ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia

Abstract

ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies—the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous ‘AA’ risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A's role in illness risk.

Introduction

A single nucleotide polymorphism rs1344706 located at gene ZNF804A (OMIM: 612282) was the first genetic variant to achieve genome wide significance for psychosis (9.96X10-9 (OR 1.12)) (O'Donovan et al., 2008a, O'Donovan et al., 2008b). Despite being relatively under-powered to replicate such a modest effect, two of three recently reported large SZ GWAS studies (Purcell et al., 2009, Sullivan et al., 2008) and a discrete replication study by Riley et al. (2009) supported association between the same risk allele and increased SZ risk. Copy number variation at this locus has also been identified for psychosis (Steinberg et al., 2010). The protein encoded by ZNF804A is uncharacterized, but given its zinc finger domain, is likely to have a role in regulating gene expression. The mouse orthologue Zfp804A is widely expressed in the brain (Allen brain atlas (http://www.brain-map.org/); known binding partners include ataxin-1, encoded by ATXN1 (OMIM: 601556).

Changes in cognitive function and brain structure are strongly associated with SZ and are predictive of level of disability (Green et al., 2004, Toulopoulou et al., 2007). Investigating the functional contribution of individual SZ risk variants to these changes has the unique advantage of enabling in vivo investigation of candidate genes at the level of brain and behavior. The utility of this approach has been demonstrated by findings with existing candidate genes for schizophrenia (including DISC1, NRG1, DTNBP1, DAOA (G72), RGS4; discussed in O'Donovan et al., 2008a, O'Donovan et al., 2008b). Recently, Esslinger et al. (2009) reported that the ZNF804A risk ‘A’ allele was associated with altered connectivity in the dorsolateral pre-frontal cortex (DLPFC) and the hippocampus. They found that connectivity between the hippocampus and DLPFC was increased in risk carriers, while connectivity between contralateral DLPFC regions and within the right DLPFC was reduced. The authors speculated the reduced connectivity in DLPFC may be a contributory factor in disturbed executive function, whereas the increased connectivity between DLPFC and hippocampus might lead to a disruption of interactions between prefrontal and limbic cortices. However, it is pertinent to note that this study only included healthy controls and no cognitive correlations with these connectivity effects were observed. A recent study by our group, involving both patients and healthy participants, suggested an alternative explanation. We found that the risk allele at ZNF804A was associated with relatively spared cognitive ability in the domains of working and episodic memory in independent samples of Irish and German patients with SZ but not controls (Walters et al., 2010). Of note, these cognitive abilities involve two of the three brain regions—the dorsolateral prefrontal cortex and hippocampus—associated with ZNF804A in the Esslinger study (Smith and Jonides, 1999, Squire et al., 2004). We further demonstrated that the association between ZNF804A and SZ increased when patients with IQs lower than 90 were excluded from the analysis. Collectively, these results suggest that ZNF804A is not associated with cognitive impairments, and appears instead to delineate an illness subtype in which cognitive deficits are not a strong feature.

Cognitive deficits have been repeatedly correlated with reduced gray matter volume in SZ (Hulshoff Pol et al., 2006). Based on our earlier cognitive study we predicted that ZNF804A risk A allele carriers would show relatively larger gray matter volumes than non-carriers either at the whole brain level or in a planned region of interest analyses of brain regions implicated by Esslinger et al. (2009) (the dorsolateral prefrontal cortex (DLPFC), the hippocampus, and the amygdala), and our behavioral study (the DLPFC and hippocampus). Avoiding sample bias, we undertook this study in a relatively large sample of patients who were independent of the sample included in our original cognitive analysis.