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

Chan Yen Kuo, Tsu Yi Chen, Pei Hsiu Kao, Winifred Huang, Chun Ruei Cho, Ya Syuan Lai, Giou Teng Yiang, Chung Feng Kao

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5 Citations (SciVal)

Abstract

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.

Original languageEnglish
Article number772584
JournalFrontiers in Molecular Neuroscience
Volume14
DOIs
Publication statusPublished - 22 Nov 2021

Bibliographical note

Funding Information:
This work was supported by grant MOST 109-2320-B-303-004-MY3 from Taiwan Ministry of Science and Technology and grant TCRD-TPE-MOST-109-15 from the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan. This work was financially supported (in part) by the Advanced Plant Biotechnology Center from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

Funding

This work was supported by grant MOST 109-2320-B-303-004-MY3 from Taiwan Ministry of Science and Technology and grant TCRD-TPE-MOST-109-15 from the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan. This work was financially supported (in part) by the Advanced Plant Biotechnology Center from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

Keywords

  • bipolar
  • dementia
  • functional subnetwork
  • genome-wide association study
  • pathway analysis
  • prior knowledge

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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