Mouse Genome-Wide Association and Systems Genetics Identify Asxl2 As a Regulator of Bone Mineral Density and Osteoclastogenesis

Abstract

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 were 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 through 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 module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells 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.

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…The implication of MLIP in the cardiac response to prohypertrophic stimulation was confirmed by an independent genome-wide association study that took advantage of the Hybrid Mouse Diversity Panel (11,12). In this experiment, a system genetics approach was undertaken to identify, in an unbiased manner, key genes important for cardiac hypertrophy and remodeling, using a similar ISO-induced hypertrophy model.…”

“…Echocardiograms were performed at baseline and at weekly intervals up to 3 weeks. genome-wide association study of directly measured and calculated echocardiographic measures was performed using the efficient mixed model association algorithm to correct for population substructure (11,12). Mouse PET [ 18 F]fluorodeoxyglucose (FDG) imaging was conducted in the Inveon TM DPET small animal scanner (Siemens, Knoxsville, TN) as previously described (13,14).…”

A Questionnaire-Based Survey on Food Safety Knowledge during Food-Handling and Food Preparation Practices among University Students

“…Even in societies with highly developed food safety systems such as the European "farm-to-fork" and the American "farmto table" approach a "weak link" can cause significant morbidity and mortality from food borne illness [3].…”

The need for mouse models in osteoporosis genetics research

“…38 This panel is very different than the CC and the DO in a number of ways. First, as the panel is ' fixed, ' in that the mice are not interbred in any way, no new allelic combinations are generated.…”

“…23 Using a combined phenotype QTL and expression QTL approach, the Asxl2 gene was identified as underlying a BMD locus on mouse chromosome 12 in the HMDP. Furthermore, a role for this gene in osteoclast differentiation has been established, solidifying this gene as a true genetic regulator of bone mass, 38 however, it has not yet been ascertained if genetic variation in this gene is associated with BMD in human subjects.…”