"It was the first gene to reach genome-wide significance for psychosis (O'Donovan et al., 2008), and its association with both schizophrenia and bipolar disorder has been subsequently confirmed in multiple genome-wide association studies (GWASs; Riley et al., 2010; Williams et al., 2011; Zhang et al., 2011). Studies of the single nucleotide polymorphism (SNP) rs1344706 in both psychiatric patients and healthy risk allele carriers have demonstrated effects on white and gray matter volume, white matter tract integrity, functional connectivity (Esslinger et al., 2009; Lencz et al., 2010; Voineskos et al., 2011; Ikuta et al., 2014; Wei et al., 2015), and cognition (Hashimoto et al., 2010; Walters et al., 2010; Esslinger et al., 2011; Walter et al., 2011; Chen et al., 2012), indicating potential functional consequences of this gene variant. While these findings illustrate the potential wide-ranging effects of a ZNF804A polymorphism, little is known about the biological functions of the gene itself. "
"Such an approach has been useful thus far for the identification of zinc finger protein 804A (ZNF804A), a genome-wide significant candidate gene associated with SZ and BD. Investigation of this gene has moved from its initial genetic association [O'Donovan et al., 2008] to neurophysiological and structural examination [Hashimoto et al., 2010; Walters et al., 2010; Donohoe et al., 2011; Esslinger et al., 2011; Rasetti et al., 2011; Voineskos et al., 2011; Chen et al., 2012; Cousijn et al., 2012; Wassink et al., 2012] to recent scrutiny of its biological impact [Hill and Bray, 2012; Hill et al., 2012; Umeda-Yano et al., 2013]. ZNF804A exemplifies the ability of one gene to effectively challenge the Kraepelinian dichotomy through a preponderance of evidence at multiple levels of analysis. "
"males, 102 males and 71 females, mean age ± SD, range 36.0 ± 12.3 years) and 449 healthy subjects (47.7% males, 214 males and 235 females, mean age ± SD, range 35.4 ± 12.8 years). All subjects were biologically unrelated within the second-degree of relationship and were of Japanese descent [25,26]. The subjects were excluded if they had neurological or medical conditions that could potentially affect the central nervous system, such as atypical headache, head trauma with loss of consciousness, chronic lung disease, kidney disease, chronic hepatic disease, thyroid disease, active cancer, cerebrovascular disease, epilepsy, seizures, substance-related disorders or mental retardation. "
[Show abstract][Hide abstract] ABSTRACT: Genome-wide significant associations of schizophrenia with eight SNPs in the CNNM2, MIR137, PCGEM1, TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear.
After performing quality control for minor-allele frequency > 5% using a JPT HapMap sample and our sample, a genotyping call rate > 95% and Hardy-Weinberg equilibrium testing (p > 0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients with schizophrenia (n = 173) and healthy subjects (n = 449).
The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T = 4.96, p = 0.0088, left T = 4.66, p = 0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p > 0.05).
Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri.
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