Journal
PLOS GENETICS
Volume 16, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1009190
Keywords
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Categories
Funding
- National Institutes of Health (NIH) [U54 HG006364, U42 OD011175, UM1 OD023221]
- NIH [UM1HG006348, UM1HG006370, 5UM1OD023222-07]
- Genome Canada
- Ontario Genomics [OGI-051]
- Medical Research Council (MRC) [MC_A410]
- MRC [53658]
- EMBL-EBI Core Funds
- CAS: The Czech Academy of Sciences [RVO 68378050]
- MEYS Ministry of Education, Youth and Sports of the Czech Republic
- MEYS
- ERDF - European Regional Development Fund
- Biotechnology and Biomedicine Centre of the CAS and Charles University in Vestec (BIOCEV) [CZ.1.05/1.1.00/02.0109]
- ERDF
- ESIF - European Structural Investment Fund [CZ.02.1.01/0.0/0.0/16_013/0001789]
- Agence Nationale de la Recherche (ANR) [ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR10-INBS-07]
- Wellcome Trust [110141, 094134, 101123]
- European Union [666869]
- German Center for Diabetes Research
- EU [653961]
- Czech Centre for Phenogenomics [LM2015040, LM2018126]
- Higher Quality and Capacity for Transgenic Models by MEYS [CZ.1.05/2.1.00/19.0395]
- Infrafrontier [01KX1012]
- MRC [MC_U142684171, MC_U142684172] Funding Source: UKRI
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The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease. Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.
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