Advanced Genetic Approaches in Discovery and Characterization of Genes Involved With Osteoporosis in Mouse and Human.

Authors:
Jinbo Yuan
Jinbo Yuan
School of Pathology and Laboratory Medicine
Chapel Hill | United States
Jennifer Tickner
Jennifer Tickner
School of Pathology and Laboratory Medicine
Australia
Benjamin H Mullin
Benjamin H Mullin
The University of Western Australia
Australia
Jinmin Zhao
Jinmin Zhao
First Affiliated Hospital of Guangxi Medical University
China
Zhiyu Zeng
Zhiyu Zeng
First Affiliated Hospital of Guangxi Medical University
China
Grant Morahan
Grant Morahan
The Walter and Eliza Hall Institute of Medical Research
Australia
Jiake Xu
Jiake Xu
University of Western Australia
Professor
Pathology
Perth, Western Australia | Australia

Front Genet 2019 2;10:288. Epub 2019 Apr 2.

School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.

Osteoporosis is a complex condition with contributions from, and interactions between, multiple genetic loci and environmental factors. This review summarizes key advances in the application of genetic approaches for the identification of osteoporosis susceptibility genes. Genome-wide linkage analysis (GWLA) is the classical approach for identification of genes that cause monogenic diseases; however, it has shown limited success for complex diseases like osteoporosis. In contrast, genome-wide association studies (GWAS) have successfully identified over 200 osteoporosis susceptibility loci with genome-wide significance, and have provided most of the candidate genes identified to date. Phenome-wide association studies (PheWAS) apply a phenotype-to-genotype approach which can be used to complement GWAS. PheWAS is capable of characterizing the association between osteoporosis and uncommon and rare genetic variants. Another alternative approach, whole genome sequencing (WGS), will enable the discovery of uncommon and rare genetic variants in osteoporosis. Meta-analysis with increasing statistical power can offer greater confidence in gene searching through the analysis of combined results across genetic studies. Recently, new approaches to gene discovery include animal phenotype based models such as the Collaborative Cross and ENU mutagenesis. Site-directed mutagenesis and genome editing tools such as CRISPR/Cas9, TALENs and ZNFs have been used in functional analysis of candidate genes and . These resources are revolutionizing the identification of osteoporosis susceptibility genes through the use of genetically defined inbred mouse libraries, which are screened for bone phenotypes that are then correlated with known genetic variation. Identification of osteoporosis-related susceptibility genes by genetic approaches enables further characterization of gene function in animal models, with the ultimate aim being the identification of novel therapeutic targets for osteoporosis.

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Source
http://dx.doi.org/10.3389/fgene.2019.00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455049PMC
April 2019

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