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Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibilitygene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific geneticvariations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37schizophrenia cases and 37 controls, we resequenced upstream of the type I–IV promoters, and the HapICE repeat regions inintron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared acrossdiagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in casescompared with controls (v2¼7.815; P¼0.05). The average nucleotide diversity (h¼10.0 10 4) was approximately twofoldhigher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greaternucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (h(case)¼13.2 10 4;h(control)¼10.0 10 4). The specific HapICE risk haplotype was associated with increased type III mRNA (F¼3.76, P¼0.028),which in turn, was correlated with an earlier age of onset (r¼ 0.343, P¼0.038). We found a novel intronic five-SNP haplotypeB730 kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that issuppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1,which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic associationmay increase risk of schizophrenia

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity