The Impact of MIR137 on Dorsolateral Prefrontal–Hippocampal Functional Connectivity in Healthy Subjects

Abstract

A recent mega-analysis combining genome-wide association study data revealed that a variant of microRNA 137 (MIR137) exhibits the most significant association with schizophrenia. Other biological evidence also consistently suggests that MIR137 may have a pivotal role in the pathogenesis of schizophrenia. However, the underlying neural mechanism remains unclear. As the disrupted dorsolateral prefrontal cortex (DLPFC) coupling with the hippocampal formation (HF) has been widely observed in schizophrenia patients, DLPFC-HF dysconnectivity can therefore be thought of as a pivotal intermediate phenotype that links genetic variants of psychiatric risk genes to schizophrenia. This study used resting-state functional magnetic resonance imaging to test whether the MIR137 variant (rs1625579) impacts DLPFC-HF functional connectivity and cognitive performance in 290 young, healthy Han Chinese individuals. To identify functional connectivity between DLPFC and HF, a seed-based functional connectivity analysis was used. The association between DLPFC-HF connectivity and working memory performance was further examined in individuals with different MIR137 genotypes. The individuals who are homozygous for the MIR137 risk allele (TT), which confers a high risk for schizophrenia, exhibited significantly different DLPFC-HF functional connectivity compared with TG individuals. Moreover, the DLPFC-HF connectivity could predict the working memory performance in MIR137 TG individuals, but not in TT individuals. The current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking MIR137 with the risk of developing schizophrenia via the intermediate phenotype of DLPFC-HF connectivity.

Bridging Integrator 1 (BIN1) Genotype Effects on Working Memory, Hippocampal Volume, and Functional Connectivity in Young Healthy Individuals

“…The same procedure was used in our previous study (Liu et al, 2014). A total of 9108/9094 out of the 10 000 comparisons made between groups of equal sample sizes indicated that the GMV of the left/right medial temporal cortex was significantly lower in the A allele carrier subsample than those in the GG group ( Po0.05), whereas none of the comparisons showed the inverse result (two-sample t-tests, All P40.05).…”

“…Previous studies have showed the laterality effects for prefrontal effects in normal controls (Van Horn et al, 1996), and the right DLPFC showed greater recruitment during the WM task in siblings of schizophrenia compared with normal controls (MacDonald et al, 2009). The connectivity of only right DLPFC with HF was found to be disrupted in schizophrenia patients (Meyer-Lindenberg et al, 2005) and high-risk individuals (Liu et al, 2014;Rasetti et al, 2011). The effect of BIN1 genotype on brain structure and FC can be interpreted by the hypothesis that the reduction in HF-DLPFC functional connectivity leads to a compensatory increase in hippocampal volume to maintain performance.…”

“…This task was performed on a computer in a quiet room outside the MRI scanner before performing magnetic resonance scanning for each subject, and the data were evaluated using E-Prime, Version 2.0 (http://www. pstnet.com/eprime.cfm) as described in our previous study (Liu et al, 2014).…”

Associations between DNA methylation and schizophrenia-related intermediate phenotypes — A gene set enrichment analysis

“…In line with that, the largest schizophrenia genome-wide association studies (GWAS) conducted to date identified variants within the hsa-miR-137 host gene, MIR137HG , as well as variants within validated miR-137 target genes to be among the top risk variants for schizophrenia [39, 40], suggesting a potential role for the miRNA in the disorder. Several studies suggest that one of the identified MIR137HG variants is associated with schizophrenia-related intermediate phenotypes such as dorsolateral prefrontal cortex hyperactivation [41] and dorsolateral prefrontal-hippocampal functional connectivity [42]. Furthermore, Wright et al [43] found significant enrichment for schizophrenia-associated genes among the list of potential and experimentally validated miR-137 targets, as well as significant enrichment of targets within schizophrenia-relevant canonical pathways, such as those involved in neuronal function and development.…”

No evidence of an association between MIR137 rs1625579 and schizophrenia in Asians

“…The full texts of the 13 literatures were screened to examine their eligibilities on the basis of the inclusion and exclusion criteria. Among these, four studies were excluded [two reported control-only studies (Li and Su, 2013;Liu et al, 2014) and two did not analyze rs1625579 (Egawa et al, 2013;Ohi et al, 2013)]. Among the nine references included, one study included two independent case-control samples from a Chinese population .…”