Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study

Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from associat...

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Autores principales:	Chan-Yen Kuo, Tsu-Yi Chen, Pei-Hsiu Kao, Winifred Huang, Chun-Ruei Cho, Ya-Syuan Lai, Giou-Teng Yiang, Chung-Feng Kao
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	genome-wide association study pathway analysis functional subnetwork prior knowledge bipolar dementia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/7fe2d24f983a453aa5f5f629c2c9be0e
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spelling	oai:doaj.org-article:7fe2d24f983a453aa5f5f629c2c9be0e2021-11-22T05:29:26ZGenetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study1662-509910.3389/fnmol.2021.772584https://doaj.org/article/7fe2d24f983a453aa5f5f629c2c9be0e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnmol.2021.772584/fullhttps://doaj.org/toc/1662-5099Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from association studies including genome-wide association (GWA) studies points to the need of improved analytic strategies to pinpoint the missing heritability for BPD. More importantly, many studies indicate that BPD has a strong association with dementia. We conducted advanced pathway analytics strategies to investigate synergistic effects of multilocus within biologically functional pathways, and further demonstrated functional effects among proteins in subnetworks to examine mechanisms underlying the complex nature of bipolarity using a GWA dataset for BPD. We allowed bipolar susceptible loci to play a role that takes larger weights in pathway-based analytic approaches. Having significantly informative genes identified from enriched pathways, we further built function-specific subnetworks of protein interactions using MetaCore. The gene-wise scores (i.e., minimum p-value) were corrected for the gene-length, and the results were corrected for multiple tests using Benjamini and Hochberg’s method. We found 87 enriched pathways that are significant for BPD; of which 36 pathways were reported. Most of them are involved with several metabolic processes, neural systems, immune system, molecular transport, cellular communication, and signal transduction. Three significant and function-related subnetworks with multiple hotspots were reported to link with several Gene Ontology processes for BPD. Our comprehensive pathway-network frameworks demonstrated that the use of prior knowledge is promising to facilitate our understanding between complex psychiatric disorders (e.g., BPD) and dementia for the access to the connection and clinical implications, along with the development and progression of dementia.Chan-Yen KuoChan-Yen KuoTsu-Yi ChenTsu-Yi ChenPei-Hsiu KaoWinifred HuangChun-Ruei ChoYa-Syuan LaiGiou-Teng YiangGiou-Teng YiangChung-Feng KaoChung-Feng KaoFrontiers Media S.A.articlegenome-wide association studypathway analysisfunctional subnetworkprior knowledgebipolardementiaNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Molecular Neuroscience, Vol 14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	genome-wide association study pathway analysis functional subnetwork prior knowledge bipolar dementia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	genome-wide association study pathway analysis functional subnetwork prior knowledge bipolar dementia Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Chan-Yen Kuo Chan-Yen Kuo Tsu-Yi Chen Tsu-Yi Chen Pei-Hsiu Kao Winifred Huang Chun-Ruei Cho Ya-Syuan Lai Giou-Teng Yiang Giou-Teng Yiang Chung-Feng Kao Chung-Feng Kao Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
description	Bipolar disorder is a complex psychiatric trait that is also recognized as a high substantial heritability from a worldwide distribution. The success in identifying susceptibility loci for bipolar disorder (BPD) has been limited due to its complex genetic architecture. Growing evidence from association studies including genome-wide association (GWA) studies points to the need of improved analytic strategies to pinpoint the missing heritability for BPD. More importantly, many studies indicate that BPD has a strong association with dementia. We conducted advanced pathway analytics strategies to investigate synergistic effects of multilocus within biologically functional pathways, and further demonstrated functional effects among proteins in subnetworks to examine mechanisms underlying the complex nature of bipolarity using a GWA dataset for BPD. We allowed bipolar susceptible loci to play a role that takes larger weights in pathway-based analytic approaches. Having significantly informative genes identified from enriched pathways, we further built function-specific subnetworks of protein interactions using MetaCore. The gene-wise scores (i.e., minimum p-value) were corrected for the gene-length, and the results were corrected for multiple tests using Benjamini and Hochberg’s method. We found 87 enriched pathways that are significant for BPD; of which 36 pathways were reported. Most of them are involved with several metabolic processes, neural systems, immune system, molecular transport, cellular communication, and signal transduction. Three significant and function-related subnetworks with multiple hotspots were reported to link with several Gene Ontology processes for BPD. Our comprehensive pathway-network frameworks demonstrated that the use of prior knowledge is promising to facilitate our understanding between complex psychiatric disorders (e.g., BPD) and dementia for the access to the connection and clinical implications, along with the development and progression of dementia.
format	article
author	Chan-Yen Kuo Chan-Yen Kuo Tsu-Yi Chen Tsu-Yi Chen Pei-Hsiu Kao Winifred Huang Chun-Ruei Cho Ya-Syuan Lai Giou-Teng Yiang Giou-Teng Yiang Chung-Feng Kao Chung-Feng Kao
author_facet	Chan-Yen Kuo Chan-Yen Kuo Tsu-Yi Chen Tsu-Yi Chen Pei-Hsiu Kao Winifred Huang Chun-Ruei Cho Ya-Syuan Lai Giou-Teng Yiang Giou-Teng Yiang Chung-Feng Kao Chung-Feng Kao
author_sort	Chan-Yen Kuo
title	Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
title_short	Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
title_full	Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
title_fullStr	Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
title_full_unstemmed	Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study
title_sort	genetic pathways and functional subnetworks for the complex nature of bipolar disorder in genome-wide association study
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7fe2d24f983a453aa5f5f629c2c9be0e
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Genetic Pathways and Functional Subnetworks for the Complex Nature of Bipolar Disorder in Genome-Wide Association Study

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