Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

Amanda J. Law, Barbara K. Lipska, Cynthia Shannon Weickert, Thomas M. Hyde, Richard E. Straub, Ryota Hashimoto, Paul J. Harrison, Joel E. Kleinman, Daniel R. Weinberger

Research output: Contribution to journalArticlepeer-review

340 Scopus citations

Abstract

Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5′ upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.

Original languageEnglish (US)
Pages (from-to)6747-6752
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number17
DOIs
StatePublished - Apr 25 2006
Externally publishedYes

Keywords

  • ErbB
  • Genetics
  • Hippocampus
  • Human postmortem brain
  • mRNA

ASJC Scopus subject areas

  • General

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