Runxu Yang , Rui Wang , Dongyan Zhao , Kun Lian , Binli Shang , Lei Dong , Xuejuan Yang , Xinglun Dang , Duo Sun , Yuqi Cheng
{"title":"通过对全转录组关联研究和 mRNA 表达谱的整合分析，确定了双相情感障碍的风险基因。","authors":"Runxu Yang , Rui Wang , Dongyan Zhao , Kun Lian , Binli Shang , Lei Dong , Xuejuan Yang , Xinglun Dang , Duo Sun , Yuqi Cheng","doi":"10.1016/j.neulet.2024.137935","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through “vast but mixed” Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS.</p></div><div><h3>Methods</h3><p>We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0).</p></div><div><h3>Results</h3><p>TWAS identified 362 genes with <em>P</em> value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (<em>P</em><sub>TWAS</sub>=1.07 × 10<sup>-11</sup>), ALOX5AP (<em>P</em><sub>TWAS</sub>=3.12 × 10<sup>-8</sup>), and PLEC (<em>P</em><sub>TWAS</sub>=1.27 × 10<sup>-7</sup>). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (<em>P</em><sub>TWAS</sub>=0.0020, <em>P</em><sub>mRNA</sub>=0.0000), TMPRSS9 (<em>P</em><sub>TWAS</sub>=0.0405, <em>P</em><sub>mRNA</sub>=0.0032), and SNX10 (<em>P</em><sub>TWAS</sub>=0.0104, <em>P</em><sub>mRNA</sub>=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species.</p></div><div><h3>Conclusions</h3><p>We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.</p></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304394024003136/pdfft?md5=d5cebb38191bbf089a3cb407d0b361e6&pid=1-s2.0-S0304394024003136-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Integrative analysis of transcriptome-wide association study and mRNA expression profile identified risk genes for bipolar disorder\",\"authors\":\"Runxu Yang , Rui Wang , Dongyan Zhao , Kun Lian , Binli Shang , Lei Dong , Xuejuan Yang , Xinglun Dang , Duo Sun , Yuqi Cheng\",\"doi\":\"10.1016/j.neulet.2024.137935\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through “vast but mixed” Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS.</p></div><div><h3>Methods</h3><p>We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0).</p></div><div><h3>Results</h3><p>TWAS identified 362 genes with <em>P</em> value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (<em>P</em><sub>TWAS</sub>=1.07 × 10<sup>-11</sup>), ALOX5AP (<em>P</em><sub>TWAS</sub>=3.12 × 10<sup>-8</sup>), and PLEC (<em>P</em><sub>TWAS</sub>=1.27 × 10<sup>-7</sup>). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (<em>P</em><sub>TWAS</sub>=0.0020, <em>P</em><sub>mRNA</sub>=0.0000), TMPRSS9 (<em>P</em><sub>TWAS</sub>=0.0405, <em>P</em><sub>mRNA</sub>=0.0032), and SNX10 (<em>P</em><sub>TWAS</sub>=0.0104, <em>P</em><sub>mRNA</sub>=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species.</p></div><div><h3>Conclusions</h3><p>We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.</p></div>\",\"PeriodicalId\":19290,\"journal\":{\"name\":\"Neuroscience Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0304394024003136/pdfft?md5=d5cebb38191bbf089a3cb407d0b361e6&pid=1-s2.0-S0304394024003136-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuroscience Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0304394024003136\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304394024003136","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Integrative analysis of transcriptome-wide association study and mRNA expression profile identified risk genes for bipolar disorder
Objective
Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through “vast but mixed” Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS.
Methods
We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0).
Results
TWAS identified 362 genes with P value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (PTWAS=1.07 × 10-11), ALOX5AP (PTWAS=3.12 × 10-8), and PLEC (PTWAS=1.27 × 10-7). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (PTWAS=0.0020, PmRNA=0.0000), TMPRSS9 (PTWAS=0.0405, PmRNA=0.0032), and SNX10 (PTWAS=0.0104, PmRNA=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species.
Conclusions
We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.
期刊介绍：
Neuroscience Letters is devoted to the rapid publication of short, high-quality papers of interest to the broad community of neuroscientists. Only papers which will make a significant addition to the literature in the field will be published. Papers in all areas of neuroscience - molecular, cellular, developmental, systems, behavioral and cognitive, as well as computational - will be considered for publication. Submission of laboratory investigations that shed light on disease mechanisms is encouraged. Special Issues, edited by Guest Editors to cover new and rapidly-moving areas, will include invited mini-reviews. Occasional mini-reviews in especially timely areas will be considered for publication, without invitation, outside of Special Issues; these un-solicited mini-reviews can be submitted without invitation but must be of very high quality. Clinical studies will also be published if they provide new information about organization or actions of the nervous system, or provide new insights into the neurobiology of disease. NSL does not publish case reports.
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