Genome‐wide supported psychosis risk variant in ZNF804A gene and impact on cortico–limbic WM integrity in schizophrenia

Abstract

Genome-wide association, case association genetic and meta-analytic studies have highlighted ZNF804A as a robust genome-wide supported susceptibility gene for schizophrenia (SCZ). In view of the possible involvement of ZNF804A gene in early neurodevelopment and cellular processes including oligodendrocyte proliferation and differentiation, we examined the effect of ZNF804A on brain WM (WM) integrity in patients with SCZ. Based on extant data in healthy controls (HC), we hypothesized that ZNF804A risk variant rs1344706 is associated with lower fractional anisotropy (FA) in brain regions within cortico-limbic circuits, namely frontal, parietal, medial temporal lobes, and cingulate gyri in SCZ. A total of 200 Chinese participants (125 patients with DSM-IV diagnosis of SCZ and 75 controls) were genotyped using blood samples, a subset of 153 participants (89 patients with DSM-IV diagnosis of SCZ and 64 controls) underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). There are significant effects of diagnosis (left cingulate gyrus: Adjusted F(1,149) = 9.36, P = 0.003) and diagnosis-genotype interactions (left parietal lobe: Adjusted F(1,147) = 7.39, P = 0.007; right parietal lobe: Adjusted F(1,147) = 6.95, P = 0.009; right medial temporal lobe: Adjusted F(1,147) = 8.79, P = 0.004; left cingulate gyrus: Adjusted F(1,147) = 8.02, P = 0.005). Specifically, we found that patients with SCZ who are risk T homozygotes have lower FA in bilateral parietal lobes, and left cingulate gyrus compared with G carriers. Compared with risk T homozygotes in HC, patients with SCZ who are risk T homozygotes have decreased FA in bilateral parietal lobes, and left cingulate gyrus as well as right medial temporal lobe. Our findings suggest that ZNF804A risk variant influence WM integrity involving cortico-limbic brain regions in SCZ and highlight the importance of investigating the impact of genome-wide supported risk factors on intermediate phenotypes with potential to shed light on the neurobiology of SCZ.

Association between variants of zinc finger genes and psychiatric disorders: Systematic review and meta-analysis

“…ZNF804A polymorphisms appears to be linked to abnormal brain structure and function in many mental illnesses (Bergmann et al, 2013;Donohoe et al, 2011;Esslinger et al, 2009;Guella et al, 2014;Kuswanto et al, 2012;Lencz et al, 2010;Mohnke et al, 2013;Rasetti et al, 2011;Schultz et al, 2014;Wassink et al, 2012;Wei et al, 2013). The rs1344706 SNP alters the thickness and functional connectivity of several regions, such as the prefrontal cortex, that comprise the default mode network (DMN; Schultz et al, 2014).…”

“…Carriers of the risk T-allele also exhibited higher WM density in the bilateral hippocampus in schizophrenia patients compared with non-risk allele carriers (Wei et al, 2013). However, another study reported that schizophrenia patients who were TT carriers had lower fractional anisotropy (i.e., a measure that correlates with fiber integrity) in the parietal lobes, left cingulate gyrus, and other corticolimbic brain regions (Kuswanto et al, 2012). Additionally, some studies provided negative results with regard to the effect of rs1344706 on WM tract integrity (Wei et al, 2013).…”

Less Cognitive and Neurological Deficits in Schizophrenia Patients Carrying Risk Variant in <b><i>ZNF804A</i></b>

“…Walter et al [52] show decreased activity in frontal and parietal cortical regions and aberrant connectivity between these regions during a theory of mind task in healthy risk allele carriers. A diffusion tensor imaging study reports lower fractional anisotropy (a measure correlated with fiber integrity) in parietal lobes and left cingulate gyrus in schizophrenia patients homozygous for the risk allele [53]. …”

White matter changes in first episode psychosis and their relation to the size of sample studied: A DTI study

“…On the other hand, changes in WM integrity may be a fundamental pathophysiological mechanism underlying the clinical presentation of schizophrenia, present before the appearance of clinical symptoms. There are several studies supporting this hypothesis, proposing the change in WM as an endophenotypical feature of the disease (Davis et al, 2003;Camchong, 2009;Abdul-Rahman et al, 2011;Kunimatsu et al, 2012;Kuswanto et al, 2012;Scheel et al, 2012). Together, the data to date strongly suggests that there is an underlying abnormality in the WM tracts of patients with schizophrenia.…”