Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility.
Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility.
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DOI：
10.1038/s41598-021-85061-4
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发表时间：
2021-03-11
影响因子：
4.6
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Wang JC;Ramaswami G;Geschwind DH
肌萎缩侧索硬化症(ALS)是一种以运动神经元丢失为特征的神经退行性疾病。已经确定了多种遗传风险因素，涉及RNA和蛋白质代谢以及细胞内运输等生物学机制。为了实现对ALS病理生理学机制的系统水平的理解，我们使用来自对照人类脊髓样本的RNA测序数据构建了基因共表达网络，识别了13个基因共表达模块，每个模块代表一个不同的生物学过程或细胞类型。对来自一系列ALS疾病相关背景的四个RNA-SEQ数据集的分析显示，与核糖体功能、创伤反应和白细胞激活相关的许多模块存在异常调节，涉及ALS病理生理学中的星形胶质细胞、少突胶质细胞、内皮细胞和小胶质细胞。为了确定潜在的因果过程，我们对整个基因组的遗传性进行了划分，发现ALS常见的遗传风险在两个特定的模块中得到丰富，SC.M4代表与RNA处理和基因调控相关的基因，SC.M2代表与细胞内运输和自噬相关的基因，并富含少突胶质细胞标记。后者模块的顶级HUB基因包括与ALS相关的风险基因，如KPNA3、TMED2和NCOA4，后者调节铁蛋白自噬，参与ALS的病理生理过程。这些不偏不倚的全基因组分析证实了系统方法在理解肌萎缩侧索硬化症的原因和驱动因素方面的效用。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease defined by motor neuron (MN) loss. Multiple genetic risk factors have been identified, implicating RNA and protein metabolism and intracellular transport, among other biological mechanisms. To achieve a systems-level understanding of the mechanisms governing ALS pathophysiology, we built gene co-expression networks using RNA-sequencing data from control human spinal cord samples, identifying 13 gene co-expression modules, each of which represents a distinct biological process or cell type. Analysis of four RNA-seq datasets from a range of ALS disease-associated contexts reveal dysregulation in numerous modules related to ribosomal function, wound response, and leukocyte activation, implicating astrocytes, oligodendrocytes, endothelia, and microglia in ALS pathophysiology. To identify potentially causal processes, we partitioned heritability across the genome, finding that ALS common genetic risk is enriched within two specific modules, SC.M4, representing genes related to RNA processing and gene regulation, and SC.M2, representing genes related to intracellular transport and autophagy and enriched in oligodendrocyte markers. Top hub genes of this latter module include ALS-implicated risk genes such as KPNA3, TMED2, and NCOA4, the latter of which regulates ferritin autophagy, implicating this process in ALS pathophysiology. These unbiased, genome-wide analyses confirm the utility of a systems approach to understanding the causes and drivers of ALS.
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影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
3.3
作者：
Husedzinovic, Alma;Neumann, Beate;Gruss, Oliver J.
通讯作者：
Gruss, Oliver J.
影响因子：
3.7
作者：
Brohawn, David G.;O'Brien, Laura C.;Bennett, James P., Jr.
通讯作者：
Bennett, James P., Jr.