Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation

Steven G. Potkin, Theo G.M. Van Erp, Ilaria Guella, Marquis P. Vawter, Jessica Turner, Gregory G. Brown, Gregory McCarthy, Douglas N. Greve, Gary H. Glover, Vince D. Calhoun, Kelvin O. Lim, Juan R. Bustillo, Aysenil Belger, Judith M. Ford, Daniel H. Mathalon, Michele Theresa Diaz, Adrian Preda, Dana Nguyen, Fabio Macciardi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)398-405
Number of pages8
JournalBiological Psychiatry
Volume75
Issue number5
DOIs
StatePublished - Mar 1 2014

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Prefrontal Cortex
Schizophrenia
Genotype
Short-Term Memory
Reaction Time
Healthy Volunteers
Sex Distribution
Genome-Wide Association Study
Age Distribution
Gene Frequency
Sample Size
Single Nucleotide Polymorphism
Regression Analysis
Magnetic Resonance Imaging
Phenotype
Brain

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Potkin, S. G., Van Erp, T. G. M., Guella, I., Vawter, M. P., Turner, J., Brown, G. G., ... Macciardi, F. (2014). Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. Biological Psychiatry, 75(5), 398-405. https://doi.org/10.1016/j.biopsych.2013.06.016
Potkin, Steven G. ; Van Erp, Theo G.M. ; Guella, Ilaria ; Vawter, Marquis P. ; Turner, Jessica ; Brown, Gregory G. ; McCarthy, Gregory ; Greve, Douglas N. ; Glover, Gary H. ; Calhoun, Vince D. ; Lim, Kelvin O. ; Bustillo, Juan R. ; Belger, Aysenil ; Ford, Judith M. ; Mathalon, Daniel H. ; Diaz, Michele Theresa ; Preda, Adrian ; Nguyen, Dana ; Macciardi, Fabio. / Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. In: Biological Psychiatry. 2014 ; Vol. 75, No. 5. pp. 398-405.
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abstract = "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.",
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Potkin, SG, Van Erp, TGM, Guella, I, Vawter, MP, Turner, J, Brown, GG, McCarthy, G, Greve, DN, Glover, GH, Calhoun, VD, Lim, KO, Bustillo, JR, Belger, A, Ford, JM, Mathalon, DH, Diaz, MT, Preda, A, Nguyen, D & Macciardi, F 2014, 'Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation', Biological Psychiatry, vol. 75, no. 5, pp. 398-405. https://doi.org/10.1016/j.biopsych.2013.06.016

Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation. / Potkin, Steven G.; Van Erp, Theo G.M.; Guella, Ilaria; Vawter, Marquis P.; Turner, Jessica; Brown, Gregory G.; McCarthy, Gregory; Greve, Douglas N.; Glover, Gary H.; Calhoun, Vince D.; Lim, Kelvin O.; Bustillo, Juan R.; Belger, Aysenil; Ford, Judith M.; Mathalon, Daniel H.; Diaz, Michele Theresa; Preda, Adrian; Nguyen, Dana; Macciardi, Fabio.

In: Biological Psychiatry, Vol. 75, No. 5, 01.03.2014, p. 398-405.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Schizophrenia miR-137 locus risk genotype is associated with dorsolateral prefrontal cortex hyperactivation

AU - Potkin, Steven G.

AU - Van Erp, Theo G.M.

AU - Guella, Ilaria

AU - Vawter, Marquis P.

AU - Turner, Jessica

AU - Brown, Gregory G.

AU - McCarthy, Gregory

AU - Greve, Douglas N.

AU - Glover, Gary H.

AU - Calhoun, Vince D.

AU - Lim, Kelvin O.

AU - Bustillo, Juan R.

AU - Belger, Aysenil

AU - Ford, Judith M.

AU - Mathalon, Daniel H.

AU - Diaz, Michele Theresa

AU - Preda, Adrian

AU - Nguyen, Dana

AU - Macciardi, Fabio

PY - 2014/3/1

Y1 - 2014/3/1

N2 - 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.

AB - 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.

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DO - 10.1016/j.biopsych.2013.06.016

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JO - Biological Psychiatry

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