24 December 2012. The suspected schizophrenia risk allele of the zinc finger gene ZNF804A is associated with lower mRNA levels of the gene during the second trimester of fetal development, according to a new study published online December 1 in the American Journal of Psychiatry. Led by Nicholas Bray of King’s College London, the study suggests that the schizophrenia risk suspect could alter normal brain development and is consistent with the neurodevelopmental hypothesis of schizophrenia.
ZNF804A, which encodes for a protein of unknown molecular function, holds the distinction of being the first gene with a single nucleotide polymorphism (SNP) that reached the generally accepted significance level of 10-8 in genomewide association studies (GWAS) of schizophrenia (O’Donovan et al., 2008). The SNP rs1344706, located within an intron of the gene, has subsequently been replicated in some, but not all, GWAS (see SRF related news story; Williams et al., 2011; Ripke et al., 2011). The rs1344706 risk allele has also been associated with larger frontal white volumes and more severe psychotic symptoms in subjects with schizophrenia (Wassink et al., 2012).
In an effort to explore possible molecular mechanisms underlying the putative association of rs1344706 with schizophrenia, first author Matthew Hill and Bray assessed the effect of rs1344706 genotype on ZNF804A mRNA expression in both fetal and adult human brain tissue. There was no effect of genotype on mRNA expression in the adult prefrontal cortex, hippocampus, and substantia nigra, or in first trimester fetal brain tissue. However, the schizophrenia risk allele of rs1344706 was associated with lower ZNF804A mRNA expression in second trimester fetal brain tissue. The authors conclude: “Although we cannot rule out effects of rs1344706 at later stages of development, our data provide evidence for a risk mechanism of schizophrenia that operates long before the overt manifestation of the illness.”—Allison A. Curley.
Hill MJ, Bray NJ. Evidence That Schizophrenia Risk Variation in the ZNF804A Gene Exerts Its Effects During Fetal Brain Development. Am J Psychiatry . 2012 Dec 1 ; 169(12):1301-8. 165543. Abstract