Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway
Background: Genome-wide association studies (GWAS) have identified numerous loci associated with diseases and traits. However, the elucidation of disease mechanisms followed by drug development has remained a challenge owing to complex gene interactions. We performed pathway analysis with MAGENTA (M...
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doaj-1cc61548cb5c4e03988bf23af48b50dc2020-11-24T21:45:44ZengElsevierInternational Journal of Cardiology: Heart & Vasculature2352-90672019-09-0124Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathwayYusuke Ebana0Yihan Sun1Xiaoxi Yang2Taiju Watanabe3Satoru Makita4Kouichi Ozaki5Toshihiro Tanaka6Hirokuni Arai7Tetsushi Furukawa8Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan; Corresponding author.Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanDepartment of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanDepartment of Cardiovascular Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanDepartment of Cardiovascular Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanLaboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, Japan; Division for Genomic Medicine, Medical Genome Center, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu City, Aichi, JapanLaboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa, Japan; Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanDepartment of Cardiovascular Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanDepartment of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, JapanBackground: Genome-wide association studies (GWAS) have identified numerous loci associated with diseases and traits. However, the elucidation of disease mechanisms followed by drug development has remained a challenge owing to complex gene interactions. We performed pathway analysis with MAGENTA (Meta-Analysis Geneset Enrichment of variaNT Associations) to clarify the pathways in genetic background of AF. Methods: The existing GWAS data were analyzed using MAGENTA. A microarray analysis was then performed for the identified pathways with human atrial tissues, followed by Gene-Set Enrichment Analysis (GSEA). Results: MAGENTA identified two novel candidate pathways for AF pathogenesis, the CTCF (CCCTC-binding factor, p = 1.00 × 10−4, FDR q = 1.64 × 10−2) and mTOR pathways (mammalian target of rapamycin, p = 3.00 × 10−4, FDR q = 3.13 × 10−2). The microarray analysis with human atrial tissue using the GSEA indicated that the mTOR pathway was suppressed in AF cases compared with non-AF cases, validating the MAGENTA results, but not CTCF pathway. Conclusions: MAGENTA identified a novel pathway, mTOR, followed by GSEA with human atrial tissue samples. mTOR pathway is a key interface that adapts the change of environments by pressure overload and metabolic perturbation. Our results indicate that the MTOR pathway is involved in the pathogenesis of AF, although the details of the basic mechanism remain unknown and further analysis for causal-relationship of mTOR pathway to AF is required. CTCF pathway is essential for construction of chromatin structure and transcriptional process. The gene-set components of CTCF overlap with those of mTOR in Biocarta. Keywords: Atrial fibrillation, Pathway analysis, mTOR, MAGENTA, Transcriptome analysishttp://www.sciencedirect.com/science/article/pii/S2352906719300880 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yusuke Ebana Yihan Sun Xiaoxi Yang Taiju Watanabe Satoru Makita Kouichi Ozaki Toshihiro Tanaka Hirokuni Arai Tetsushi Furukawa |
spellingShingle |
Yusuke Ebana Yihan Sun Xiaoxi Yang Taiju Watanabe Satoru Makita Kouichi Ozaki Toshihiro Tanaka Hirokuni Arai Tetsushi Furukawa Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway International Journal of Cardiology: Heart & Vasculature |
author_facet |
Yusuke Ebana Yihan Sun Xiaoxi Yang Taiju Watanabe Satoru Makita Kouichi Ozaki Toshihiro Tanaka Hirokuni Arai Tetsushi Furukawa |
author_sort |
Yusuke Ebana |
title |
Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway |
title_short |
Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway |
title_full |
Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway |
title_fullStr |
Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway |
title_full_unstemmed |
Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway |
title_sort |
pathway analysis with genome-wide association study (gwas) data detected the association of atrial fibrillation with the mtor signaling pathway |
publisher |
Elsevier |
series |
International Journal of Cardiology: Heart & Vasculature |
issn |
2352-9067 |
publishDate |
2019-09-01 |
description |
Background: Genome-wide association studies (GWAS) have identified numerous loci associated with diseases and traits. However, the elucidation of disease mechanisms followed by drug development has remained a challenge owing to complex gene interactions. We performed pathway analysis with MAGENTA (Meta-Analysis Geneset Enrichment of variaNT Associations) to clarify the pathways in genetic background of AF. Methods: The existing GWAS data were analyzed using MAGENTA. A microarray analysis was then performed for the identified pathways with human atrial tissues, followed by Gene-Set Enrichment Analysis (GSEA). Results: MAGENTA identified two novel candidate pathways for AF pathogenesis, the CTCF (CCCTC-binding factor, p = 1.00 × 10−4, FDR q = 1.64 × 10−2) and mTOR pathways (mammalian target of rapamycin, p = 3.00 × 10−4, FDR q = 3.13 × 10−2). The microarray analysis with human atrial tissue using the GSEA indicated that the mTOR pathway was suppressed in AF cases compared with non-AF cases, validating the MAGENTA results, but not CTCF pathway. Conclusions: MAGENTA identified a novel pathway, mTOR, followed by GSEA with human atrial tissue samples. mTOR pathway is a key interface that adapts the change of environments by pressure overload and metabolic perturbation. Our results indicate that the MTOR pathway is involved in the pathogenesis of AF, although the details of the basic mechanism remain unknown and further analysis for causal-relationship of mTOR pathway to AF is required. CTCF pathway is essential for construction of chromatin structure and transcriptional process. The gene-set components of CTCF overlap with those of mTOR in Biocarta. Keywords: Atrial fibrillation, Pathway analysis, mTOR, MAGENTA, Transcriptome analysis |
url |
http://www.sciencedirect.com/science/article/pii/S2352906719300880 |
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