DISCOVERING THE GENES AFFECTED BY
SCHIZOPHRENIA USING DNA MICRO-ARRAY
Yang Qiu*,
Edward M. Rubin, and Jan-Fang Cheng. Lawrence Berkeley
National Lab, Genome Sciences Department, Berkeley, CA
Schizophrenia is a
devastating psychiatric disorder that affects 1% of the
population. Genetic factors make important contributions to
the etiologies of this disease. It is highly likely that
multiple genes and environmental factors are involved.
Chromosome 6p has been shown to have linkage with
schizophrenia in several independent studies. The current
drug treating schizophrenia including clozapine, risperidone
and olanzapine are all far from perfect with substantial side
effects. It is thus important to be able to identify the
genes affected by schizophrenia, which would greatly enhance
the drug discovery leading to a better treatment.
We are taking advantages of
the technology of DNA-micro-array at Lawrence Berkeley
National Lab which can hold thousands of genes on one single
glass side and the development of the human and mouse Unigen
set (uniquely expressed sequences) through the effort of
genome community. The expression of thousands of genes at
different physiological condition can be analyzed in
parallel. New genes can be identified and biological
functions of the genes can be further studied. The DNAs to be
spotted on the DNA micro-array are as follows: (1) 10,000
human unigen clones representing~20% of expressed human
genes, (2) 309 BAC clones available from the physical mapping
project covering 90% of the schizophrenia candidate region at
chromosome 6p, (3) 269 genes singly selected through thorough
literature search which include neurotransmitter receptor
(dopamine receptor, glutamate receptor, serotonin receptor,
acetylcholine receptor, etc.), brain function related genes
and other possible genes involved in schizophrenia, (4) ~40
clones identified to be differentially expressed in
neuropsychiatric disorders by Stanley Neurovirology
Laboratory at the Johns Hopkins University School of
Medicine.
The postmortem brain tissue
from individuals with schizophrenia and normal controls will
be obtained from Stanley Foundation Neuropathology
Consortium. Total RNAs are to be extracted from the different
brain tissues and hybridized with the DNA micro-array. The
genes that are affected in schizophrenia can be identified
when using a large sample sets to minimize the individual
variations in the gene expression.
Meanwhile, a mouse model for
schizophrenia is underway for this study. It has been
established that the mice treated with psychotic drug PCP
(angel dust) mimic some symptoms of schizophrenia in which
the prepulse inhibition is diminished in schizophrenia
patients. We are treating mice with PCP as well as some
antipsychotic drugs including clozapine and risperidone. The
gene expression patterns in the mouse brain will be followed
at different times after each treatment using the DNA
micro-array. The genes that are affected by drugs can be
identified as the candidate genes for schizophrenia.