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An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In...

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Detalles Bibliográficos
Autores principales: Park, Sungmin, Kim, Daeun, Song, Jaeseung, Joo, Jong Wha J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004271/
https://www.ncbi.nlm.nih.gov/pubmed/33809961
http://dx.doi.org/10.3390/ijms22063216
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author Park, Sungmin
Kim, Daeun
Song, Jaeseung
Joo, Jong Wha J.
author_facet Park, Sungmin
Kim, Daeun
Song, Jaeseung
Joo, Jong Wha J.
author_sort Park, Sungmin
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes’ independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS.
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spelling pubmed-80042712021-03-28 An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates Park, Sungmin Kim, Daeun Song, Jaeseung Joo, Jong Wha J. Int J Mol Sci Article Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes’ independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS. MDPI 2021-03-22 /pmc/articles/PMC8004271/ /pubmed/33809961 http://dx.doi.org/10.3390/ijms22063216 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Park, Sungmin
Kim, Daeun
Song, Jaeseung
Joo, Jong Wha J.
An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title_full An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title_fullStr An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title_full_unstemmed An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title_short An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
title_sort integrative transcriptome-wide analysis of amyotrophic lateral sclerosis for the identification of potential genetic markers and drug candidates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004271/
https://www.ncbi.nlm.nih.gov/pubmed/33809961
http://dx.doi.org/10.3390/ijms22063216
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