Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density

MARK3 GWAS 基因座骨矿物质密度的功能剖析

• 批准号: 10512047
• 负责人: Thomas L Clemens
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512047
• 关键词: 14q32; Affect; Affinity; Area; Base Pairing; Bioenergetics; Biological; Biological Assay; Biology; Bone Density; CRISPR/Cas technology; Capital; Cell division; Chromosome Mapping; Chromosomes; Collaborations; Complex; Data; Dissection; Elements; Femur; Genes; Genetic; Genetic Determinism; Genetic Variation; Genomics; Heritability; Human; In Vitro; Intervention; Introns; Knowledge; Link; Luciferases; Methodological Studies; Microtubules; Mus; Mutation; Neck; Network-based; Neuronal Differentiation; Osteoblasts; Osteoporosis; Pathology; Pathway interactions; Persons; Phenotype; Phosphotransferases; Predisposition; Prevalence; Process; Protein-Serine-Threonine Kinases; RNA Splicing; Regulator Genes; Regulatory Pathway; Reporter; Research; Risk; Role; Scientist; Serine; Signal Transduction; Skeleton; Testing; Thick; Universities; Variant; Veterans; Veterans Health Administration; Virginia; bone; bone mass; career; causal variant; follow-up; fracture risk; genome wide association study; genome-wide; genomic locus; global health; knock-down; male; men; mineralization; notch protein; novel; novel therapeutics; osteoporosis with pathological fracture; patient population; programs; skeletal; social; synergism; trait

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.

男性骨质疏松症的患病率仍未得到充分认识。退伍军人患者群体 健康管理局（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 矿物质密度（BMD）是骨质疏松性骨折的高度遗传性预测因子。大规模基因组范围 关联研究 (GWAS) 已识别出数十个包含变异 (SNP) 的基因位点，这些变异与 与骨密度。这些位点构成了关于新型骨骼调节基因和未开发信息的宝库。 控制其功能的可遗传基因组元件。然而，尽管它们有可能为骨生物学提供信息， 即使是单个位点，精确的因果变异和目标基因也尚未明确确定。使用 新开发的策略将 BMD GWAS 涉及的基因映射到骨共表达网络上，我们 预测了 64 个 GWAS 位点中 30 个的因果基因。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 (MARK3)（该基因座中的五个基因之一）是因果关系。 MARK3 编码保守的 丝氨酸/苏氨酸激酶已知可调节多种过程，包括不对称细胞分裂和神经元分裂 分化，但其在骨骼中的潜在作用尚不清楚。 Mark3 缺陷小鼠的临时评估 无论是整体还是有条件（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，我们开发了一种综合方法来确定精确的因果关系 与 MARK3 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。这 研究分为两个目标： 具体目标 1：定义潜在的因果遗传机制 Chr14q32.32 BMD GWAS 基因座。具体目标 2：确定 Mark3 在骨骼中的功能。这个项目是 由 Thomas Clemens（BLR&D 高级 VA 研究职业科学家，附属机构）构思并共同领导 与约翰·霍普金斯大学）和查尔斯·法伯在弗吉尼亚大学的赞助下 合作安排。他们的互补研究项目的协同作用已经建立 在之前的项目中。我们坚信，该方法将定义受以下影响的生物网络 突变将极大地有助于理解其病理学并为 干涉。