Elsevier

Biological Psychiatry

Volume 75, Issue 5, 1 March 2014, Pages 398-405
Biological Psychiatry

Archival Report
Schizophrenia miR-137 Locus Risk Genotype Is Associated with Dorsolateral Prefrontal Cortex Hyperactivation

https://doi.org/10.1016/j.biopsych.2013.06.016Get rights and content

Background

miR-137 dysregulation has been implicated in the etiology of schizophrenia, but its functional role remains to be determined.

Methods

Functional magnetic resonance imaging scans were acquired on 48 schizophrenia patients and 63 healthy volunteers (total sample size N = 111 subjects), with similar mean age and sex distribution, while subjects performed a Sternberg Item Response Paradigm with memory loads of one, three, and five numbers. Dorsolateral prefrontal cortex (DLPFC) retrieval activation for the working memory load of three numbers, for which hyperactivation had been shown in schizophrenia patients compared with control subjects, was extracted. The genome-wide association study confirmed schizophrenia risk single nucleotide polymorphism rs1625579 (miR-137 locus) was genotyped (schizophrenia: GG n = 0, GT n = 9, TT n = 39; healthy volunteers: GG = 2, GT n = 15, and TT n = 46). Fisher’s exact test examined the effect of diagnosis on rs1625579 allele frequency distribution (p = nonsignificant). Mixed model regression analyses examined the effects of diagnosis and genotype on working memory performance measures and DLPFC activation.

Results

Patients showed significantly higher left DLPFC retrieval activation on working memory load 3, lower working memory performance, and longer response times compared with controls. There was no effect of genotype on working memory performance or response times in either group. However, individuals with the rs1625579 TT genotype had significantly higher left DLPFC activation than those with the GG/GT genotypes.

Conclusions

Our study suggests that the rs1625579 TT (miR-137 locus) schizophrenia risk genotype is associated with the schizophrenia risk phenotype DLPFC hyperactivation commonly considered a measure of brain inefficiency.

Section snippets

Participants

Forty-eight patients with schizophrenia (mean age ± SD = 37.0 ± 10.7, 35 male subjects) and 63 healthy volunteers (mean age ± SD = 37.6 ± 12.4, 39 male subjects) with similar mean age, sex, handedness, and race distributions, recruited from 9 sites part of the Function Biomedical Informatics Network Phase 2 study on multicenter functional imaging, participated in the study (Table 1). Study participants were between the ages of 18 and 70, had regular hearing levels (<25 db loss in either ear),

Results

Mixed-model regression analyses confirmed left DLPFC hyperactivation for SIRP load 3 probes in SZ patients compared with healthy volunteers (t100 = 1.91, p = .03). Individuals carrying the common miR-137 schizophrenia risk genotype (rs1625579 TT) showed hyperactivation compared with those carrying the less frequent GG/GT genotype (t100 = 2.17, p = .02; Figure 2). The analysis of additive effects of genotype and diagnoses showed significant effects of genotype (TT > GG/GT; t99 = 1.99, p = .03)

Discussion

The main finding of our study is that the rs1625579 TT (miR-137) schizophrenia risk genotype is associated with left DLPFC hyperactivation compared with the combined GG/GT genotype irrespective of diagnosis. Given equivalent working memory performance between rs1625579 TT and GG/GT carriers, we interpret the observed DLPFC hyperactivation in individuals with the rs1625579 TT genotype compared with those with the GG/GT genotypes as being consistent with neural inefficiency in rs1625579

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      Citation Excerpt :

      This study examined the effects of the MIR137 rs1625579 genotype on neural correlates of working memory. Consistent with van Erp et al.'s (2014) fMRI study, we found that the risk allele homozygotes (TT) exhibited altered activation (less deactivation) at the PCC as compared to the GT heterozygotes during working memory. Less deactivation at the PCC when performing working memory tasks has been found in schizophrenia patients (Bittner et al., 2015; Fryer et al., 2013; Haatveit et al., 2016; Kim et al., 2009; Wu et al., 2014) and has been linked to poorer working memory performance (Eryilmaz et al., 2016; Pu et al., 2016; Zhou et al., 2016), which was replicated in the current study (See Supplementary Fig. S1).

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