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

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Abstract

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.

Introduction

O'Donovan et al.'s whole genome association study (O'Donovan et al., 2008) first reported that SNP rs1344706 in the gene of zinc-finger protein 804A (ZNF804A) showed the most significant association with schizophrenia. Since then, this association has been replicated in many studies across different ethnic populations, including Han Chinese as reported by Zhang et al. (2011) and ourselves (Chen et al., 2012). ZNF804A has a zinc finger at its N-terminus and interacts with many other proteins (Girgenti et al., 2012, Hess et al., 2015, Hill et al., 2012), but the exact mechanism of the contribution of rs1344706 to schizophrenia is still unknown.

Researchers have examined the neural mechanisms involved in the rs1344706–schizophrenia association. In a study of 115 healthy volunteers, Esslinger et al., 2009, Esslinger et al., 2011 reported that rs1344706 was associated with functional connectivity from the right dorsolateral prefrontal cortex (rDLPFC) to the left hippocampal formation (lHF) during an N-back task, but not during an emotion recognition (face matching) task or at the resting state. Two other studies using similar N-back tasks replicated Esslinger et al.'s results: Rasetti et al.'s fMRI study (2011) with three samples (96 healthy controls, 83 siblings of patients with schizophrenia and 33 patients) and Paulus et al.'s fMRI study (2013) with 94 healthy controls.

Functional connectivity may be based on structural connectivity (Greicius et al., 2009, Quigley et al., 2003). Therefore, it is possible that rs1344706 affects the structural connectivity between rDLPFC and lHF. One possible route to connect DLPFC with the contralateral HF is via the cingulum tract (Lawes et al., 2008, Morris et al., 1999, Schmahmann et al., 2007), with the anterior cingulate cortex (ACC) and the posterior cingulate cortex (PCC) as two important intervening nodes (Greicius et al., 2009, Palesi et al., 2012, van den Heuvel et al., 2008). Previous diffusion tensor imaging (DTI) studies have reconstructed the tract connecting the PCC/precuneus and the medial frontal cortex/ACC (Greicius et al., 2009, van den Heuvel et al., 2008) and the tract connecting the HF and the PCC (Greicius et al., 2009, Palesi et al., 2012, Supekar et al., 2010). The fiber connection between the ACC and the DLPFC has been suggested to be a part of the anterior corona radiate (Croxson et al., 2005, Gowin et al., 2013).

In the current study, we first tried to replicate the previous finding that rs1344706 was associated with the functional connectivity from the rDLPFC to the lHF during an N-back task using the same method as in Esslinger et al.'s study (2009). Then, using DTI data, we reconstructed tracts between the rDLPFC and the lHF with two important nodes (the ACC and the PCC). The association between rs1344706 and the mean FA value of each reconstructed tract was tested to see whether any of the tracts was affected by rs1344706. Finally, using fMRI data acquired during the N-back task and the resting state, we tested the effects of rs1344706 on the functional connectivity between brain regions that were connected by the affected tract(s). Through this approach, we aimed to find the subconnections that were affected by rs1344706.

Section snippets

Subjects

Participants in the fMRI study were 87 healthy controls, including 78 who were involved in one of our previous studies (Zhang et al., 2015) and 9 who were newly recruited. Due to their excessive head motion (> 2 mm or 2°), six subjects were excluded from the N-back fMRI analysis and three were excluded from the resting state fMRI analysis. All subjects were recruited by advertisement and were screened for any personal or family history of psychiatric disorders by experienced psychiatrists during

Demographic and behavioral data

No significant difference between genotypes was found for all demographic factors (see Table 1, Table 2). Performance on the N-back task was also matched between genotype groups (see Table 2). The distribution of rs1344706 genotypes was similar to previous reports about Han Chinese population (Chen et al., 2012, Zhang et al., 2011). No deviation from Hardy–Weinberg equilibrium for rs1344706 was found (P > 0.05).

DTI analysis

The tracts of lHF–PCC, PCC–ACC, and ACC–rDLPFC are shown in Fig. 1. We did not find

Discussion

In this study, we first replicated the previous finding that SNP rs1344706 was associated with the functional connectivity from the rDLPFC to the lHF during an N-back task, but not at resting state. We then used the DTI data to reconstruct the fibers connecting the rDLPFC and lHF, through two intervening nodes, yielding three tracts (lHF–PCC, PCC–ACC, and ACC–rDLPFC). Only the lHF–PCC tract showed a significant association with rs1344706. Additional analyses of the fMRI data from both the

Contributors

Li J, Dong Q and Chen CS designed the study and wrote the protocol. Zhang ZF, Chen XY, Yu P managed the literature searches and analyses. Zhang QM, Zhai JG, Chen M, Ji F, Wang CY, Xiang YT, Wu HJ, Sun XC, Gu H, Zhang H, Du BQ, Deng XX, and Li DW selected and evaluated the sample of healthy volunteers. Zhang ZF undertook the statistical analysis and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Role of the funding source

This work was supported by grants from the National Key Basic Research Program of China (2014CB846103), the Natural Science Foundation of China (81571045), the Beijing Higher Education Young Elite Teacher Project (YETP0249), the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (300072) and the Fundamental Research Funds for the Central Universities, the National Science Foundation of Shandong Province (ZR2012HM065), the Development Project of Medical Science

Acknowledgments

We would like to thank all the healthy volunteers.

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