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

doi:10.3389/fnmol.2021.772584

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

Front Mol Neurosci. 2021 Nov 22:14:772584. doi: 10.3389/fnmol.2021.772584. eCollection 2021.

Authors

Chan-Yen Kuo^{1

2}, Tsu-Yi Chen^{3

4}, Pei-Hsiu Kao⁵, Winifred Huang⁶, Chun-Ruei Cho⁵, Ya-Syuan Lai⁵, Giou-Teng Yiang^{3

4}, Chung-Feng Kao^{5

7}

Affiliations

¹ Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan.
² Department of Nursing, Cardinal Tien College of Healthcare and Management, New Taipei, Taiwan.
³ Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan.
⁴ Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan.
⁵ Department of Agronomy, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan.
⁶ School of Management, University of Bath, Bath, United Kingdom.
⁷ Advanced Plant Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.

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.

Keywords: bipolar; dementia; functional subnetwork; genome-wide association study; pathway analysis; prior knowledge.