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Cousijn H, Rijpkema M, Harteveld A, Harrison PJ, Fernández G, Franke B, Arias-Vásquez A. Schizophrenia risk gene ZNF804A does not influence macroscopic brain structure: an MRI study in 892 volunteers. Mol Psychiatry . 2012 Jan 24 ; PubMed Abstract

Comments on Paper and Primary News
Comment by:  Roberta RasettiDaniel Weinberger (SRF Advisor)
Submitted 9 February 2012 Posted 9 February 2012

The paper by Cousijn et al. is an important addition to the expanding literature on the potential mechanism through which ZNF804A confers increased risk for psychosis. In their paper, Cousijn et al. reported that neither rs1344706 nor other SNPs typed in the ZNF804A gene affected any volumetric or voxel-based morphometry (VBM) parameter, suggesting that the association of ZNF804A with psychosis is unlikely mediated through an effect on brain structure. When the ZNF804A association with schizophrenia first appeared, we explored the modulation of brain structures with VBM by ZNF804A rs1344706 in a sample of healthy volunteers (N = 179). Our experience with other genes associated with risk for schizophrenia that also showed effects on brain volume measures in normal subjects (e.g., DISC1, COMT, BDNF, etc.) led us to expect similar results with ZNF804A. Instead, the results were decidedly negative (data not published), quite similar to those reported by Cousijn et al. We chose not to publish because no single sample can prove the negative. Given the much larger sample of the study...  Read more

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Comment by:  Aristotle VoineskosJames L. Kennedy (SRF Advisor) (Disclosure)
Submitted 13 February 2012 Posted 13 February 2012

Although the recent study by Cousijn et al. provides a very large sample size for an imaging-genetics study, their brain phenotypes based on volumetric analyses, at least in cortical gray matter, are confounded by the fact that cortical brain volume is a product of cortical thickness and surface area. These dependent measures (cortical thickness and surface area) are under different genetic (Panizzon et al., 2009), environmental (Raznahan et al., 2010), and cellular (Chenn and Walsh, 2002) control. Therefore, the use of volumetric phenotypes creates a challenge in determining whether a negative finding, even from a large study, is definitive in its assessment of the association of a genetic variant with brain structure.


Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL, Prom-Wormley E, Neale M, Jacobson K, Lyons MJ, Grant MD, Franz CE, Xian H, Tsuang M, Fischl B, Seidman L, Dale A, Kremen WS. Distinct genetic influences on cortical surface area and cortical thickness. Cereb Cortex . 2009 Nov 1 ; 19(11):2728-35. Abstract

Raznahan A, Cutter W, Lalonde F, Robertson D, Daly E, Conway GS, Skuse DH, Ross J, Lerch JP, Giedd JN, Murphy DD. Cortical anatomy in human X monosomy. Neuroimage . 2010 Feb 15 ; 49(4):2915-23. Abstract

Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. Jul 19 2002;297(5580):365-369. Abstract

View all comments by Aristotle Voineskos
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Comment by:  Gary DonohoeAiden Corvin
Submitted 1 March 2012 Posted 1 March 2012

This study by Cousijn et al. represents the largest structural MRI study of the effects of ZNF804A on brain volume to have been carried out to date. In a sample of 892 healthy young adults, voxel brain morphometry was carried out focusing on both whole brain, grey matter, white matter, and eight circumscribed brain structures: nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, hippocampus, putamen, and thalamus. Two hundred sixty-six common ZNF804A variants were considered, including the rs1344706 variant that remains the most strongly associated with schizophrenia. No significant—or even trend-level—associations were observed.

Since the original identification of ZNF804A almost four years ago, there has been a flurry of neurocognitive and neuroanatomical studies seeking to establish the neural mechanism(s) by which increased schizophrenia risk associated with this gene might be mediated at the level of either brain structure or function. The study by Cousijn et al. accords with a previously and similarly large neuropsychological study...  Read more

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Comment by:  Helena CousijnAlejandro Arias-Vasquez
Submitted 24 April 2012 Posted 24 April 2012

Reply by authors to previous comments
First of all, we would like to thank the three research groups for their comments. As Corvin and Donohoe pointed out, it is important for the field to know what disease risk variants are not doing. Given the known structural changes in brain volume seen in schizophrenia, we decided to investigate the association of ZNF804A with brain volume. Our results show that the association between ZNF804A and schizophrenia is unlikely to be mediated by effects on brain volume variation. We were pleased with the comment of Rasetti and Weinberger, who confirmed our null finding in their sample. However, both studies do not exclude the possibility that differences might be found in patients. Voineskos and Kennedy are right in pointing out that our study does not provide evidence that there is no effect of variation in ZNF804A on cortical thickness; it would be of interest to study this in a large sample. Also, looking at white matter differences as measured by DTI in a sufficiently large sample might provide us with more insight into the...  Read more

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