Study Report

Reference	Guella, I., 2013 PMID: 24315717
Citation	Guella, I., A. Sequeira, et al. (2013). "Evidence of allelic imbalance in the schizophrenia susceptibility gene ZNF804A in human dorsolateral prefrontal cortex." Schizophr Res.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	A total of 1372 subjects participated, including 422 SZ, 382 BD and 507 control subjects.
SNP/Region/Marker Size	2 SNPs
Predominant Ethnicity	Caucasian
Population	Costa Rican
Gender	44.1% male of SZ, 42.1% male of BD, 56.9% male of controls

Sample Status	i) 3 extended families with SZ and BD (N = 107); ii) unrelated individuals with diagnoses of SZ (n = 390) and BD (n = 368); and iii) unrelated controls (N = 507) with no family history of SZ, BD, suicide or hospitalization for psychiatric reasons,with no self-reports of suicide attempts, psychosis, diagnosis of SZ, BD, or use ofmedications for depression or psychiatric conditions.
Technique	DNA samples were genotyped for ZNF804A SNPs rs12476147 by a pre-validated TaqMan assay (Applied Biosystems, Foster City, CA) and for rs1344706 using an in-house developed allele-specific PCR assay.
Statistical Method	All procedures were performed using the R program and the software package PLINK v1.07. For each SNP, a DFAM (family-based association for disease traits) analysis was performed. The level of statistical significance was set at 5%.
Result Summary	While no significant association between rs1344706 and SZ or BD was observed in the Costa Rica sample, we observed an increased risk of SZ for the minor allele (A) of the exonic rs12476147 SNP (p=0.026). Our ASE assay detected a significant over-expression of the rs12476147 A allele in DLPFC of rs1344706 heterozygous subjects. Interestingly, cDNA allele ratios were significantly different according to the intronic rs1344706 genotypes (p-value=0.03), with the rs1344706 A allele associated with increased ZNF804A rs12476147 A allele expression (average 1.06, p-value=0.02, for heterozygous subjects vs. genomic DNA). In conclusion, we have demonstrated a significant association of rs12476147 with SZ, and using a powerful within-subject design, an allelic expression imbalance of ZNF804A exonic SNP rs12476147 in the DLPFC. Although this data does not preclude the possibility of other functional variants in ZNF804A, it provides evidence that the rs1344706 SZ risk allele is the cis-regulatory variant directly responsible for this allelic expression imbalance in adult cortex.