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）是骨质疏松骨折的高度可遗传的预测指标（REF）。大规模基因组广泛的关联研究（GWAS）已牢固地识别出数十个遗传基因座（SNP）与BMD相关。这些基因座构成了有关新型骨骼调节的未开发信息的宝库基因和控制其功能的基因组元素。但是，尽管他们有可能告知骨骼生物学，尚未确定的确切因果变异和靶基因确定甚至一个基因座。使用新开发的策略来映射BMD GWA与骨共同的基因表达网络，我们预测了64个GWAS基因座中30个因果基因。一个位于染色体上的基因座 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/苏氨酸激酶调节包括不对称细胞分裂和神经元分化在内的各种过程，但其潜力在骨骼中的作用尚不清楚。对全球或有条件的MARK3缺乏的小鼠的临时评估（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相关的确切因果变异的综合方法并确定活动如何在成骨细胞中的激酶控制骨骼质量。研究分为三个目标：特定目标1：定义 CHR14Q32.32 BMD GWAS基因座的基础的因果遗传机制。具体目标2：确定 Mark3在骨骼特异性目标中的功能3：体内调节SNP的测试功能。这个项目受孕，将由约翰·霍普金斯大学和查尔斯·法伯的托马斯·克莱门斯共同领导根据多PI安排的主持，在弗吉尼亚大学。他们免费的协同作用研究计划已经在以前的项目中建立。我们坚信这种方法将定义受突变影响的生物网络将有助于理解其病理学并为干预提供重要目标。