Towards understanding the schizophrenia code: An expanded convergent functional genomics approach

Helen Le-Niculescu, Y. Balaraman, S. Patel, J. Tan, K. Sidhu, R. E. Jerome, Howard Edenberg, R. Kuczenski, M. A. Geyer, John Nurnberger, S. V. Faraone, M. T. Tsuang, Alexander Niculescu

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Identifying genes for schizophrenia through classical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a psychomimetic agent - phencyclidine (PCP), and an anti-psychotic - clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validating findings. Topping the list of candidate genes, we have three genes involved in GABA neurotransmission (GABRA1, GABBR1, and GAD2), one gene involved in glutamate neurotransmission (GRIA2), one gene involved in neuropeptide signaling (TAC1), two genes involved in synaptic function (SYN2 and KCNJ4), six genes involved in myelin/glial function (CNP, MAL, MBP, PLP1, MOBP and GFAP), and one gene involved in lipid metabolism (LPL). These data suggest that schizophrenia is primarily a disorder of brain functional and structural connectivity, with GABA neurotransmission playing a prominent role. These findings may explain the EEG gamma band abnormalities detected in schizophrenia. The analysis also revealed other high probability candidates genes (neurotransmitter signaling, other structural proteins, ion channels, signal transduction, regulatory enzymes, neuronal migration/neurite outgrowth, clock genes, transcription factors, RNA regulatory genes), pathways and mechanisms of likely importance in pathophysiology. Some of the pathways identified suggest possible avenues for augmentation pharmacotherapy of schizophrenia with other existing agents, such as benzodiazepines, anticonvulsants and lipid modulating agents. Other pathways are new potential targets for drug development. Lastly, a comparison with our earlier work on bipolar disorder illuminates the significant molecular overlap between schizophrenia and bipolar disorder.

Original languageEnglish
Pages (from-to)129-158
Number of pages30
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume144
Issue number2
DOIs
StatePublished - Mar 5 2007

Fingerprint

Genomics
Schizophrenia
Genes
Synaptic Transmission
Bipolar Disorder
gamma-Aminobutyric Acid
Phencyclidine
Genetic Linkage
Clozapine
Pharmacogenetics
Medical Genetics
Brain
Brain Diseases
Regulator Genes
Myelin Sheath
Neuropeptides
Benzodiazepines
Ion Channels
Lipid Metabolism
Neuroglia

Keywords

  • Brain
  • Clozapine
  • Convergent functional genomics
  • Microarray
  • Phencyclidine (PCP)
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)

Cite this

Towards understanding the schizophrenia code : An expanded convergent functional genomics approach. / Le-Niculescu, Helen; Balaraman, Y.; Patel, S.; Tan, J.; Sidhu, K.; Jerome, R. E.; Edenberg, Howard; Kuczenski, R.; Geyer, M. A.; Nurnberger, John; Faraone, S. V.; Tsuang, M. T.; Niculescu, Alexander.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 144, No. 2, 05.03.2007, p. 129-158.

Research output: Contribution to journalArticle

Le-Niculescu, Helen ; Balaraman, Y. ; Patel, S. ; Tan, J. ; Sidhu, K. ; Jerome, R. E. ; Edenberg, Howard ; Kuczenski, R. ; Geyer, M. A. ; Nurnberger, John ; Faraone, S. V. ; Tsuang, M. T. ; Niculescu, Alexander. / Towards understanding the schizophrenia code : An expanded convergent functional genomics approach. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2007 ; Vol. 144, No. 2. pp. 129-158.
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