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

基本信息

批准号：
10255877
负责人：
Thomas L Clemens
金额：
$ 54.92万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255877
关键词：
14q32 Affect Alleles Area Automobile Driving Base Pairing Bioenergetics Biological Biological Assay Biology Bone Density CRISPR/Cas technology Capital Cell division Chromosomes Collaborations Complex Data Dissection Elements Enhancers Generations Genes Genetic Genetic Determinism Genomics Heritability Human In Vitro Intervention Knowledge Lead Link Luciferases Maps Methodological Studies Mus Mutation Neck Network-based Neuronal Differentiation Osteoblasts Osteoporosis Pathology Pathway interactions Phenotype Phosphotransferases Predisposition Process Protein-Serine-Threonine Kinases Regulator Genes Regulatory Pathway Reporter Research Role Scanning Signal Transduction Skeleton System Testing Thick Transgenic Mice Universities Variant Virginia base bone bone mass causal variant follow-up fracture risk genome wide association study genome-wide genomic locus global health in vivo knock-down mineralization notch protein novel novel therapeutics osteoporosis with pathological fracture programs skeletal social synergism trait

项目摘要

SUMMARY/ABSTRACT Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture (ref). 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 identified by 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 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 three 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 Specific Aim 3: Test function of the regulatory SNP(s) in vivo. This project was conceived and will be jointly headed by Thomas Clemens at Johns Hopkins University and Charles Farber at the University of Virginia under the auspices of a Multi PI 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.

摘要/摘要骨矿物质密度（BMD）是骨质疏松性骨折的高度遗传性预测因子（参考）。大规模基因组广泛关联研究 (GWAS) 已可靠地鉴定出数十个含有变异 (SNP) 的基因位点与骨密度有关。这些位点构成了关于新型骨骼调节的未开发信息的宝库基因和控制其功能的可遗传基因组元件。然而，尽管它们有可能告知在骨生物学中，尚未明确确定由靶基因识别的精确因果变异即使是单个位点。使用新开发的策略将 BMD GWAS 涉及的基因映射到骨骼上通过表达网络，我们预测了 64 个 GWAS 位点中 30 个的因果基因。位于染色体上的一个基因座 14q32.32 包含与股骨颈 BMD 高度相关的 SNP (P=5.0 x 10-16)，我们预测 MARK3 是该基因座中的五个基因之一，是因果关系。 MARK3 编码已知的保守丝氨酸/苏氨酸激酶调节不同的过程，包括不对称细胞分裂和神经元分化，但其潜力在骨骼中的作用尚不清楚。对 Mark3 整体或有条件缺陷的小鼠进行临时评估（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，我们开发了识别与 MARK3 相关的精确因果变异并确定活性的综合方法成骨细胞中的这种激酶控制骨量。这些研究分为三个目标：具体目标 1：定义 Chr14q32.32 BMD GWAS 位点的因果遗传机制。具体目标 2：确定 Mark3 如何在骨骼中发挥作用具体目标 3：测试体内调节性 SNP 的功能。这个项目由约翰·霍普金斯大学的托马斯·克莱门斯 (Thomas Clemens) 和查尔斯·法伯 (Charles Farber) 构思并共同领导在多 PI 安排的赞助下在弗吉尼亚大学进行。他们互补的协同作用研究计划已在之前的项目中确定。我们坚信该方法将定义受突变影响的生物网络将大大有助于理解它们病理学并为干预提供重要目标。