Systems genetics in diversity outbred mice inform BMD GWAS and identify determinants of bone strength.
Basel Maher Al-BarghouthiLarry D MesnerGina M CalabreseDaniel BrooksSteven M TommasiniMary L BouxseinMark C HorowitzClifford J RosenKevin NguyenSamuel HaddoxEmily A FarberSuna Onngut-GumuscuDaniel PompCharles R FarberPublished in: Nature communications (2021)
Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.
Keyphrases
- bone mineral density
- postmenopausal women
- body composition
- genome wide
- rna seq
- endothelial cells
- genome wide identification
- single cell
- dna methylation
- copy number
- bone loss
- bioinformatics analysis
- machine learning
- bone regeneration
- metabolic syndrome
- transcription factor
- data analysis
- genome wide analysis
- network analysis