Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis.
Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis.
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DOI：
10.1371/journal.pgen.1002038
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Lusis AJ
中科院分区：
文献类型：
--
作者：
Farber CR;Bennett BJ;Orozco L;Zou W;Lira A;Kostem E;Kang HM;Furlotte N;Berberyan A;Ghazalpour A;Suwanwela J;Drake TA;Eskin E;Wang QT;Teitelbaum SL;Lusis AJ
在发现影响骨矿物质密度（BMD）的基因方面已经取得了重大进展;然而，我们对其遗传基础的理解仍然不完整。在目前的研究中，全基因组关联（GWA）和共表达网络分析中使用的最近描述的杂交小鼠多样性面板（HMDP），以确定和功能特性的新的BMD基因。在HMDP中，全身、脊柱和股骨BMD的GWA揭示了四个显著的关联（− log 10 P>5.39），影响染色体上至少一个BMD性状（Chrs.）。7、11、12和17。这些关联共涉及163个基因，每个关联包含14至112个基因。通过鉴定骨中受局部eQTL调控或具有潜在功能性非同义（NS）SNP的那些基因，将该列表减少到26个功能候选者。该分析揭示，在染色体12上最显著的BMD SNP是预测为功能性的额外性梳样-2（Asxl 2）基因中的NS SNP。通过观察到Asxl 2敲除小鼠具有降低的BMD，证实了Asxl 2参与骨量调节。为了开始阐明Asxl 2影响BMD的机制，使用来自HMDP菌株的皮质骨基因表达微阵列数据创建基因共表达网络。Asxl 2被鉴定为富含参与骨髓细胞分化的基因的共表达模块的成员。在骨中，破骨细胞是骨髓来源的骨吸收细胞，表明Asxl 2可能在破骨细胞分化中起作用。一致的是，在骨髓巨噬细胞中敲低Asxl 2会损害它们形成破骨细胞的能力。这项研究确定了一种新的骨密度和破骨细胞生成的调节因子，并强调了GWA和系统遗传学在小鼠中解剖复杂遗传性状的作用。骨质疏松症是一种骨质疏松且容易骨折的疾病。最能预测骨折的骨骼特征是低骨矿物质密度（BMD），这是一种主要由遗传控制的特征。近年来，在发现影响BMD的基因方面取得了重大进展;然而，我们对其遗传基础的理解仍然很原始。在这项研究中，我们在小鼠中使用全基因组关联来鉴定额外的性梳样-2（Asxl 2）作为新的BMD基因。在我们的遗传分析的确认中，Asxl 2缺陷的小鼠具有降低的BMD。为了评估其在骨中的功能，在大量近交系小鼠品系的骨中测量了Asxl 2和数万个其他基因的表达水平。Asxl 2表现出一种表达模式，表明在破骨细胞中起关键作用的基因，破骨细胞是负责骨吸收的细胞。对Asxl 2的进一步研究可能揭示治疗和预防骨质疏松症的新的治疗靶点。
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. Osteoporosis is a disease of weak and fracture-prone bones. The characteristic of bone that is most predictive of fractures is low bone mineral density (BMD), a trait primarily controlled by genetics. In recent years, significant advances have been made in the discovery of genes affecting BMD; however, our understanding of its genetic basis is still primitive. In this study, we used genome-wide association in the mouse to identify additional sex combs like-2 (Asxl2) as a novel BMD gene. In confirmation of our genetic analysis, mice deficient in Asxl2 had reduced BMD. To evaluate its function in bone, the expression levels of Asxl2 and tens of thousands of other genes were measured in bone in a large number of inbred mouse strains. Asxl2 demonstrated a pattern of expression indicative of genes that play a critical role in osteoclasts, the cells that are responsible for bone resorption. Further study of Asxl2 may reveal novel therapeutic targets for the treatment and prevention of osteoporosis.
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