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| Psychiatry Research: Molecular Genetics Studies of Complex Disorders |
| Carlos Pato, Michele Pato (University of Southern California.), M.H. Azevedo, C.R. Oliveira (CNC) |
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These studies are focused on the identification of candidate genes for Schizophrenia and Bipolar Disorder through the use of linkage and association analysis. For this purpose two populations have been analyzed: a relatively homogenous population from Azores, augmented by a similarly homogenous subsample from Madeira, and a mainland Portuguese population. To date we have collected 3000 DNA samples, including 700 schizophrenic patients, 500 bipolar patients, and 1400 unaffected family members. Additionally, 350 unaffected (i.e. no history of psychiatric disorder) subjects of Azorean descent have been collected as a control group. The schizophrenic sample includes 100 multiplex (2 or more affected members) families, and the bipolar sample includes 120 multiplex families.
In 2006, these studies have utilized "state of the art" DNA and RNA microarray technology to identify chromosomal regions of linkage to each disorder, as well as areas of increased expression in the presence of illness. This convergent genetic-genomic approach has led to the identification of several areas in the human genome to target for follow-up study, most notably on Chromosome 5 for schizophrenia and psychosis, and on Chromosome 6 for Bipolar Disorder. Additionally, collaborators from the Broad Institute in the United States and from the Centre on Addiction and Mental Health (CAMH) in Toronto, Canada have been using the sample, collectively known as the “Portuguese Island Collection,” to investigate specific candidate genes for schizophrenia, including neuregulin 1, syntaxin 1A, and genes from the dopaminergic and serotonergic systems. We have also formed the International Shizophrenia collaborative to use whole genome approaches to define the genomics of this disorder. |
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| PUBLICATIONS |
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| Pato CN, Middleton FA, Gentile KL, Morley CP, Medeiros HM, Macedo A, Azevedo MH, Pato MT, (2005) “Genetic linkage to chromosome 6q22 is a consistent finding in Portuguese subpopulations and may generalize to broader populations. Am J Med Genet B Neuropsychiatr Genet. Apr 5;134(1):119-21. |
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| Middleton FA, Pato MT,Gentile KL, McGann L, Brown AM, Trauzzi M, Diab H, Morley CP, Medeiros HM, Macedo A, Azevedo MH, Pato CN, (2005) Jul 5 “Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches”. Am J Med Genet B Neuropsychiatr Genet.; 136(1):12-25. |
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| Petryshen TL, Middleton FA, Kirby A, Aldinger KA, Purcell S, Tahl AR, Morley CP, McGann L, Gentile KL, Rockwell GN, Medeiros HM, Carvalho C, Macedo A, Dourado A, Valente J, Ferreira CP, Patterson NJ, Azevedo MH, Daly5 MJ, Pato CN, Pato MT, Sklar P, (2005) Apr “Support for involvement of neuregulin 1 in schizophrenia pathophysiology”, Mol Psychiatry.; 10(4):366-74, 328. |
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| Albert HC Wong, Likhodi O, Trakalo J, Yusuf M, Sinha A, Pato CN, Pato MT, Van Tol HHM, and Kennedy JL, (2005) Jul 26 “Genetics and transcription of 14-3-3 Isoforms in schizophrenia and bipolar disorder” Schizophrenia Research, [Epub ahead of print]. |
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| Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, Kirby A, Morley CP, McGann L, Gentile KL, Medeiros HM, Carvalho C, Macedo A, Albus M, Maier W, Trixler M, Eichhammer P, Azevedo MH, Schwab SG, Wildenauer DB, Pato MT, Pato CN, Daly MJ, Sklar P, (2005) Dec “Genetic Investigation of chromosome 5q GABAa Receptor subunit genes in schizophrenia”, Mol Psychiatry. 10(12):105. |
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| Matthew B. McQueen, B. Devlin, Stephen V. Faraone, Vishwajit L. Nimgaonkar, Pamela Sklar, Jordan W. Smoller, Rami Abou Jamra, Margot Albus, Silviu-Alin Bacanu, Miron Baron, Thomas B. Barrett, Wade Berrettini, Deborah Blacker, William Byerley, Sven Cichon, William Coryell, Nick Craddock, Mark Daly, J. Raymond DePaulo, Howard J. Edenberg, Tatiana Foroud, Michael Gill, T. Conrad Gilliam, Marian Hamshere, Ian Jones, Lisa Jones, Suh-Hang Juo, John R. Kelsoe, David Lambert, Christoph Lange, Bernard Lerer, Jianjun Liu, Wolfgang Maier, James D. MacKinnon, Melvin G. McInnis, Francis J. McMahon, Dennis L. Murphy, Markus M. Nöthen, John I. Nurnberger, Jr., Carlos N. Pato, Michele T. Pato, James B. Potash, Peter Propping, Ann E. Pulver, John P. Rice, Marcella Rietschel, William Scheftner, Johannes Schumacher, Ricardo Segurado, Kristel Van Steen, Weiting Xie, Peter Zandi, and Nan M. Laird, (2005) Oct; “Combined Analysis from Eleven Linkage Studies of Bipolar Disorder Provides Strong Evidence for Susceptibility Loci on Chromosomes 6q and 8q” Am J Hum Genet. 77(4):582-95. Epub 2005 Aug 15. |
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| Ni X, Trakalo J, Valente J, Azevedo MH, Pato MT, Pato CN, Kennedy JL, (2005) Jul 19 “Human p53 tumor suppressor gene (TP53) and schizophrenia: Case-control and family studies”. Neurosci Lett. [Epub ahead of print] |
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| Middleton FA, Trauzzi MG, Shrimpton AE, Gentile KL, Morley CP, Medeiros H, Pato MT, Pato CN,Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays. Am J Med Genet B Neuropsychiatr Genet. (2006) Jan 5;141(1):28-32 |
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