Cis- and Trans-Regulatory Loci are Implicated with Stress Response in Lymphoblastic Cell Lines

Brandi Rollins; Adolfo Sequeira; Marquis P. Vawter
Society of Biological Psychiatry. 2007.


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 trans-regulatory 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.