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

doi:10.1073/pnas.0602002103

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

*Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, United Kingdom; and
^‡Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1385

Communicated by Gerald D. Fischbach, Columbia University College of Physicians and Surgeons, New York, NY, March 13, 2006 (received for review September 16, 2005)

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.

Footnotes

^†To whom correspondence should be addressed. E-mail: amanda.law{at}psych.ox.ac.uk
Author contributions: A.J.L., B.K.L., R.H., J.E.K., and D.R.W. designed research; A.J.L., B.K.L., and R.E.S. performed research; A.J.L., C.S.W., T.M.H., P.J.H., and J.E.K. contributed new reagents/analytical tools; A.J.L., B.K.L., and D.R.W. analyzed data; and A.J.L. and D.R.W. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

htSNP,

haplotype-tagging SNP;

LD,

linkage disequilibrium;

NRG1,

neuregulin 1;

PMI,

postmortem interval;

SRF,

serum response factor.