Evidence of sex-modulated association of ZNF804A with schizophrenia

Background: The single nucleotide polymorphism (SNP) rs1344706 in ZNF804A (2q32.1) has been associated with schizophrenia in a genome-wide association study (GWAS). A recent candidate gene study, which replicated the positive association with rs1344706, identified another positive SNP (rs7597593) in ZNF804A associated with schizophrenia. Methods: We performed an association study of rs7597593 in four GWAS cohorts of European ancestry. Postmortem human brain expression data of normal Caucasian individuals (n = 89) was also analyzed for examining the effect of rs7597593 on ZNF804A messenger RNA expression, using logistic regression and linear regression. Results: We found that rs7597593 was significantly associated with schizophrenia in the combined GWAS datasets (n = 5023, odds ratio [OR]_combined = 1.15, p = .0011). Analysis of stratification by sex showed that the association was driven by the female subjects (OR = 1.29, p = .0002) and was not significant in male subjects (OR = 1.08, p = .148) in the combined sample of four cohorts. A sex by genotype interaction was near significant in both the Genetic Association Information Network sample (p = .0532) and the combined sample of four cohorts (p _combined = .0531). Gene expression analysis showed no main effects but a significant female-specific association (p_female = .047, p _male = .335) and sex by genotype interaction (p = .0166) for rs7597593. Conclusions: Our data suggest a clinical and molecular modulation by sex of the association of ZNF804A SNP rs7597593 and risk of schizophrenia.