DISC1 mRNA Expression is Not Influenced by Common Cis-Acting Regulatory Polymorphisms or Imprinting

The hypothesis that genetic variation in Disrupted in Schizophrenia 1 (DISC1) influences risk of schizophrenia and other major psychiatric disorders is supported by a growing body of genetic association data and plausible functional biology. Risk of psychiatric disorder is not attributable to non-synonymous changes that alter the protein coding sequence of DISC1, although certain such variants possibly contribute to risk haplotypes. Thus, it is widely hypothesized that the risk variants at DISC1 influence its expression. As a complicating factor, it has also been recently proposed that DISC1 is subject to imprinting, a hypothesis that would profoundly influence the interpretation of current genetic studies. We have tested these two main hypotheses using allelic expression analysis. Of 148 human brain mRNA samples, 65 were informative for analysis. However, only a single sample showed evidence for unequal expression of paternal and maternal transcripts. Analysis of the proximal promoter region in that subject revealed the presence of a previously unknown duplication of the 22 nucleotides -168 to -147 relative to the transcription start site. However, the altered expression in that subject did not appear to be explained by this insertion. Our data robustly demonstrate that DISC1 is not imprinted in the adult human brain, and strongly suggest that reports of genetic association between DISCI and psychiatric disorder are not explicable by sequence changes that alter mRNA abundance. (C) 2008 Wiley-Liss, Inc.