Human Molecular Genetics Advance Access published online on August 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl222
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1 Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute for Mental Health, NIH, DHHS, 9000 Rockville Pike, 10 Center Drive, Bldg. 10, Rm. 4N306, Bethesda, MD 20892-1385
* To whom correspondence should be addressed. Linkage, association and post-mortem studies have implicated regulator of G protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein coupled receptors (GPCRs), as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the DLPFC between normal controls and patients with schizophrenia in two independent cohorts ( > 100 subjects each), (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls, and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling, and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.
Received May 25, 2006
Revised August 3, 2006
Accepted August 3, 2006
Article
RGS4 mRNA Expression in Postmortem Human Cortex Is Associated with COMT Val158Met Genotype and COMT Enzyme Activity
Barbara K. Lipska 1 *, Shruti Mitkus 2, Mark Caruso 2, Thomas M. Hyde 2, Jingshan Chen 2, Radhakrishna Vakkalanka 2, Richard E. Straub 2, Daniel R. Weinberger 2, and Joel E. Kleinman 2
2 Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute for Mental Health, NIH, DHHS, 9000 Rockville Pike, Bethesda, MD 20892-1385
Barbara K. Lipska, E-mail: lipskab{at}intra.nimh.nih.gov
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