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News Brief: Schizophrenia Gene Suspect Affects Fetal Brain

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.

Reference:
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

 
Comments on News and Primary Papers
Comment by:  Michael O'Donovan, SRF Advisor
Submitted 11 January 2013 Posted 11 January 2013

Hill and Bray report mRNA expression analysis of the schizophrenia risk gene ZNF804A in adult and fetal brain. Importantly, they used an allele-specific expression assay that allows them to isolate cis-acting effects influencing ZNF804A expression (cis effects on expression are those which are restricted to the particular copy of a gene carrying the feature that influences expression, for example, a regulatory polymorphism at the gene locus) from artifacts related to RNA quality and more general trans-effects on gene expression (trans-effects influence expression of both copies and may arise as a result of environmental exposures such as drugs, or variable levels of a transcription factor). As a result, they were able to sensitively search for possible relationships between gene expression and genotype at rs1344706, the ZNF804A single-nucleotide polymorphism (SNP) that is currently the most strongly schizophrenia-associated variant (see Williams et al., 2011). Previous work by Williams and colleagues using similar methodology to...  Read more


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