1. ¹Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
2. ²Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA
3. ³Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
4. ⁴Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA
5. ⁵Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA
6. ⁶Department of Psychiatry, Queens University, Belfast, UK
7. ⁷The Health Research Board, Dublin, Ireland

Correspondence: Dr B Riley, Department of Psychiatry and Human Genetics, Virginia Commonwealth University, 800 E. Leigh St., PO Box 980424, Richmond, VA 23298-0424, USA. E-mail: bpriley@vcu.edu

Received 27 March 2009; Revised 4 June 2009; Accepted 16 September 2009; Published online 20 October 2009.

Abstract

A recent genome-wide 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 three of the most promising single-nucleotide polymorphisms (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). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control 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 on the basis of 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 with the C allele. Expression is increased in schizophrenic cases compared with 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 A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.