Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density

男性骨质疏松症的患病率仍未得到充分认识。退伍军人的病人群体 卫生管理局(VHA)主要是男性，许多退伍军人可能面临骨质疏松症的风险。骨 骨密度(BMD)是骨质疏松性骨折的高度遗传性预测因子。大规模全基因组 关联研究已经确定了数十个含有强烈关联的变异(SNP)的遗传基因座 有骨密度。这些基因座构成了关于新的骨骼调节基因和 控制其功能的可遗传的基因组成分。然而，尽管它们有可能为骨骼生物学提供信息， 精确的因果变异和靶基因甚至没有一个基因的确定。vbl.使用 我们开发了一种新的策略，将与骨密度相关的基因映射到骨共表达网络上 预测了基因座中的30个致病基因。位于染色体14q32.32上的一个基因座含有SNPs 与股骨颈骨密度高度相关(P=5.0x10-16)，我们预测微管亲和力- 该基因座的五个基因之一--调节激酶3(Mark3)是有原因的。Mark3编码一个保守的 已知的丝氨酸/苏氨酸激酶调节不同的过程，包括细胞不对称分裂和神经元 分化，但其在骨中的潜在作用尚不清楚。Mark3基因缺陷小鼠的初步评估 无论是全局的还是有条件的(成骨细胞)都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原因 与Mark3连锁的变异体(S)，并确定成骨细胞中这种激酶的活性如何控制骨量。这个 研究分为两个目标：具体目标1：确定导致高血压的原因遗传机制 CHA14q32.32位点骨密度GWAs。具体目标2：确定Mark3在骨骼中的功能。这个项目是 构思并将由Thomas Clemens(BLR&D高级退伍军人研究职业科学家附属)共同领导 与约翰·霍普金斯大学)和查尔斯·法伯在弗吉尼亚大学 协作安排。他们的免费研究项目的协同作用已经建立起来了 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 突变将在很大程度上有助于了解它们的病理，并为 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.