Replication of association between schizophrenia and ZNF804A in the Irish Case Control Study of Schizophrenia (ICCSS) sample

Abstract

A recent genomewide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of Schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators we genotyped 3 of the most promising SNPs from the Cardiff study. We replicate association with rs1344706 (trend test one tailed p=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one tailed p=0.21), and only a trend with rs9922369 in RGRIP1L (one tailed p=0.0515). Based on these results, we completed genotyping of 11 additional LD-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass QC criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (p=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A based on family history or sex of case. The associated SNP rs1344706 lies in ~30 bp of conserved mammalian sequence and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1L and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared to the C allele. Expression is increased in schizophrenic cases compared to controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.