A Genome-Wide Association Study and Complex Network Identify Four Core Hub Genes in Bipolar Disorder

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2017 Dec 20

PMID 29257106

Citations 7

Authors

Zengyan Xie

Xianyan Yang

Xiaoya Deng

Mingyue Ma

Kunxian Shu

Affiliations

Soon will be listed here.

Abstract

Bipolar disorder is a common and severe mental illness with unsolved pathophysiology. A genome-wide association study (GWAS) has been used to find a number of risk genes, but it is difficult for a GWAS to find genes indirectly associated with a disease. To find core hub genes, we introduce a network analysis after the GWAS was conducted. Six thousand four hundred fifty eight single nucleotide polymorphisms (SNPs) with < 0.01 were sifted out from Wellcome Trust Case Control Consortium (WTCCC) dataset and mapped to 2045 genes, which are then compared with the protein-protein network. One hundred twelve genes with a degree >17 were chosen as hub genes from which five significant modules and four core hub genes (, , , and ) were found. These core hub genes have not been reported to be directly associated with BD but may function by interacting with genes directly related to BD. Our method engenders new thoughts on finding genes indirectly associated with, but important for, complex diseases.

Citing Articles

Optical coherence tomography-guided Brillouin microscopy highlights regional tissue stiffness differences during anterior neural tube closure in the Mthfd1l murine mutant.

Ambekar Y, Caiaffa C, Wlodarczyk B, Singh M, Schill A, Steele J Development. 2024; 151(10).

PMID: 38682273 PMC: 11165724. DOI: 10.1242/dev.202475.

Transcriptome-Wide Identification of G-to-A RNA Editing in Chronic Social Defeat Stress Mouse Models.

Tao J, Ren C, Wei Z, Zhang F, Xu J, Chen J Front Genet. 2021; 12:680548.

PMID: 34093668 PMC: 8173075. DOI: 10.3389/fgene.2021.680548.

Involvement of myocyte enhancer factor 2c in the pathogenesis of autism spectrum disorder.

Chaudhary R, Agarwal V, Kaushik A, Rehman M Heliyon. 2021; 7(4):e06854.

PMID: 33981903 PMC: 8082549. DOI: 10.1016/j.heliyon.2021.e06854.

Emerging roles for MEF2 in brain development and mental disorders.

Assali A, Harrington A, Cowan C Curr Opin Neurobiol. 2019; 59:49-58.

PMID: 31129473 PMC: 6874740. DOI: 10.1016/j.conb.2019.04.008.

Population-based genome-wide association study of cognitive decline in older adults free of dementia: identification of a novel locus for the attention domain.

Kamboh M, Fan K, Yan Q, Beer J, Snitz B, Wang X Neurobiol Aging. 2019; 84:239.e15-239.e24.

PMID: 30954325 PMC: 6739197. DOI: 10.1016/j.neurobiolaging.2019.02.024.

References

Chen H, Wang N, Zhao X, Ross C, OShea K, McInnis M . Gene expression alterations in bipolar disorder postmortem brains. Bipolar Disord. 2013; 15(2):177-87. PMC: 3582727. DOI: 10.1111/bdi.12039. View

Ruzicka W, Subburaju S, Benes F . Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder. JAMA Psychiatry. 2015; 72(6):541-51. PMC: 5547581. DOI: 10.1001/jamapsychiatry.2015.49. View

Chen H, Ross C, Wang N, Huo Y, MacKinnon D, Potash J . NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene. Eur J Hum Genet. 2002; 9(12):922-30. DOI: 10.1038/sj.ejhg.5200747. View

Szklarczyk D, Morris J, Cook H, Kuhn M, Wyder S, Simonovic M . The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016; 45(D1):D362-D368. PMC: 5210637. DOI: 10.1093/nar/gkw937. View

Noor A, Lionel A, Cohen-Woods S, Moghimi N, Rucker J, Fennell A . Copy number variant study of bipolar disorder in Canadian and UK populations implicates synaptic genes. Am J Med Genet B Neuropsychiatr Genet. 2014; 165B(4):303-13. DOI: 10.1002/ajmg.b.32232. View

Emamalizadeh B, Jamshidi J, Movafagh A, Ohadi M, Shekari Khaniani M, Kazeminasab S . RIT2 Polymorphisms: Is There a Differential Association?. Mol Neurobiol. 2016; 54(3):2234-2240. DOI: 10.1007/s12035-016-9815-4. View

Iossifov I, Zheng T, Baron M, Gilliam T, Rzhetsky A . Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network. Genome Res. 2008; 18(7):1150-62. PMC: 2493404. DOI: 10.1101/gr.075622.107. View

Gouvea E, Ota V, Noto C, Santoro M, Spindola L, Moretti P . Gene expression alterations related to mania and psychosis in peripheral blood of patients with a first episode of psychosis. Transl Psychiatry. 2016; 6(10):e908. PMC: 5315542. DOI: 10.1038/tp.2016.159. View

. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. 2011; 43(10):977-83. PMC: 3637176. DOI: 10.1038/ng.943. View

10.

Barabasi A, Oltvai Z . Network biology: understanding the cell's functional organization. Nat Rev Genet. 2004; 5(2):101-13. DOI: 10.1038/nrg1272. View

11.

Saito T, Guan F, Papolos D, Lau S, Klein M, Fann C . Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Mol Psychiatry. 2001; 6(4):387-95. DOI: 10.1038/sj.mp.4000871. View

12.

Benes F, Lim B, Subburaju S . Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars. Proc Natl Acad Sci U S A. 2009; 106(28):11731-6. PMC: 2703668. DOI: 10.1073/pnas.0903066106. View

13.

Drago A, Crisafulli C, Sidoti A, Calabro M, Serretti A . The microtubule-associated molecular pathways may be genetically disrupted in patients with Bipolar Disorder. Insights from the molecular cascades. J Affect Disord. 2015; 190:429-438. DOI: 10.1016/j.jad.2015.10.016. View

14.

Eszlari N, Kovacs D, Petschner P, Pap D, Gonda X, Elliott R . Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry. 2016; 6:e745. PMC: 4872445. DOI: 10.1038/tp.2016.19. View

15.

Hunsberger J, Chibane F, Elkahloun A, Henderson R, Singh R, Lawson J . Novel integrative genomic tool for interrogating lithium response in bipolar disorder. Transl Psychiatry. 2015; 5:e504. PMC: 4445744. DOI: 10.1038/tp.2014.139. View

16.

Doherty J, Owen M . Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice. Genome Med. 2014; 6(4):29. PMC: 4062063. DOI: 10.1186/gm546. View

17.

Schweiger R, Linial M, Linial N . Generative probabilistic models for protein-protein interaction networks--the biclique perspective. Bioinformatics. 2011; 27(13):i142-8. PMC: 3117378. DOI: 10.1093/bioinformatics/btr201. View

18.

Mitchell A, Javidfar B, Pothula V, Ibi D, Shen E, Peter C . MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry. 2017; 23(1):123-132. PMC: 5966823. DOI: 10.1038/mp.2016.254. View

19.

Yuan P, Zhou R, Wang Y, Li X, Li J, Chen G . Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia. J Affect Disord. 2009; 124(1-2):164-9. PMC: 2875351. DOI: 10.1016/j.jad.2009.10.017. View

20.

Chen P, Chen J, Huang K, Ji W, Wang T, Li T . Analysis of association between common SNPs in ErbB4 and bipolar affective disorder, major depressive disorder and schizophrenia in the Han Chinese population. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 36(1):17-21. DOI: 10.1016/j.pnpbp.2011.09.011. View