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Published Online: 1 December 2012

Evidence That Schizophrenia Risk Variation in the ZNF804A Gene Exerts Its Effects During Fetal Brain Development

Matthew J. Hill, Ph.D., and Nicholas J. Bray, Ph.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 169, Number 12
https://doi.org/10.1176/appi.ajp.2012.11121845
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Abstract

Objective

The single-nucleotide polymorphism rs1344706, located within an intron of the ZNF804A gene, exhibits genome-wide significant association with schizophrenia. Although genotype at rs1344706 is associated with altered functional brain connectivity, the molecular mechanisms mediating its association with schizophrenia have not been clearly defined. Given its location in noncoding sequence, the authors tested association between rs1344706 and ZNF804A expression in adult and fetal human brain.

Method

Highly quantitative measures of relative allelic expression were used to assess the effect of rs1344706 genotype on the mRNA expression of ZNF804A in the dorsolateral prefrontal cortex, hippocampus, and substantia nigra of the adult human brain and in human brain tissue from the first and second trimester of gestation.

Results

Genotype at rs1344706 had no significant effect on the regulation of ZNF804A in any of the three adult brain regions examined. In contrast, rs1344706 genotype had a significant effect on ZNF804A allelic expression in second-trimester fetal brain, with the schizophrenia risk (T) allele associated with reduced ZNF804A expression.

Conclusions

The T allele of rs1344706 is associated with a relative decrease in ZNF804A expression during the second trimester of fetal brain development. These data provide evidence for a schizophrenia risk mechanism that is operational in (and possibly specific to) the fetal brain.

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Supplementary Material

Supplementary Material (1301_ds001.pdf)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 169 • Number 12 • December 2012
Pages: 1301 - 1308
PubMed: 23212061

History

Received: 21 December 2011
Revision received: 1 June 2012
Accepted: 20 July 2012
Published online: 1 December 2012
Published in print: December 2012

Authors

Affiliations

Matthew J. Hill, Ph.D.
From the Department of Neuroscience, Institute of Psychiatry, King’s College London.
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Nicholas J. Bray, Ph.D.
From the Department of Neuroscience, Institute of Psychiatry, King’s College London.
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Notes

Address correspondence to Dr. Bray ([email protected]).
Presented in part at the 19th World Congress of Psychiatric Genetics, Washington, D.C., Sept. 10–14, 2011.

Funding Information

Drs. Hill and Bray report no financial relationships with commercial interests.
Supplementary Material
Supported by the Medical Research Council (grant G0802166).

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