Journal Article

Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia

Cynthia Shannon Weickert, Ana L. Miranda-Angulo, Jenny Wong, William R. Perlman, Sarah E. Ward, Vakkalanka Radhakrishna, Richard E. Straub, Daniel R. Weinberger and Joel E. Kleinman

in Human Molecular Genetics

Volume 17, issue 15, pages 2293-2309
Published in print August 2008 | ISSN: 0964-6906
Published online April 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn130
Variants in the estrogen receptor alpha gene and its mRNA contribute to risk for schizophrenia

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Estrogen modifies human emotion and cognition and impacts symptoms of schizophrenia. We hypothesized that the variation in the estrogen receptor alpha (ESR1) gene and 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 = 0.01–0.001). In a follow-up family-based association analysis, we found overtransmission of PvuII allele C and a PvuII C-containing haplotype (P = 0.01–0.03) 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 schizophrenia. 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 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, the variation in the ESR1 gene is associated with schizophrenia and the mechanism of this association may involve alternative gene regulation and transcript processing.

Journal Article.  11377 words.  Illustrated.

Subjects: Genetics and Genomics

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