Human Molecular Genetics Advance Access published online on April 18, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn130
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Variants in the Estrogen Receptor Alpha Gene and its mRNA Contribute to Risk for Schizophrenia
1 MiNDS Unit, Section on Neuropathology, NIMH, NIH, Bethesda, USA 20892 2 Section on Neuropathology Laboratory, CBDB, NIMH, NIH, Bethesda, USA 20892 3 Clinical Brain Disorders Branch, GCAP, NIMH, NIH, Bethesda, USA 20892 4 Schizophrenia Research Laboratory, SRI, POWMRI, UNSW, Sydney, Australia 2031
Corresponding Author: Professor Cyndi Shannon Weickert Maquarie Bank Foundation Chair of Schizophrenia Research UNSW Department of Psychiatry Prince of Wales Medical Research Institute Corner of Barker and Easy Street Randwick, Sydney, NSW 2031 Australia Office Phone: +61 2 9399 1117 Office Fax: +61 2 9399 1005 email: cyndi{at}powmri.edu.au
Received January 3, 2008; Revised March 12, 2008; Accepted April 15, 2008
Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that variation in the estrogen receptor alpha (ESR1) gene and in cortical ESR1 mRNA is associated with schizophrenia. In a small case-control genetic association analysis of postmortem brain tissue, genotype CC (rs2234693) and haplotypes containing the C allele of a single nucleotide polymorphism (SNP) in intron1 (PvuII) were more frequent in African American schizophrenics (p=0.01 to 0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (p=0.01-p=0.03) to African American and Caucasian patients with schizophrenia. Schizophrenics with the "at risk" PvuII genotype had lower ESR1 mRNA levels in the frontal cortex. Eighteen ESR1 splice variants and decreased frequencies of the wild-type ESR1 mRNA were detected in schizophrenica. In one patient, a unique ESR1 transcript with a genomic insert encoding a premature stop codon and a truncated ESR1 protein lacking most of the estrogen binding domain was the only transcript detected. Using a luciferase assay, we found that mRNA encoding a truncated ESR1 significantly attenuates gene expression at estrogen-response elements (ERE) demonstrating a dominant negative function. An intron 6 SNP [rs2273207(G)] was associated with an ESR1 splice variant missing exon seven. The T allele of another intron 6 SNP was part of a 3’ haplotype less common in schizophrenia [rs2273206(T), rs2273207(G), rs2228480(G)]. Thus, variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.
* The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors