Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Convolutional Neural Network Visualization for Identification of Risk Genes in Bipolar Disorder

Author(s): Qixuan Yue, Jie Yang, Qian Shu, Mingze Bai and Kunxian Shu*

Volume 20, Issue 6, 2020

Page: [429 - 441] Pages: 13

DOI: 10.2174/1566524019666191129111753

Price: $65

Abstract

Background: Bipolar disorder (BD) is a type of chronic emotional disorder with a complex genetic structure. However, its genetic molecular mechanism is still unclear, which makes it insufficient to be diagnosed and treated.

Methods and Results: In this paper, we proposed a model for predicting BD based on single nucleotide polymorphisms (SNPs) screening by genome-wide association study (GWAS), which was constructed by a convolutional neural network (CNN) that predicted the probability of the disease. According to the difference of GWAS threshold, two sets of data were named: group P001 and group P005. And different convolutional neural networks are set for the two sets of data. The training accuracy of the model trained with group P001 data is 96%, and the test accuracy is 91%. The training accuracy of the model trained with group P005 data is 94.5%, and the test accuracy is 92%. At the same time, we used gradient weighted class activation mapping (Grad-CAM) to interpret the prediction model, indirectly to identify high-risk SNPs of BD. In the end, we compared these high-risk SNPs with human gene annotation information.

Conclusion: The model prediction results of the group P001 yielded 137 risk genes, of which 22 were reported to be associated with the occurrence of BD. The model prediction results of the group P005 yielded 407 risk genes, of which 51 were reported to be associated with the occurrence of BD.

Keywords: Bipolar disorder, SNP, risk gene, CNN, Grad-CAM, GWAS.

« Previous Next »
[1]
Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet 2016; 387(10027): 1561-72.
[http://dx.doi.org/10.1016/S0140-6736(15)00241-X] [PMID: 26388529.]
[2]
John A, McGregor J, Jones I, et al. Premature mortality among people with severe mental illness - New evidence from linked primary care data. Schizophr Res 2018; 199: 154-62.
[http://dx.doi.org/10.1016/j.schres.2018.04.009] [PMID: 29728293]
[3]
Nielsen RE, Kugathasan P, Straszek S, Jensen SE, Licht RW. Why are somatic diseases in bipolar disorder insufficiently treated? Int J Bipolar Disord 2019; 7(1): 12.
[http://dx.doi.org/10.1186/s40345-019-0147-y] [PMID: 31055668]
[4]
Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016; 21(12): 1696-709.
[http://dx.doi.org/10.1038/mp.2016.3] [PMID: 26903267]
[5]
Chen J, Peng H, Han G, Cai H, Cai J. HOGMMNC: a higher order graph matching with multiple network constraints model for gene-drug regulatory modules identification. Bioinformatics 2019; 35(4): 602-10.
[http://dx.doi.org/10.1093/bioinformatics/bty662] [PMID: 30052773]
[6]
LeCun Y, Bengio Y, Hinton G. Deep learning. Nature 2015; 521(7553): 436-44.
[http://dx.doi.org/10.1038/nature14539] [PMID: 26017442]
[7]
LeCun Y, Bottou L, Bengio Y, et al. Gradient-based learning applied to document recognition. Proc IEEE 1998; 86(11): 2278-324.
[http://dx.doi.org/10.1109/5.726791]
[8]
Kalchbrenner N, Grefenstette E, Blunsom P. A convolutional neural network for modelling sentences arXiv preprint arXiv: 14042188 2014.
[9]
Salagre E, Dodd S, Aedo A, et al. Towards precision psychiatry in bipolar disorder: Staging 2.0. Front Psychiatry 2018; 9: 641.
[http://dx.doi.org/10.3389/fpsyt.2018.00641] [PMID: 30555363]
[10]
Sun Q, Yue Q, Zhu F, et al. The Identification research of bipolar disorder based on CNN. J Phys Conf Ser 2019; 1168(3)032125
[http://dx.doi.org/10.1088/1742-6596/1168/3/032125]
[11]
Xie Z, Yang X, Deng X, Ma M, Shu K. A genome-wide association study and complex network identify four core hub genes in bipolar disorder. Int J Mol Sci 2017; 18(12): 2763.
[http://dx.doi.org/10.3390/ijms18122763] [PMID: 29257106]
[12]
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447(7145): 661-78.
[http://dx.doi.org/10.1038/nature05911] [PMID: 17554300]
[13]
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81(3): 559-75.
[http://dx.doi.org/10.1086/519795] [PMID: 17701901]
[14]
Turner SD. qqman: An R package for visualizing GWAS results using QQ and manhattan plots. bioRxiv 2014; 1005165
[15]
Chollet F. 2015.Keras https://github.com/fchollet/keras
[16]
Abadi M, Barham P, Chen J, et al. Tensorflow: A system for large-scale machine learning. 12th USENIX Symposium on Operating Systems Design and Implementation (OSDI 16) 265-83.
[17]
Hinton GE, Srivastava N, Krizhevsky A, et al. Improving neural networks by preventing co-adaptation of feature detectors arXiv preprint arXiv:12070580: 2012.
[18]
Selvaraju RR, Cogswell M, Das A, et al. Grad-cam: Visual explanations from deep networks via gradient-based localization. Proceedings of the IEEE International Conference on Computer Vision. 618-26.
[http://dx.doi.org/10.1109/ICCV.2017.74]
[19]
LeNail ANN-SVG. Publication-ready neural network architecture schematics. Journal of Open Source Software 2019; 4: 747.
[http://dx.doi.org/10.21105/joss.00747]
[20]
Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res 2015; 43(Database issue): D36-42.
[http://dx.doi.org/10.1093/nar/gku1055] [PMID: 25355515]
[21]
Chang SH, Gao L, Li Z, Zhang WN, Du Y, Wang J. BDgene: a genetic database for bipolar disorder and its overlap with schizophrenia and major depressive disorder. Biol Psychiatry 2013; 74(10): 727-33.
[http://dx.doi.org/10.1016/j.biopsych.2013.04.016] [PMID: 23764453]
[22]
Green EK, Hamshere M, Forty L, et al. WTCCC. Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample. Mol Psychiatry 2013; 18(12): 1302-7.
[http://dx.doi.org/10.1038/mp.2012.142] [PMID: 23070075]
[23]
Xu W, Cohen-Woods S, Chen Q, et al. Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1. BMC Med Genet 2014; 15(1): 2.
[http://dx.doi.org/10.1186/1471-2350-15-2] [PMID: 24387768]
[24]
Chen X, Long F, Cai B, Chen X, Chen G. A novel relationship for schizophrenia, bipolar and major depressive disorder Part 7: A hint from chromosome 7 high density association screen. Behav Brain Res 2015; 293: 241-51.
[http://dx.doi.org/10.1016/j.bbr.2015.06.043] [PMID: 26192912]
[25]
Jamain S, Cichon S, Etain B, et al. Common and rare variant analysis in early-onset bipolar disorder vulnerability. PLoS One 2014; 9(8)e104326
[http://dx.doi.org/10.1371/journal.pone.0104326] [PMID: 25111785]
[26]
Malhotra D, McCarthy S, Michaelson JJ, et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 2011; 72(6): 951-63.
[http://dx.doi.org/10.1016/j.neuron.2011.11.007] [PMID: 22196331]
[27]
Yosifova A, Mushiroda T, Stoianov D, et al. Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population. J Affect Disord 2009; 117(1-2): 87-97.
[http://dx.doi.org/10.1016/j.jad.2008.12.021] [PMID: 19328558]
[28]
Cho CH, Lee HJ, Woo HG, Choi JH, Greenwood TA, Kelsoe JR. CDH13 and HCRTR2 may be associated with hypersomnia symptom of bipolar depression: a genome-wide functional enrichment pathway analysis. Psychiatry Investig 2015; 12(3): 402-7.
[http://dx.doi.org/10.4306/pi.2015.12.3.402] [PMID: 26207136]
[29]
Steinberg S, de Jong S, Mattheisen M, et al. Common variant at 16p11.2 conferring risk of psychosis. Mol Psychiatry 2014; 19(1): 108-14.
[http://dx.doi.org/10.1038/mp.2012.157] [PMID: 23164818]
[30]
Georgieva L, Rees E, Moran JL, et al. De novo CNVs in bipolar affective disorder and schizophrenia. Hum Mol Genet 2014; 23(24): 6677-83.
[http://dx.doi.org/10.1093/hmg/ddu379] [PMID: 25055870]
[31]
Szczepankiewicz A, Leszczyńska-Rodziewicz A, Pawlak J, et al. Epistatic interaction between CRHR1 and AVPR1b variants as a predictor of major depressive disorder. Psychiatr Genet 2013; 23(6): 239-46.
[http://dx.doi.org/10.1097/YPG.0000000000000007] [PMID: 23962971]
[32]
Ollila HM, Soronen P, Silander K, et al. Findings from bipolar disorder genome-wide association studies replicate in a Finnish bipolar family-cohort. Mol Psychiatry 2009; 14(4): 351-3.
[http://dx.doi.org/10.1038/mp.2008.122] [PMID: 19308021]
[33]
Moskvina V, Craddock N, Holmans P, et al. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009; 14(3): 252-60.
[http://dx.doi.org/10.1038/mp.2008.133] [PMID: 19065143]
[34]
Zeng Z, Wang T, Li T, et al. Common SNPs and haplotypes in DGKH are associated with bipolar disorder and schizophrenia in the Chinese Han population. Mol Psychiatry 2011; 16(5): 473-5.
[http://dx.doi.org/10.1038/mp.2010.86] [PMID: 20733578]
[35]
Drago A, Crisafulli C, Sidoti A, Calabrò 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 2016; 190: 429-38.
[http://dx.doi.org/10.1016/j.jad.2015.10.016] [PMID: 26551401]
[36]
Koefoed P, Andreassen OA, Bennike B, et al. Combinations of SNPs related to signal transduction in bipolar disorder. PLoS One 2011; 6(8)e23812
[http://dx.doi.org/10.1371/journal.pone.0023812] [PMID: 21897858]
[37]
Noor A, Lionel AC, Cohen-Woods S, et al. 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.
[http://dx.doi.org/10.1002/ajmg.b.32232] [PMID: 24700553]
[38]
Byrne EM, Heath AC, Madden P A F, et al. Testing the role of circadian genes in conferring risk for psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 2014; 165B(3): 254-60.
[http://dx.doi.org/10.1002/ajmg.b.32230] [PMID: 24687905]
[39]
Gonzalez S, Camarillo C, Rodriguez M, et al. A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32. Am J Med Genet B Neuropsychiatr Genet 2014; 165B(6): 479-91.
[http://dx.doi.org/10.1002/ajmg.b.32251] [PMID: 25044503]
[40]
Karlsson R, Graae L, Lekman M, et al. MAGI1 copy number variation in bipolar affective disorder and schizophrenia. Biol Psychiatry 2012; 71(10): 922-30.
[http://dx.doi.org/10.1016/j.biopsych.2012.01.020] [PMID: 22381734]
[41]
Sklar P, Ripke S, Scott LJ, et al. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43(10): 977-83.
[http://dx.doi.org/10.1038/ng.943] [PMID: 21926972]
[42]
Zain MA, Roffeei SN, Zainal NZ, Kanagasundram S, Mohamed Z. Nonsynonymous polymorphisms of the PDLIM5 gene association with the occurrence of both bipolar disorder and schizophrenia. Psychiatr Genet 2013; 23(6): 258-61.
[http://dx.doi.org/10.1097/YPG.0000000000000015]] [PMID: 24064681]
[43]
Le Hellard S, Lee AJ, Underwood S, et al. Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder. Biol Psychiatry 2007; 61(6): 797-805.
[http://dx.doi.org/10.1016/j.biopsych.2006.06.029] [PMID: 16996484]
[44]
Lencz T, Guha S, Liu C, et al. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nat Commun 2013; 4: 2739.
[http://dx.doi.org/10.1038/ncomms3739] [PMID: 24253340]
[45]
Hattori E, Toyota T, Ishitsuka Y, et al. Preliminary genome-wide association study of bipolar disorder in the Japanese population. [J] Am J Med Genet B Neuropsychiatr Genet 2009; 150B(8): 1110-7.
[http://dx.doi.org/10.1002/ajmg.b.30941] [PMID: 19259986]
[46]
Crisafulli C, Shim DS, Andrisano C, et al. Case-control association study of 14 variants of CREB1, CREBBP and CREM on diagnosis and treatment outcome in major depressive disorder and bipolar disorder. Psychiatry Res 2012; 198(1): 39-46.
[http://dx.doi.org/10.1016/j.psychres.2011.08.022] [PMID: 22386572]
[47]
Jan WC, Yang SY, Chuang LC, et al. Exploring the associations between genetic variants in genes encoding for subunits of calcium channel and subtypes of bipolar disorder. J Affect Disord 2014; 157: 80-6.
[http://dx.doi.org/10.1016/j.jad.2013.12.044] [PMID: 24581832]
[48]
Fiorentino A, O’Brien NL, Locke DP, et al. Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. Bipolar Disord 2014; 16(6): 583-91.
[http://dx.doi.org/10.1111/bdi.12203] [PMID: 24716743]
[49]
Detera-Wadleigh SD, Liu CY, Maheshwari M, et al. Sequence variation in DOCK9 and heterogeneity in bipolar disorder. Psychiatr Genet 2007; 17(5): 274-86.
[http://dx.doi.org/10.1097/YPG.0b013e328133f352] [PMID: 17728666]
[50]
Johnson C, Drgon T, McMahon FJ, Uhl GR. Convergent genome wide association results for bipolar disorder and substance dependence. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(2): 182-90.
[http://dx.doi.org/10.1002/ajmg.b.30900] [PMID: 19127564]
[51]
McQuillin A, Bass N, Anjorin A, et al. Analysis of genetic deletions and duplications in the University College London bipolar disorder case control sample. Eur J Hum Genet 2011; 19(5): 588-92.
[http://dx.doi.org/10.1038/ejhg.2010.221] [PMID: 21206513]
[52]
Bergen SE, O’Dushlaine CT, Ripke S, et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol Psychiatry 2012; 17(9): 880-6.
[http://dx.doi.org/10.1038/mp.2012.73] [PMID: 22688191]
[53]
Huang J, Perlis RH, Lee PH, et al. Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry 2010; 167(10): 1254-63.
[http://dx.doi.org/10.1176/appi.ajp.2010.09091335] [http://dx.doi.org/20713499]]
[54]
Forero DA, Herteleer L, De Zutter S, et al. A network of synaptic genes associated with schizophrenia and bipolar disorder. Schizophr Res 2016; 172(1-3): 68-74.
[http://dx.doi.org/10.1016/j.schres.2016.02.012] [PMID: 26899345]
[55]
Kuo PH, Chuang LC, Liu JR, et al. Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study. Prog Neuropsychopharmacol Biol Psychiatry 2014; 51: 58-64.
[http://dx.doi.org/10.1016/j.pnpbp.2014.01.003] [PMID: 24444492]
[56]
Kostyrko A, Hauser J, Rybakowski JK, Trzeciak WH. Screening of chromosomal region 21q22.3 for mutations in genes associated with neuronal Ca2+ signalling in bipolar affective disorder. Acta Biochim Pol 2006; 53(2): 317-20.
[PMID: 16733555]
[57]
Hamshere ML, Green EK, Jones IR, et al. Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept. Br J Psychiatry 2009; 195(1): 23-9.
[http://dx.doi.org/10.1192/bjp.bp.108.061424] [PMID: 19567891]
[58]
Anitha A, Nakamura K, Yamada K, et al. Gene and expression analyses reveal enhanced expression of pericentrin 2 (PCNT2) in bipolar disorder. Biol Psychiatry 2008; 63(7): 678-85.
[http://dx.doi.org/10.1016/j.biopsych.2007.07.010] [http://dx.doi.org/17884020]
[59]
Kirov G, Lowry CA, Stephens M, et al. Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder. Mol Psychiatry 2001; 6(6): 671-7.
[http://dx.doi.org/10.1038/sj.mp.4000899] [PMID: 11673795]
[60]
Rezazadeh M, Gharesouran J, Mirabzadeh A, Khorram Khorshid HR, Biglarian A, Ohadi M. A primate-specific functional GTTT-repeat in the core promoter of CYTH4 is linked to bipolar disorder in human. Prog Neuropsychopharmacol Biol Psychiatry 2015; 56: 161-7.
[http://dx.doi.org/10.1016/j.pnpbp.2014.09.001] [PMID: 25240857]
[61]
Georgi B, Craig D, Kember RL, et al. Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. PLoS Genet 2014; 10(3)e1004229
[http://dx.doi.org/10.1371/journal.pgen.1004229] [PMID: 24625924]

Rights & Permissions Print Cite
Article Metrics
22
8
© 2024 Bentham Science Publishers | Privacy Policy