Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density

男性骨质疏松症的患病率仍然没有得到充分认识。退伍军人的患者人群 健康管理局（VHA）主要是男性，许多退伍军人可能有骨质疏松症的风险。骨 骨密度（BMD）是骨质疏松性骨折的高度可遗传的预测因子。大规模全基因组 关联研究（GWAS）已经确定了数十个携带变异（SNP）的遗传基因座，这些变异与 关于BMD这些位点构成了一个关于新的骨骼调控基因的未开发信息的宝库， 控制其功能的遗传基因组元件。然而，尽管它们有可能为骨骼生物学提供信息， 精确的致病变异体和靶基因甚至还没有被确定地鉴定为单个基因座。使用 一种新开发的将BMD GWAS相关基因定位到骨共表达网络的策略，我们 预测64个GWAS位点中的30个的致病基因。位于染色体14q32.32上的一个位点含有SNP 与股骨颈BMD高度相关（P=5.0 x 10-16），我们预测微管亲和力- 调节激酶3（MARK 3）是该位点的五个基因之一，是致病基因。MARK 3编码一个保守的 已知丝氨酸/苏氨酸激酶调节多种过程，包括不对称细胞分裂和神经元分裂。 分化，但其在骨中的潜在作用是未知的。Mark 3缺陷小鼠的临时评估 无论是整体还是条件性的（成骨细胞）显示出非常相似的骨骼表型。 基于这些令人兴奋的发现，我们开发了一种全面的方法来确定确切的因果关系， 与MARK 3相关的变体，并确定成骨细胞中该激酶的活性如何控制骨量。的 研究分为两个目标：具体目标1：确定因果遗传机制的基础上， Chr14q32.32 BMD GWAS基因座。具体目标2：确定Mark 3如何在骨骼中发挥作用。这个项目是 构想并将由托马斯克莱门斯（BLR&D高级VA研究职业科学家附属 与约翰霍普金斯大学）和查尔斯法伯在弗吉尼亚大学的赞助下， 合作安排。他们的互补研究计划的协同作用已经建立起来 在以前的项目中。我们坚信，该方法将定义受影响的生物网络， 突变将大大有助于了解他们的病理，并提供重要的目标， 干预

The prevalence of osteoporosis among men is still under-recognized. The patient population of the Veterans Health Administration (VHA) is predominantly male and many Veterans may be at risk of osteoporosis. Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Large-scale genome wide association studies (GWAS) have identified dozens of genetic loci harboring variants (SNPs) robustly associated with BMD. These loci constitute a treasure trove of untapped information on novel skeletal regulatory genes and the heritable genomic elements that control their function. However, despite their potential to inform bone biology, the precise causal variants and target genes have not been definitively identified for even a single locus. Using a strategy newly developed to map genes implicated by BMD GWAS onto a bone co-expression network, we predicted causal genes for 30 of 64 GWAS loci. One locus located on chromosome 14q32.32 contained SNPs highly associated with femoral neck BMD (P=5.0 x 10-16) and we predicted that the Microtubule Affinity- Regulating Kinase 3 (MARK3), one of five genes in the locus, was causal. MARK3 encodes a conserved serine/threonine kinase known to regulate diverse processes including asymmetric cell division, and neuronal differentiation, but its potential role in bone was unknown. Provisional assessment of mice deficient in Mark3 either globally or conditionally (osteoblast) revealed closely similar skeletal phenotypes. Based on these exciting findings, we developed a comprehensive approach to identify the precise causal variant(s) linked to MARK3 and determine how the activity of this kinase in osteoblasts controls bone mass. The studies are divided into two aims: Specific Aim 1: Define the causal genetic mechanism underlying the Chr14q32.32 BMD GWAS locus. Specific Aim 2: Determine how Mark3 functions in bone. This project was conceived and will be jointly headed by Thomas Clemens (BLR&D Senior VA Research Career Scientist affiliated with Johns Hopkins University) and Charles Farber at the University of Virginia under the auspices of a collaboration arrangement. The synergy of their complimentary research programs has already been established in previous projects. We strongly believe that the approach will define the biological networks impacted by mutation will contribute substantially to the understanding of their pathology and provide important targets for intervention.