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Identification of a Core Module for Bone Mineral Density through the Integration of a Co-expression Network and GWAS Data.
Cell Reports ( IF 8.8 ) Pub Date : 2020-09-15 , DOI: 10.1016/j.celrep.2020.108145
Olivia L Sabik 1 , Gina M Calabrese 2 , Eric Taleghani 2 , Cheryl L Ackert-Bicknell 3 , Charles R Farber 4
Affiliation  

The “omnigenic” model of the genetic architecture of complex traits proposed two categories of causal genes: core and peripheral. Core genes are hypothesized to directly regulate disease and may serve as therapeutic targets. Using a cell-type- and time-point-specific gene co-expression network for mineralizing osteoblasts, we identify a co-expression module enriched for genes implicated by bone mineral density (BMD) genome-wide association studies (GWASs), correlated with in vitro osteoblast mineralization and associated with skeletal phenotypes in human monogenic disease and mouse knockouts. Four genes from this module (B4GALNT3, CADM1, DOCK9, and GPR133) are located within the BMD GWAS loci with colocalizing expression quantitative trait loci (eQTL) and exhibit altered BMD in mouse knockouts, suggesting that they are causal genetic drivers of BMD in humans. Our network-based approach identifies a “core” module for BMD and provides a resource for expanding our understanding of the genetics of bone mass.



中文翻译:

通过整合共表达网络和 GWAS 数据确定骨矿物质密度的核心模块。

复杂性状遗传结构的“全基因”模型提出了两类因果基因:核心基因和外围基因。核心基因被假设为直接调节疾病并可作为治疗靶点。使用细胞类型和时间点特异性基因共表达网络来矿化成骨细胞,我们确定了一个共表达模块,该模块富含与骨矿物质密度 (BMD) 全基因组关联研究 (GWAS) 相关的基因,与体外成骨细胞矿化并与人类单基因疾病和小鼠基因敲除的骨骼表型相关。该模块的四个基因(B4GALNT3CADM1DOCK9GPR133) 位于 BMD GWAS 基因座内,具有共定位表达数量性状基因座 (eQTL),并在小鼠敲除中表现出改变的 BMD,表明它们是人类 BMD 的因果遗传驱动因素。我们基于网络的方法确定了 BMD 的“核心”模块,并为扩展我们对骨量遗传学的理解提供了资源。

更新日期:2020-09-15
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