ABSTRACT: Abstract Background: Following both meta-analysis and extensive resequencing, the single-nucleotide polymorphism of allele A, rs1344706, located in intron 2 of the zinc-finger protein gene ZNF804A, continues to be the common variant most strongly associated with schizophrenia risk (P = 1.1_10–13). ZNF804a is highly expressed in adult brain and functional effects on both protein expression, and altered DNA–protein interaction have been reported. In addition, the ZNF804A rs1344706 A allele has recently been reported to be associated with worse clinical outcome. We were interested in examining whether another proxy for worse clinical outcome, the Positive and Negative Syndrome Scale (PANSS) excitement factor, is associated with a ZNF804a genotype. We hypothesized that a single-nucleotide polymorphism in ZNF804a could be associated with impulsivity. The aim of this study was to assess the association of a single-nucleotide polymorphism rs1344706 with the PANSS excitement factor. Methods: We tested the effect of rs1344706 (A/C) genotype in 133 individuals with DSM-5 chronic schizophrenia using the PANSS. Scores on the PANSS excitement factor were compared between individuals who expressed allele A and those who expressed allele C (individuals with the heterogeneous allele A/C were combined to the C group). General Linear Model (GLM) was used to analyze the differences between groups for the PANSS Excitement Factor (assessed by the summation of: excitement, hostility, uncooperativeness, and poor impulse control). Results: A total of 133 subjects were sampled for ZNF804; however, PANSS data were available for 122 subjects. Of the 122, 68.85% (n = 84) of subjects presented with allele A and 31.15% (n = 38) with allele C. In all, 67.85% (n = 57) of the individuals with allele A were African Americans, and 28.95% (n = 11) of individuals with allele C were African Americans, and 39.47% (n = 15) were Hispanics. The PANSS total score for the entire sample was 72.64 (SD = 9.33). PANSS excitement factor scores ranged from 4 to 15 in group A and 4 to 14 in group C. GLM analysis showed a significant difference in ZNF804, F(1, 121) = 5.595, P = .020, between individuals with allele A compared to those with allele C. The mean excitement factor score for allele A was lower (mean = 7.762, SE = 0.273) than for allele C group (mean = 8.921, SE = 0.427). Conclusion: While the risk “A” allele at rs1344706 has been associated with altered functional brain connectivity and represents a risk factor for psychosis, our results shows an association of the “C” allele at rs1344706 with impulsivity in chronic schizophrenia patients. The difference in our findings when compared to previous reports may have to do with the differing ethnic distribution of our population, which is predominantly African American. This finding could be of nosological value for biological subtyping across the spectrum of schizophrenia, although important limitations should be noted such as small sample size and lack of ethnic diversity of our population.
