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Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance

Published online by Cambridge University Press:  22 December 2015

G. Pergola ,
P. Di Carlo ,
I. Andriola ,
B. Gelao ,
S. Torretta ,
M. T. Attrotto ,
L. Fazio ,
A. Raio ,
D. Albergo  and
R. Masellis
...Show all authors
G. Pergola*
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
P. Di Carlo
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
I. Andriola
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
B. Gelao
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
S. Torretta
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
M. T. Attrotto
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
L. Fazio
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
A. Raio
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
D. Albergo
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy
R. Masellis
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy Psychiatry Unit, Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy
A. Rampino
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy Psychiatry Unit, Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy
G. Blasi
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy Psychiatry Unit, Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy
A. Bertolino*
Affiliation:
Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari ‘Aldo Moro’, Piazza Giulio Cesare 11, 70124 Bari, Italy Psychiatry Unit, Bari University Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy NORD DTA, pRED, Hoffman – La Roche Ltd, Grenzacherstrasse 183, Basel, Switzerland
*
*Addresses for correspondence: A. Bertolino, M.D., Ph.D. and G. Pergola, Ph.D., Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, ‘Aldo Moro’, Piazza Giulio Cesare, 11, 70120 Bari, Italy. (Email: alessandro.bertolino@uniba.it)
*Addresses for correspondence: A. Bertolino, M.D., Ph.D. and G. Pergola, Ph.D., Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, ‘Aldo Moro’, Piazza Giulio Cesare, 11, 70120 Bari, Italy. (Email: alessandro.bertolino@uniba.it)
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Abstract

Background

The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects.

Method

We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122).

Results

Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.

Conclusions

Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

Keywords

Expression quantitative trait lociGRIN2BN-methyl-d-aspartateprefrontal cortexworking memory
Type
Original Articles
Information
Psychological Medicine , Volume 46 , Issue 6 , April 2016 , pp. 1135 - 1150
Copyright
Copyright © Cambridge University Press 2015 

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