Prioritization of candidate genes for attention deficit hyperactivity disorder by computational analysis of multiple data sources

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder characterized by hyperactivity, inattention and increased impulsivity. In recent years, a large number of genetic studies for ADHD have been published and related genetic data has been accumulated dramatically. To provide researchers a comprehensive ADHD genetic resource, we previously developed the first genetic database for ADHD (ADHDgene). The abundant genetic data provides novel candidates for further study. Meanwhile, it also brings new challenge for selecting promising candidate genes for replication and verification research. In this study, we surveyed the computational tools for candidate gene prioritization and selected five tools, which integrate multiple data sources for gene prioritization, to prioritize ADHD candidate genes in ADHDgene. The prioritization analysis resulted in 16 prioritized candidate genes, which are mainly involved in several major neurotransmitter systems or in nervous system development pathways. Among these genes, nervous system development related genes, especially SNAP25, STX1A and the gene-gene interactions related with each of them deserve further investigations. Our results may provide new insight for further verification study and facilitate the exploration of pathogenesis mechanism of ADHD.

Keywords

gene prioritization / attention deficit hyperactivity disorder / candidate genes / multiple data sources

References

[1] Aerts, S., Lambrechts, D., Maity, S., Van Loo, P., Coessens, B., De Smet, F., Tranchevent, L.-C., De Moor, B., Marynen, P., Hassan, B., . (2006). Gene prioritization through genomic data fusion. Nat Biotech 24, 537-544 .10.1038/nbt1203
[2] Aerts, S., Van Loo, P., Thijs, G., Mayer, H., de Martin, R., Moreau, Y., and De Moor, B. (2005). TOUCAN 2: the all-inclusive open source workbench for regulatory sequence analysis. Nucleic Acids Res 33, W393-396 .10.1093/nar/gki354
[3] Aerts, S., Vilain, S., Hu, S., Tranchevent, L.C., Barriot, R., Yan, J., Moreau, Y., Hassan, B.A., and Quan, X.J. (2009). Integrating computational biology and forward genetics in Drosophila. Plos Genet 5, e1000351.10.1371/journal.pgen.1000351
[4] Altschul, S.F., Gish, W., Miller, W., Myers, E.W., and Lipman, D.J. (1990). Basic local alignment search tool. J Mol Biol 215, 403-410 .
[5] Arnsten, A.F. (2006). Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways. J Clin Psychiatry 67Suppl 8, 7-12 .
[6] Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T., . (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25, 25-29 .10.1038/75556
[7] Biederman, J., Newcorn, J., and Sprich, S. (1991). Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148, 564-577 .
[8] Brookes, K., Xu, X., Chen, W., Zhou, K., Neale, B., Lowe, N., Anney, R., Franke, B., Gill, M., Ebstein, R., . (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 11, 934-953 .10.1038/sj.mp.4001869
[9] Brookes, K.J., Knight, J., Xu, X., and Asherson, P. (2005). DNA pooling analysis of ADHD and genes regulating vesicle release of neurotransmitters. Am J Med Genet B Neuropsychiatr Genet 139B, 33-37 .10.1002/ajmg.b.30216
[10] Chen, J., Aronow, B.J., and Jegga, A.G. (2009a). Disease candidate gene identification and prioritization using protein interaction networks. BMC Bioinformatics 10, 73.10.1186/1471-2105-10-73
[11] Chen, J., Bardes, E.E., Aronow, B.J., and Jegga, A.G. (2009b). ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res 37, W305-W311 .10.1093/nar/gkp427
[12] Chen, J., Xu, H., Aronow, B.J., and Jegga, A.G. (2007). Improved human disease candidate gene prioritization using mouse phenotype. BMC Bioinformatics 8, 392.10.1186/1471-2105-8-392
[13] Chen, Y., Wang, W., Zhou, Y., Shields, R., Chanda, S.K., Elston, R.C., and Li, J. (2011a). In silico gene prioritization by integrating multiple data sources. PLoS ONE 6, e21137.10.1371/journal.pone.0021137
[14] Chen, Y.A., Tripathi, L.P., and Mizuguchi, K. (2011b). TargetMine, anintegrated data warehouse for candidate gene prioritisation and target discovery. PLoS ONE 6, e17844.10.1371/journal.pone.0017844
[15] Elbers, C.C., Onland-Moret, N.C., Franke, L., Niehoff, A.G., van der Schouw, Y.T., and Wijmenga, C. (2007). A strategy to search for common obesity and type 2 diabetes genes. Trends in endocrinology and metabolism: TEM 18, 19-26 .
[16] Faraone, S.V., and Doyle, A.E. (2001). The nature and heritability of attention-deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 10, 299-316 , viii-ix.
[17] Faraone, S.V., Perlis, R.H., Doyle, A.E., Smoller, J.W., Goralnick, J.J., Holmgren, M.A., and Sklar, P. (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatr 57, 1313-1323 .10.1016/j.biopsych.2004.11.024
[18] Flicek, P., Amode, M.R., Barrell, D., Beal, K., Brent, S., Chen, Y., Clapham, P., Coates, G., Fairley, S., Fitzgerald, S., . (2011). Ensembl 2011. Nucleic Acids Res 39, D800-806 .10.1093/nar/gkq1064
[19] Frank, S.P., Thon, K.P., Bischoff, S.C., and Lorentz, A. (2011). SNAP-23 and syntaxin-3 are required for chemokine release by mature human mast cells. Mol Immunol 49, 353-358 .10.1016/j.molimm.2011.09.011
[20] Franke, L., Bakel, H.v., Fokkens, L., de Jong, E.D., Egmont-Petersen, M., and Wijmenga, C. (2006). Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes. Am J Hum Genet 78, 1011-1025 .10.1086/504300
[21] Gizer, I.R., Ficks, C., and Waldman, I.D. (2009). Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126, 51-90 .10.1007/s00439-009-0694-x
[22] Guan, L., Wang, B., Chen, Y., Yang, L., Li, J., Qian, Q., Wang, Z., Faraone, S.V., and Wang, Y. (2009). A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population. Mol Psychiatry 14, 546-554 .10.1038/sj.mp.4002139
[23] Ivanov, I., Bansal, R., Hao, X., Zhu, H., Kellendonk, C., Miller, L., Sanchez-Pena, J., Miller, A.M., Chakravarty, M.M., Klahr, K., . (2010). Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 167, 397-408 .10.1176/appi.ajp.2009.09030398
[24] Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M., and Hirakawa, M.. (2010). KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 38, D355-360 .10.1093/nar/gkp896
[25] Kang, H.J., Kawasawa, Y.I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A.M., Pletikos, M., Meyer, K.A., Sedmak, G., . (2011). Spatio-temporal transcriptome of the human brain. Nature 478, 483-489 .10.1038/nature10523
[26] Kennedy, M.J., and Ehlers, M.D. (2011). Mechanisms and function of dendritic exocytosis. Neuron 69, 856-875 .10.1016/j.neuron.2011.02.032
[27] Keshava Prasad, T.S., Goel, R., Kandasamy, K., Keerthikumar, S., Kumar, S., Mathivanan, S., Telikicherla, D., Raju, R., Shafreen, B., Venugopal, A., . (2009). Human protein reference database--2009 update. Nucleic Acids Res 37, D767-772 .10.1093/nar/gkn892
[28] Kohler, S., Bauer, S., Horn, D., and Robinson, P.N. (2008). Walking the interactome for prioritization of candidate disease genes. Am J Hum Genet 82, 949-958 .10.1016/j.ajhg.2008.02.013
[29] Lasky-Su, J., Neale, B.M., Franke, B., Anney, R.J., Zhou, K., Maller, J.B., Vasquez, A.A., Chen, W., Asherson, P., Buitelaar, J., . (2008). Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet 147B, 1345-1354 .10.1002/ajmg.b.30867
[30] Levin, E.D. (2002). Nicotinic receptor subtypes and cognitive function. J Neurobiol 53, 633-640 .10.1002/neu.10151
[31] Liu, S.T., Sharon-Friling, R., Ivanova, P., Milne, S.B., Myers, D.S., Rabinowitz, J.D., Brown, H.A., and Shenk, T. (2011). Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress. Proc Natl Acad Sci U S A 108, 12869-12874 .10.1073/pnas.1109796108
[32] McKusick, V.A. (2007). Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 80, 588-604 .10.1086/514346
[33] Mulder, N.J., and Apweiler, R. (2008). The InterPro database and tools for protein domain analysis. Current protocols in bioinformatics/editoral board, Andreas D. Baxevanis et al. Chapter 2, Unit 27 .
[34] Nakamura, K., Iwata, Y., Anitha, A., Miyachi, T., Toyota, T., Yamada, S., Tsujii, M., Tsuchiya, K.J., Iwayama, Y., Yamada, K., . (2011). Replication study of Japanese cohorts supports the role of STX1A in autism susceptibility. Prog Neuropsychopharmacol Biol Psychiatry 35, 454-458 .10.1016/j.pnpbp.2010.11.033
[35] Neale, B.M., Medland, S.E., Ripke, S., Asherson, P., Franke, B., Lesch, K.P., Faraone, S.V., Nguyen, T.T., Schafer, H., Holmans, P., . (2010). Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49, 884-897 .10.1016/j.jaac.2010.06.008
[36] Oades, R.D. (2008). Dopamine-serotonin interactions in attentiondeficit hyperactivity disorder (ADHD). Prog Brain Res 172, 543-565 .10.1016/S0079-6123(08)00926-6
[37] Ribases, M., Ramos-Quiroga, J.A., Hervas, A., Bosch, R., Bielsa, A., Gastaminza, X., Artigas, J., Rodriguez-Ben, S., Estivill, X., Casas, M., . (2009). Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol Psychiatry 14, 71-85 .10.1038/sj.mp.4002100
[38] Sharp, S.I., McQuillin, A., and Gurling, H.M. (2009). Genetics of attention-deficit hyperactivity disorder (ADHD). Neuropharmacology 57, 590-600 .10.1016/j.neuropharm.2009.08.011
[39] Smoot, M.E., Ono, K., Ruscheinski, J., Wang, P.L., and Ideker, T. (2011). Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27, 431-432 .10.1093/bioinformatics/btq675
[40] Sollner, T., Whiteheart, S.W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P., and Rothman, J.E. (1993). SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318-324 .10.1038/362318a0
[41] Sun, J., Jia, P., Fanous, A.H., Webb, B.T., van den Oord, E.J.C.G., Chen, X., Bukszar, J., endler, K.S., and Zhao, Z. (2009). A multi-dimensional evidence-based candidate gene prioritization approach for complex diseases-schizophrenia as a case. Bioinformatics 25, 2595-6602 .10.1093/bioinformatics/btp428
[42] Swanson, J.M., Kinsbourne, M., Nigg, J., Lanphear, B., Stefanatos, G.A., Volkow, N., Taylor, E., Casey, B.J., Castellanos, F.X., and Wadhwa, P.D. (2007). Etiologic subtypes of attention-deficit/ hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev 17, 39-59 .10.1007/s11065-007-9019-9
[43] Teber, E.T., Liu, J.Y., Ballouz, S., Fatkin, D., and Wouters, M.A. (2009). Comparison of automated candidate gene prediction systems using genes implicated in type 2 diabetes by genomewide association studies. BMC Bioinformatics 10Suppl 1, S69.10.1186/1471-2105-10-S1-S69
[44] Thienpont, B., Zhang, L., Postma, A.V., Breckpot, J., Tranchevent, L.C., Van Loo, P., Mollgard, K., Tommerup, N., Bache, I., Tumer, Z., . (2010). Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet 86, 839-849 .10.1016/j.ajhg.2010.04.011
[45] Tiffin, N., Adie, E., Turner, F., Brunner, H.G., van Driel, M.A., Oti, M., Lopez-Bigas, N., Ouzounis, C., Perez-Iratxeta, C., Andrade-Navarro, M.A., . (2006). Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes. Nucleic Acids Res 34, 3067-3081 .10.1093/nar/gkl381
[46] Tranchevent, L.-C., Barriot, R., Yu, S., Van Vooren, S., Van Loo, P., Coessens, B., De Moor, B., Aerts, S., and Moreau, Y. (2008). Endeavour update: a web resource for gene prioritization in multiple species. Nucleic Acids Res 36, W377-384 .10.1093/nar/gkn325
[47] Tranchevent, L.-C., Capdevila, F.B., Nitsch, D., De Moor, B., De Causmaecker, P., and Moreau, Y. (2010). A guide to web tools to prioritize candidate genes. Brief Bioinform 12, 22-32 .10.1093/bib/bbq007
[48] Volkow, N.D., Wang, G.J., Tomasi, D., Kollins, S.H., Wigal, T.L., Newcorn, J.H., Telang, F.W., Fowler, J.S., Logan, J., Wong, C.T., . (2012). Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci 32, 841-849 .10.1523/JNEUROSCI.4461-11.2012
[49] Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., and Bader, M. (2003). Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76.10.1126/science.1078197
[50] Zhang, K., Chang, S., Cui, S., Guo, L., Zhang, L., and Wang, J. (2011a). ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association study by one analytical framework. Nucleic Acids Res 39, W437-443 .10.1093/nar/gkr391
[51] Zhang, K., Cui, S., Chang, S., Zhang, L., and Wang, J. (2010). i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study. Nucleic Acids Res 38, W90-95 .10.1093/nar/gkq324
[52] Zhang, L., Chang, S., Li, Z., Zhang, K., Du, Y., Ott, J., and Wang, J. (2012). ADHDgene: a genetic database for attention deficit hyperactivity disorder. Nucleic Acids Res 40, D1003-1009 .10.1093/nar/gkr992
[53] Zhou, K., Dempfle, A., Arcos-Burgos, M., Bakker, S.C., Banaschewski, T., Biederman, J., Buitelaar, J., Castellanos, F.X., Doyle, A., Ebstein, R.P., . (2008). Meta-analysis of genomewide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B, 1392-1398 .10.1002/ajmg.b.30878