Cis- and Trans-Regulatory Loci are Implicated with Stress Response in
Lymphoblastic Cell Lines
Brandi Rollins, Adolfo Sequeira, Marquis P. Vawter
Psychiatry, University of California, Irvine, Irvine, CA
Background: Drug abuse and acute psychological stressors are associated with
a risk for schizophrenia. By inducing a stress response in cells and studying the
altered gene expression we may identify candidate genes and potential
regulatory regions for schizophrenia. We combined genome-wide linkage
analysis with genome-wide expression analysis to identify cis- and transregulatory loci.
Methods: We extracted total RNA from lymphoblastic cell lines to measure the
effects of stress on exon expression under two environmental conditions. Five
subjects with schizophrenia and 5 unaffected family members matched for
gender and age were analyzed with exon arrays consisting of 1.4 million putative
exons. Linkage using a microsatellite marker genome scan and our top 100
differentially expressed exons was performed.
Results: Strong evidence of linkage to cis- and trans-regulatory loci of exon
expression quantitative traits was found (LOD>3.0); in addition to differential
exon expression and overall transcript expression differences in schizophrenia.
There is evidence that exons containing SNPs hybridize differentially to
Affymetrix probes suggesting allelic expression can be detected using the exon
array platform.
Conclusions: Loci that contribute large trans-regulatory effects might be an
important mechanism for transcript alteration in schizophrenia. The cis-linkage
results indicate the microsatellite markers may be in linkage disequilibrium with
genes containing functional variants that alter expression. LOD scores will be
validated by permutation analyses. Further investigation must be done to define
the role of heterogeneous nuclear RNAs and to determine if we are finding stress
regulated or disease related genes.