Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia

Abstract

Context The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. Objective To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. Design Case-control analysis of covariance. Setting University-based research hospital. Participants Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. Main Outcome Measures Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. Results The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F =3.98, P=.02; F =4.95, P=.007; and F =3.08, P =.05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F =3.93, P=.02) and frontal WM volumes (F =7.16, P < .001) and on psychotic symptom severity (F =6.07, P=.003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F =4.61, P=.03), replicating a previously reported association. Conclusions A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.

A systematic review of the effect of genes mediating neurodevelopment and neurotransmission on brain morphology: Focus on schizophrenia

“…95 The TT subjects (n = 18) also showed reduced GMV in the angular gyrus, parahippocampal gyrus, posterior cingulate, medial orbitofrontal gyrus/gyrus rectus, left inferior frontal gyrus, right inferior temporal gyrus and right cerebellum (FDR-corrected P < 0.05). A similar study by Wassink et al 94 reported greater total (F = 3.98, P < 0.02), frontal (F = 4.95, P < 0.007) and parietal lobe (F = 3.08, P < 0.05) WMV in patients with schizophrenia (N = 335) homozygous for the T allele (n = 126), when compared to non-risk allele carriers (n = 209). The association with altered WMV across the entire brain supports the hypothesis that ZNF804A influences neural connectivity patterns across a distributed network of brain regions.…”

“…Nevertheless, structural and functional imaging studies have revealed the role of this SNP (rs1344706) in brain connectivity. 94 Healthy volunteers (N = 39) homozygous for the risk allele (T/T) (n = 18) of the ZNF804A gene rs1344706 polymorphism showed larger total WMV than carriers of the G allele (n = 21) (F (1,27) = 4.61, P < 0.041, partial eta = 0.146). 95 The TT subjects (n = 18) also showed reduced GMV in the angular gyrus, parahippocampal gyrus, posterior cingulate, medial orbitofrontal gyrus/gyrus rectus, left inferior frontal gyrus, right inferior temporal gyrus and right cerebellum (FDR-corrected P < 0.05).…”

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

“…In another study, schizophrenia patients who were homozygous for the TT genotype also had relatively larger GMV in the superior temporal gyrus compared with non-carriers (AC/CC). However, other studies did not replicate these findings in schizophrenia or bipolar disorder patients (Bergmann et al, 2013;Wassink et al, 2012). Several studies focused on the effects of rs1344706 variation on WM tract integrity.…”

Forty years of structural imaging in psychosis: promises and truth

“…Following emerging interest in more derived measures of anatomy such as cortical complexity, gyrification, symmetry and thickness(34), a few studies have addressed these alterations in psychotic patients (15,(35)(36)(37)(38)(39)(40)(41)(42). Multimodal studies involved the use of MRI, eye tracking and markers of dopamine activity (25), MRI and PET(43), MRI and EEG measures (44), MRI and fMRI (40,41), MRI and genetics (32,38,45,46). Most studies focused on first-episode samples, with several MRI studies investigating the psychotic spectrum by including samples at genetic risk (28,33,37,(47)(48)(49)(50)(51)(52)(53)(54)(55) and a few studies that have investigated subjects at clinical risk for psychosis (14,31,(56)(57)(58).…”