues Solan Barbara Ostanek Nathan J. Pavlos Fernando Rivadeneira Ivan Soldatovic Jeroen van de Peppel Bram van der Eerden Wim van Hul Susanna Balcells Janja Marc Sjur Reppe Sjur Reppe Sjur Reppe Kent Søe Kent Søe Kent Søe David Karasik David Karasik |
| author_facet |
Martina Rauner Martina Rauner Ines Foessl Melissa M. Formosa Melissa M. Formosa Erika Kague Vid Prijatelj Vid Prijatelj Vid Prijatelj Nerea Alonso Lopez Bodhisattwa Banerjee Dylan Bergen Dylan Bergen Björn Busse Ângelo Calado Eleni Douni Eleni Douni Yankel Gabet Natalia García Giralt Daniel Grinberg Nika M. Lovsin Xavier Nogues Solan Barbara Ostanek Nathan J. Pavlos Fernando Rivadeneira Ivan Soldatovic Jeroen van de Peppel Bram van der Eerden Wim van Hul Susanna Balcells Janja Marc Sjur Reppe Sjur Reppe Sjur Reppe Kent Søe Kent Søe Kent Søe David Karasik David Karasik |
| author_sort |
Martina Rauner |
| title |
Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| title_short |
Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| title_full |
Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| title_fullStr |
Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| title_full_unstemmed |
Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques |
| title_sort |
perspective of the gemstone consortium on current and future approaches to functional validation for skeletal genetic disease using cellular, molecular and animal-modeling techniques |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/ab5cda7f24e346b4a98b3e682c545407 |
| work_keys_str_mv |
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