Abstract
Changes in gene expression and genetic variations in coding regions have likely functional impact, potentially associated with complex diseases, such as neuropsychiatric conditions. A current need for high throughput analysis of genomic data is leading to the development and improvement of sophisticated bioinformatics approaches, which allows the processing of large amounts of sequence and gene expression data. In this study, we identified new potential genetic variations prioritizing genes related to glutamatergic and GABAergic systems, using different bioinformatics resources. The CLCbio Workbench Combined platform was initially used to build expressed sequence tags and mRNA files retrieved, respectively, from the Goldenpath and National Center for Biotechnology Information databases and latter to perform multiple batches of Smith–Waterman alignments. The PMUT software was used to increase an accurate association between potential variations and pathogenic predictions. The annotation revealed various classes of variations and most of them are deletions ranging from 1 to 7 bp. Bioinformatic pipelines seem to be useful approaches to help screening for genetic variations with potential impact in gene expression. Further analysis will foster this aim to provide celerity at the massive analysis of data currently generated in large scale high throughput experiments.
References
Buxbaum JD, Silverman JM, Smith CJ et al (2002) Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7:311–316
Capriotti E, Calabrese R, Casadio R (2006) Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729–2734
Choi KH, Higgs BW, Wendland JR et al (2011) Gene expression and genetic variation data implicate PCLO in bipolar disorder. Biol Psychiatry 69(4):353–359
Choudary PV, Molnar M, Evans SJ et al (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102:15653–15658
Craddock N, Jones L, Jones IR et al (2010) Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype. Mol Psychiatry 15:146–153
de Souza MB, de Lemos RR, da Cunha JE, de Lima Filho JL, de Oliveira JR (2010) Searching for new genetic risk factors for neuropsychiatric disorders in expression databases. J Mol Neurosci 41:193–197
DeLong R (2004) Autism and familial major mood disorder: are they related? J Neuropsychiatry Clin Neurosci 16:199–213
Ferrer-Costa C, Orozco M, de la Cruz X (2004) Sequence-based prediction of pathological mutations. Proteins 57:811–819
Ferrer-Costa C, Orozco M, de la Cruz X (2005) Use of bioinformatics tools for the annotation of disease-associated mutations in animal models. Proteins 61:878–887
Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat Rev Genet 7:85–97
Iwamoto K, Kakiuchi C, Bundo M, Ikeda K, Kato T (2004) Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders. Mol Psychiatry 9:406–416
Karolewicz B, Maciag D, O'Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G (2010) Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 13:411–420
Krystal JH, Sanacora G, Blumberg H et al (2002) Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry 7(Suppl 1):S71–S80
Lemos R, Castelletti CH, Lima Filho JL, Marques E, Oliveira JR (2009) In silico identification of new genetic variations as potential risk factors for Alzheimer's disease in a microarray-oriented simulation. J Mol Neurosci 39:241–147
Lemos R, Oliveira DF, Zatz M, Oliveira JR (2011) Population and computational analysis of the MGEA6 P521A variation as a risk factor for familial idiopathic basal ganglia calcification (Fahr's disease). J Mol Neurosci 43:333–336
Luscher B, Shen Q, Sahir N (2011) The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 16:383–406
Macintyre G, Bailey J, Haviv I, Kowalczyk A (2010) is-rSNP: a novel technique for in silico regulatory SNP detection. Bioinformatics 26:524–530
Merali Z, Du L, Hrdina P et al (2004) Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 24:1478–1485
Mooney S (2005) Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis. Brief Bioinform 6:44–56
Oliveira JR, Carvalho DR, Pontual D et al (2000) Analysis of the serotonin transporter polymorphism (5-HTTLPR) in Brazilian patients affected by dysthymia, major depression and bipolar disorder. Mol Psychiatry 4:348–349
Panitz F, Stengaard H, Hornshøj H et al (2007) SNP mining porcine ESTs with MAVIANT, a novel tool for SNP evaluation and annotation. Bioinformatics 23:387–391
Reumers J, Schymkowitz J, Rousseau F (2009) Using structural bioinformatics to investigate the impact of non synonymous SNPs and disease mutations: scope and limitations. BMC Bioinforma 10(Suppl 8):S9
Rosenfeld JA, Malhotra AK, Lencz T (2010) Novel multi-nucleotide polymorphisms in the human genome characterized by whole genome and exome sequencing. Nucleic Acids Res 38:6102–6111
Rudolph U, Knoflach F (2011) Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov 10:1–13
Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437
Schousboe A, Waagepetersen HS (2007) GABA: homeostatic and pharmacological aspects. Prog Brain Res 160:9–19
Sequeira A, Mamdani F, Ernst C et al (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 4:65–85
Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B (2010) gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry 686:512–522
Smith TF, Waterman MS (1981) Identification of common molecular subsequences. J Mol Biol 147:195–197
Teufel A, Krupp M, Weinmann A, Galle PR (2006) Current bioinformatics tools in genomic biomedical research (Review). Int J Mol Med 17:967–973
Togsverd M, Werge T, Tankó LB et al (2008) Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction. J Affect Disord 106:169–172
Tsunoka T, Kishi T, Ikeda M et al (2009) Association analysis of group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry 33:875–879
Acknowledgments
We are greatly indebted to Henrique Castelletti and Roberta Rodrigues de Lemos for their technical support. This study received financial support from the following Brazilian funding agencies and academic bureaus: LIKA-JIKA, PROPESQ-UFPE, CAPES, CNPq, and FACEPE.
Conflict of interest
There is no conflict of interest in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
de Souza, M.B.R., de Oliveira, J.R.M. Searching for New Genetic Variations in Expression Databases for the GABAergic and Glutamatergic Systems. J Mol Neurosci 48, 257–264 (2012). https://doi.org/10.1007/s12031-012-9771-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-012-9771-z