Identification and Functional Studies of Regulatory Variants Responsible for the Association of <b><i>NRG3</i></b> with a Delusion Phenotype in Schizophrenia

We previously reported genetic linkage for Schizophrenia (SZ) (NPL of 4.7) at 10q22 in the Ashkenazi Jewish (AJ) population. In follow up fine mapping we found strong evidence of association between three intronic single nucleotide variants (SNVs) in the 5' end of Neuregulin 3 ( NRG3) and the delusion factor score of our phenotypic principal component analysis. Two independent groups replicated these findings, indicating that variants in NRG3 confer risk for a delusion-rich SZ subtype. To identify the causative variants, we sequenced the 162 kb linkage disequilibrium (LD) block covering the NRG3 5' end in 47 AJ SZ patients at the extremes of the delusion factor quantitative trait distribution. Among the identified variants we found 5 noncoding SNVs present on the high delusion factor haplotype and significantly overrepresented in high delusion factor subjects. We tested these for regulatory effects and found that risk alleles of rs10883866 and rs60827755 decreased and increased, respectively, the expression of a reporter gene as compared to the reference allele. In post-mortem brain RNA quantification experiments we found the same variants also perturb relative expression of alternative NRG3 isoforms. In summary, we have identified regulatory SNVs contributing to the association of NRG3 with delusion symptoms in SZ.