Qiumei Zhang

The Effects of CACNA1C Gene Polymorphism on Spatial Working Memory in Both Healthy Controls and Patients with Schizophrenia or Bipolar Disorder

CACNA1C gene polymorphism (rs1006737) is a susceptibility factor for both schizophrenia (SCZ) and bipolar disorder (BP). However, its role in working memory, a cognitive function that is impaired in both diseases, is not clear. Using three samples, including healthy controls, patients with SCZ, and patients currently in manic episodes of BP, this study tested the association between the SNP rs1006737 and spatial working memory as measured by an N-back task and a dot pattern expectancy (DPX) task. Among SCZ patients and healthy controls, the clinical risk allele was associated with impaired working memory, but the association was either in opposite direction or non-significant in patients with BP. These results indicated that rs1006737 may have differential effects on working memory in different disease populations and pointed to the necessity for more studies in different patient populations.

Evidence of IQ-Modulated Association Between ZNF804A Gene Polymorphism and Cognitive Function in Schizophrenia Patients

ZNF804A gene polymorphism rs1344706 has been suggested as the most compelling case of a candidate gene for schizophrenia by a genome-wide association study and several replication studies. The current study of 570 schizophrenia patients and 448 controls again found significantly different genotype frequencies of rs1344706 between patients and controls. More important, we found that this association was modulated by IQ, with a stronger association among individuals with relatively high IQ, which replicated results of Walters et al, 2010. We further examined whether this IQ-modulated association also existed between the SNP and the intermediate phenotypes (working memory and executive functions) of schizophrenia. Data were available from an N-back task (366 patients and 414 controls) and the attention network task (361 patients and 416 controls). We found that the SNP and IQ had significant interaction effects on the intermediate phenotypes for patients, but not for controls. The disease risk allele was associated with poorer cognitive function in patients with high IQ, but better cognitive function in patients with low IQ. Together, these results indicated that IQ may modulate the role of rs1344706 in the etiology of both schizophrenia and its cognitive impairments, and pointed to the necessity of considering general cognitive function as indexed by IQ in the future studies of genetic bases of schizophrenia.

Associations between TCF4 gene polymorphism and cognitive functions in schizophrenia patients and healthy controls.

The SNP rs2958182 was reported to be significantly associated with schizophrenia (SCZ) in Han Chinese. This study examined this SNP’s associations with cognitive functions in 580 SCZ patients and 498 controls. Cognitive functions were assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-RC), the Attention Network Task (ANT), the Stroop task, the dot pattern expectancy (DPX), task and the N-back working memory task. Results showed significant or marginally significant interaction effects between genotype and diagnosis status on IQ (P=0.011) and attention-related tasks (ie, the forward digit span of WAIS-RC, P=0.005; the ANT conflict effect; P=0.020, and its ratios over mean reaction time (RT), P=0.036; the Stroop conflict effect, P=0.032, and its ratios over mean RT, P=0.062; and the DPX task’s error rate under the BX condition, P<0.001, and the error rate of BX minus the error rate of AY (BX−AY), P=0.002). There were no such interaction effects on the measures of working memory (all P-values >0.05). Further analysis of the significant genotype-by-diagnosis interactions showed that the risk (T) allele was associated with better performance on cognitive tasks in patients but with worse performance in controls. These results seem to indicate that the association between this SNP and selected cognitive functions may be of an inverted U-shaped pattern. Future research is needed to replicate these results and to explore the biochemical mechanisms behind this association.

Risk variants in the S100B gene, associated with elevated S100B levels, are also associated with visuospatial disability of schizophrenia.

Rs9722 and rs1051169 have been reported as affecting the levels of S100B in the serum or the brain, and haplotypes containing these two SNPs have been associated with schizophrenia. The current study investigated the role of the S100B gene in an endophenotype of schizophrenia-spatial disability. 304 schizophrenia patients and 196 healthy controls were given a block design task and a mental rotation task. Results showed that the two aforementioned SNPs and related haplotypes were associated with the spatial disability of schizophrenia patients. Specifically, risk factors for the elevated S100B levels, including the A allele of rs9722, the G allele of rs1051169, and the AG haplotype, were associated with a poorer performance on both tests of spatial ability, especially the mental rotation task. These results implicate a role for S100B gene polymorphisms in the cognitive functions of schizophrenia patients and encourage further investigation into spatial disability as an endophenotype of schizophrenia.

Evidence for the contribution of NOS1 gene polymorphism (rs3782206) to prefrontal function in schizophrenia patients and healthy controls.

Nitric oxide (NO), a gaseous neurotransmitter, has been implicated in the pathogenesis of schizophrenia. Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the nitric oxide synthase 1 (NOS1), have been found to convey a risk for schizophrenia. This study examined the role of NOS1 gene polymorphisms in cognitive functions and related neural mechanism. First, with a sample of 580 schizophrenia patients and 720 healthy controls, we found that rs3782206 genotype had main effects on the 1-back task (P=0.005), the 2-back task (P=0.049), the AY condition of the dot-pattern expectancy (DPX) task (P=0.001), and the conflict effect of the attention network (ANT) test (P<0.001 for RT differences and P=0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P=0.009), the AY condition of the DPX (P<0.001), and the Stroop conflict effect (P=0.003 for RT differences and P=0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in five measures for the patients (1-back, P=0.025; BX, P=0.017; AY, P<0.001; ANT conflict effect (RT differences), P=0.005; Stroop conflict effect (RT differences), P=0.019) and three measures for the controls ( for the 2-back task, P=0.042; for the ANT conlict effect (RT differences), P=0.013; for the ANT conflict effect (RT ratios), P=0.028). Then, with a separate sample of 78 healthy controls, we examined the association between rs3782206 and brain activation patterns during the N-back task and the Stroop task. Whole brain analyses found that the risk allele carriers showed reduced activation at the right inferior frontal gyrus (IFG) during both tasks. Finally, we examined functional connectivity seeded from the right IFG to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex under three conditions (the N-back task, the Stroop task, and the resting state). Results showed reduced connectivity with the DLPFC for the risk allele carriers mainly in the Stroop task and the resting state. Taken together, results of this study strongly suggested a link between NOS1 gene polymorphism at rs3782206 and cognitive functions and their neural underpinnings at the IFG. These results have important implications for our understanding of the neural mechanism underlying the association between NOS1 gene polymorphism and schizophrenia.

Effect of rs1344706 in the ZNF804A gene on the connectivity between the hippocampal formation and posterior cingulate cortex

ZNF804A is one of the most promising candidate genes for schizophrenia. Previous fMRI studies have repeatedly shown an association between SNP rs1344706 in this gene and the functional connectivity from the right dorsolateral prefrontal cortex (rDLPFC) to the left hippocampal formation (lHF) during the N-back task. However, the rDLPFC-lHF functional connectivity included several subconnections and it is not known whether rs1344706 plays the same role in these subconnections. This study addressed that question using both fMRI and DTI data of 87 subjects. First, we replicated the association between rs1344706 and the rDLPFC-lHF functional connectivity using our fMRI data from the N-back task. Second, we reconstructed fiber connections between rDLPFC and lHF using our DTI data, which included three subconnections: from lHF to posterior cingulate cortex (PCC), from PCC to anterior cingulated cortex (ACC), and from ACC to rDLPFC. We found that only the lHF-PCC tract showed significantly lower fractional anisotropy (FA) in risk allele homozygotes. Finally, we analyzed the fMRI data (from the N-back task and the resting state). Both consistently showed relatively lower lHF-PCC functional connectivity in risk allele homozygotes. Taken together, the disconnectivity of the lHF-PCC tract seems to be a plausible intermediate phenotype that links rs1344706 and schizophrenia.

Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex.

Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N‐back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N‐back task. These findings helped to elucidate the role of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp 37:2398–2406, 2016.

The ANK3 gene and facial affect processing: An ERP study

ANK3 is one of the most promising candidate genes for bipolar disorder (BD). A polymorphism (rs10994336) within the ANK3 gene has been associated with BD in at least three genome‐wide association studies of BD [McGuffin et al., 2003; Kieseppä, 2004; Edvardsen et al., 2008]. Because facial affect processing is disrupted in patients with BD, the current study aimed to explore whether the BD risk alleles are associated with the N170, an early event‐related potential (ERP) component related to facial affect processing. We collected data from two independent samples of healthy individuals (Ns = 83 and 82, respectively) to test the association between rs10994336 and an early event‐related potential (ERP) component (N170) that is sensitive to facial affect processing. Repeated‐measures analysis of covariance in both samples consistently revealed significant main effects of rs10994336 genotype (Sample I: F (1, 72) = 7.24, P = 0.009; Sample II: F (1, 69) = 11.81, P = 0.001), but no significant interaction of genotype × electrodes (Ps > 0.05) or genotype × emotional conditions (Ps > 0.05). These results suggested that rs10994336 was linked to early ERP component reflecting facial structural encoding during facial affect processing. These results shed new light on the brain mechanism of this risk SNP and associated disorders such as BD.

The effects of CACNA1C gene polymorphism on prefrontal cortex in both schizophrenia patients and healthy controls

CACNA1C gene polymorphism rs2007044 has been reported to be associated with schizophrenia, but its underlying brain mechanism is not clear. First, we conducted an exploratory functional magnetic resonance imaging (fMRI) study using an N-BACK task and a Stroop task in 194 subjects (55 schizophrenia patients and 139 healthy controls). Our whole brain analysis found that the risk allele was associated with reduced activation of the left inferior frontal gyrus (IFG) during the Stroop task (cluster size = 390 voxels, P < 0.05 TFCE-FWE corrected; peak MNI coordinates: x = -57, y = -6, z = 30). We also conducted a functional near-infrared spectroscopy (fNIRS) study using the same Stroop task in an independent sample of 126 healthy controls to validate the fMRI finding. Our repeated-measures ANCOVA on the six channels (20, 27, 33, 34, 40 and 46) within the left IFG also found significant result. The polymorphism rs2007044 showed significant effect on the oxy-Hb data (F = 5.072, P = 0.026) and showed significant interaction effect with channels on the deoxy-Hb data (F = 2.841, P = 0.015). Taken together, results of this study suggested that rs2007044 could affect the activation of the left IFG, which was a possible brain mechanism underlying the association between CACNA1C gene polymorphism and schizophrenia.

Effect of rs1344706 in the ZNF804A gene on the brain network

ZNF804A rs1344706 (A/C) was the first SNP that reached genome-wide significance for schizophrenia. Recent studies have linked rs1344706 to functional connectivity among specific brain regions. However, no study thus far has examined the role of this SNP in the entire functional connectome. In this study, we used degree centrality to test the role of rs1344706 in the whole-brain voxel-wise functional connectome during the resting state. 52 schizophrenia patients and 128 healthy controls were included in the final analysis. In our whole-brain analysis, we found a significant interaction effect of genotype × diagnosis at the precuneus (PCU) (cluster size = 52 voxels, peak voxel MNI coordinates: x = 9, y = − 69, z = 63, F = 32.57, FWE corrected P < 0.001). When we subdivided the degree centrality network according to anatomical distance, the whole-brain analysis also found a significant interaction effect of genotype × diagnosis at the PCU with the same peak in the short-range degree centrality network (cluster size = 72 voxels, F = 37.29, FWE corrected P < 0.001). No significant result was found in the long-range degree centrality network. Our results elucidated the contribution of rs1344706 to functional connectivity within the brain network, and may have important implications for our understanding of this risk genes role in functional dysconnectivity in schizophrenia.