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.
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 that of Hill and Bray had shown that in adult brain, chromosomes carrying the schizophrenia risk allele at rs1344706 express ZNF804A at a higher level than those which do not carry the risk allele. However, the relationship between higher expression and genotype at rs1344706 was not perfect. Moreover, since another polymorphism at the ZNF804A locus was much better correlated with gene expression than rs1344706, but was only weakly associated with schizophrenia risk, Williams and colleagues concluded that the observed overexpression was not likely to be the mechanism underpinning the association between ZNF804A and schizophrenia.
In the present study, Bray and Hill reach the same conclusion with respect to adult brain. However, when they extended their work into fetal brain, a very different picture emerged. Specifically, in second-trimester fetal brain, chromosomes carrying rs1344706 were underexpressed. This is in stark contrast to the findings of higher expression in adult brain. Moreover, they also found that genotype at rs1344706 was strongly correlated with cis-measures of ZNF804A expression to an extent that is consistent with, although does not prove, the hypothesis that rs1344706 is, per se, the functional variant. The finding of a strong correlation between a schizophrenia risk allele and a gene function that is observed only in the second trimester of fetal development but not in adult brain supports the widely held hypothesis that the origins of schizophrenia, at least in part, begin during brain development. That conclusion is necessarily somewhat tentative since it is not established that the observed changes in expression are relevant to disease. However, the absence of protein-coding variants to explain the ZNF804A association, and the evidence from earlier work by the same authors (Hill and Bray, 2011) showing that binding of as yet unknown nuclear proteins to ZNF804A DNA is sensitive to genotype at rs1344706, make a good circumstantial case that it may be. Regardless, the demonstration of developmental specificity in the functional associations of a strongly implicated schizophrenia risk variant emphasizes the importance of studying regulatory effects of risk alleles at a range of developmental time points, and point to the need to augment genetic studies of gene expression with larger-scale studies using tissues from a range of developmental time points.
Hill MJ, Bray NJ. Allelic differences in nuclear protein binding at a genome-wide significant risk variant for schizophrenia in ZNF804A. Mol Psychiatry . 2011 Aug 1 ; 16(8):787-9. Abstract
Williams HJ, Norton N, Dwyer S, Moskvina V, Nikolov I, Carroll L, Georgieva L, Williams NM, Morris DW, Quinn EM, Giegling I, Ikeda M, Wood J, Lencz T, Hultman C, Lichtenstein P, Thiselton D, Maher BS, , Malhotra AK, Riley B, Kendler KS, Gill M, Sullivan P, Sklar P, Purcell S, Nimgaonkar VL, Kirov G, Holmans P, Corvin A, Rujescu D, Craddock N, Owen MJ, O'Donovan MC. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry . 2011 Apr ; 16(4):429-41. Abstract
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