Data Set Group2: UCLA GSE27483 BXD Bone Femur ILM Mouse WG-6 v1.1 (Jan13)

Data Set: UCLA GSE27483 BXD Bone Femur ILM Mouse WG-6 v1.1 (Jan13) RSN GN Accession: GN410 GEO Series: GSE27483 Title: Bone microarray profiles from the Hybrid Mouse Diversity Panel Organism: Mouse (Mus musculus, mm10) Group: BXD Tissue: Bone Femur mRNA Dataset Status: Public Platforms: Illumina Mouse WG-6 v1, v1.1 (GPL6105) Normalization: RSN

Contact Information Aldons Lusis University of California, Los Angeles UCLA Med-Cardio/Microbio BOX 951679 Los Angeles, CA 90095 USA Tel. 310 825-1359 jlusis@mednet.ucla.edu Website Download datasets and supplementary data files GN410_MeanDataAnnotated_rev051716.txt.zip (N/A) GN410_StdError_rev081815.txt (N/A)

Specifics of this Data Set:

None

Summary:

Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis was used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal and femoral BMD revealed four significant associations (-log10P > 5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12 and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism though which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression gene module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cell of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits.

About the cases used to generate this set of data:

About the tissue used to generate this set of data:

About the array platform:

Illumina mouse-6 v1.1 expression beadchip

About data values and data processing:

The expression values were transformed using the Variance Stabilizing Transformation (VST), and normalized with the Robust Spline Normalization (RSN) algorithm using the LumiR R package. After normalization, the ComBat software was used to adjust for batch effects using an empirical Bayes method.

Notes:

Experiment Type:

RNA from cortical bone (femoral diaphysis free of marrow) were profiled from 99 Hybrid Mouse Diversity Panel strains were profiled. Sixteen-week old male mice were used in this study. A total of 1-3 mice per strain were arrayed.

Contributor:

Citation:

Farber CR, Bennett BJ, Orozco L, Zou W et al. Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis. PLoS Genet 2011 Apr;7(4):e1002038. PMID: 21490954 Calabrese G, Bennett BJ, Orozco L, Kang HM et al. Systems genetic analysis of osteoblast-lineage cells. PLoS Genet 2012 Dec;8(12):e1003150. PMID: 23300464.

Data source acknowledgment:

Calabrese G, Bennett BJ, Orozco L, Kang HM, Eskin E, Dombret C, De Backer O, Lusis AJ, Farber CR.

Study Id:

162

• The UT Center for Integrative and Translational Genomics
• NIGMS Systems Genetics and Precision Medicine project (R01 GM123489, 2017-2021)
• NIDA NIDA Core Center of Excellence in Transcriptomics, Systems Genetics, and the Addictome (P30 DA044223, 2017-2022)
• NIA Translational Systems Genetics of Mitochondria, Metabolism, and Aging (R01AG043930, 2013-2018)
• NIAAA Integrative Neuroscience Initiative on Alcoholism (U01 AA016662, U01 AA013499, U24 AA013513, U01 AA014425, 2006-2017)
• NIDA, NIMH, and NIAAA (P20-DA 21131, 2001-2012)
• NCI MMHCC (U01CA105417), NCRR, BIRN, (U24 RR021760)