Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

Abstract 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 underst...

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Autores principales:	Jerry C. Wang, Gokul Ramaswami, Daniel H. Geschwind
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/57ce8c4e63e04689a29f9c91424b88b9
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spelling	oai:doaj.org-article:57ce8c4e63e04689a29f9c91424b88b92021-12-02T13:33:51ZGene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility10.1038/s41598-021-85061-42045-2322https://doaj.org/article/57ce8c4e63e04689a29f9c91424b88b92021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85061-4https://doaj.org/toc/2045-2322Abstract 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.Jerry C. WangGokul RamaswamiDaniel H. GeschwindNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jerry C. Wang Gokul Ramaswami Daniel H. Geschwind Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
description	Abstract 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.
format	article
author	Jerry C. Wang Gokul Ramaswami Daniel H. Geschwind
author_facet	Jerry C. Wang Gokul Ramaswami Daniel H. Geschwind
author_sort	Jerry C. Wang
title	Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
title_short	Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
title_full	Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
title_fullStr	Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
title_full_unstemmed	Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
title_sort	gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/57ce8c4e63e04689a29f9c91424b88b9
work_keys_str_mv	AT jerrycwang genecoexpressionnetworkanalysisinhumanspinalcordhighlightsmechanismsunderlyingamyotrophiclateralsclerosissusceptibility AT gokulramaswami genecoexpressionnetworkanalysisinhumanspinalcordhighlightsmechanismsunderlyingamyotrophiclateralsclerosissusceptibility AT danielhgeschwind genecoexpressionnetworkanalysisinhumanspinalcordhighlightsmechanismsunderlyingamyotrophiclateralsclerosissusceptibility
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Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility

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