Xuebin Zheng

Meta-analysis and brain imaging data support the involvement of VRK2 (rs2312147) in schizophrenia susceptibility

Recent genome-wide association studies have reported a set of schizophrenia susceptibility genes, but many of them await further replications in additional samples. Here we analyzed 5 genome-wide supported variants in a Han Chinese sample, and the variant rs2312147 at VRK2 showed significant association, which was confirmed in the meta-analysis combining multiple Asian and European samples (P=3.17×10(-4), N=7498). Rs2312147 is also associated with brain structure in healthy subjects, including the total brain volume and the white matter volume. Gene expression analyses indicated an up-regulation of VRK2 in schizophrenia patients. Our data provide further evidence for the contribution of VRK2 to schizophrenia.

ZNF804A and schizophrenia susceptibility in Asian populations

ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case–control samples (10 Chinese and 2 Japanese samples; N = 21,062), and the meta‐analyses indicated non‐significant association of rs1344706 with schizophrenia (P = 0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520 kb) identified no association except for SNP rs359895 (P = 7.8 × 10−5, N = 5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up‐regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P = 0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations.

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

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 F1,149 = 9.36, P = 0.003) and diagnosis–genotype interactions (left parietal lobe: Adjusted F1,147 = 7.39, P = 0.007; right parietal lobe: Adjusted F1,147 = 6.95, P = 0.009; right medial temporal lobe: Adjusted F1,147 = 8.79, P = 0.004; left cingulate gyrus: Adjusted F1,147 = 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.

The association between rare large duplication of 16p11.2 and schizophrenia in the Singaporean Chinese population.

Fig. 1. The LRR of the five duplications of the 550 kb CNV. X-axis showed the chromosome positions, while y-axis represented the LRR values. Each point in grey indicated the LRR at each SNP position. The red and blue bars represented duplications (copy number ≥ 3) and normal variations (copy number = 2), respectively. The association between rare large duplication of 16p11.2 and schizophrenia in the Singaporean Chinese population

An evaluation of association between a novel hippocampal biology related SNP (rs7294919) and schizophrenia.

Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919’s association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.