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


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.