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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doaj-9fdc1e98200349c78c9cdb544850563c2021-03-23T00:02:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01223216321610.3390/ijms22063216An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug CandidatesSungmin Park0Daeun Kim1Jaeseung Song2Jong Wha J. Joo3Department of Computer Engineering, Dongguk University, Seoul 04620, KoreaDepartment of Life Science, Dongguk University, Seoul 04620, KoreaDepartment of Life Science, Dongguk University, Seoul 04620, KoreaDepartment of Computer Engineering, Dongguk University, Seoul 04620, KoreaAmyotrophic 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.https://www.mdpi.com/1422-0067/22/6/3216amyotrophic lateral sclerosistranscriptome-wide association studydrug repositioningenrichment analysiscausal gene |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sungmin Park Daeun Kim Jaeseung Song Jong Wha J. Joo |
spellingShingle |
Sungmin Park Daeun Kim Jaeseung Song Jong Wha J. Joo An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates International Journal of Molecular Sciences amyotrophic lateral sclerosis transcriptome-wide association study drug repositioning enrichment analysis causal gene |
author_facet |
Sungmin Park Daeun Kim Jaeseung Song Jong Wha J. Joo |
author_sort |
Sungmin Park |
title |
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_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_sort |
integrative transcriptome-wide analysis of amyotrophic lateral sclerosis for the identification of potential genetic markers and drug candidates |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-03-01 |
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. |
topic |
amyotrophic lateral sclerosis transcriptome-wide association study drug repositioning enrichment analysis causal gene |
url |
https://www.mdpi.com/1422-0067/22/6/3216 |
work_keys_str_mv |
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