Multicenter Study

. 2014 Oct;39(11):2560-9.

doi: 10.1038/npp.2014.107. Epub 2014 May 13.

Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence

Thomas P White¹, Eva Loth², Katya Rubia³, Lydia Krabbendam⁴, Robert Whelan⁵, Tobias Banaschewski⁶, Gareth J Barker⁷, Arun L W Bokde⁸, Christian Büchel⁹, Patricia Conrod¹⁰, Mira Fauth-Bühler¹¹, Herta Flor⁶, Vincent Frouin¹², Jürgen Gallinat¹³, Hugh Garavan⁵, Penny Gowland¹⁴, Andreas Heinz¹³, Bernd Ittermann¹⁵, Claire Lawrence¹⁶, Karl Mann⁶, Marie-Laure Paillère¹⁷, Frauke Nees¹⁸, Tomas Paus¹⁹, Zdenka Pausova²⁰, Marcella Rietschel⁶, Trevor Robbins²¹, Michael N Smolka²², Sukhwinder S Shergill¹, Gunter Schumann²; IMAGEN Consortium

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK.
² MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
³ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, London, UK.
⁴ Department of Educational Neuroscience, Faculty of Psychology and Education, VU University Amsterdam, Amsterdam, The Netherlands.
⁵ 1] Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland [2] Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA.
⁶ Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁷ Institute of Psychiatry, King's College London, London, UK.
⁸ Institute of Neuroscience and Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁹ Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany.
¹⁰ 1] Institute of Psychiatry, King's College London, London, UK [2] Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada.
¹¹ 1] Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany [2] Department of Addictive Behaviour and Addiction Medicine, Heidelberg University, Heidelberg, Germany.
¹² Neurospin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Paris, France.
¹³ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Department of Physics and Astronomy, University of Nottingham, Nottingham, UK.
¹⁵ Physikalisch-Technische Bundesanstalt (PTB), Braunschweig und Berlin, Berlin, Germany.
¹⁶ School of Psychology, University of Nottingham, Nottingham, UK.
¹⁷ 1] Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 'Imaging & Psychiatry', University Paris Sud, Orsay, France [2] AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France.
¹⁸ Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
¹⁹ 1] School of Psychology, University of Nottingham, Nottingham, UK [2] Rotman Research Institute, University of Toronto, Toronto, ON, Canada [3] Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
²⁰ The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
²¹ Behavioural and Clinical Neurosciences Institute, Department of Experimental Psychology, University of Cambridge, Cambridge, UK.
²² Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.

PMID: 24820538
PMCID: PMC4207335
DOI: 10.1038/npp.2014.107

Multicenter Study

Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence

Thomas P White et al. Neuropsychopharmacology. 2014 Oct.

. 2014 Oct;39(11):2560-9.

doi: 10.1038/npp.2014.107. Epub 2014 May 13.

Authors

Affiliations

¹ Department of Psychosis Studies, Institute of Psychiatry, King's College London, London, UK.
² MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.
³ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, London, UK.
⁴ Department of Educational Neuroscience, Faculty of Psychology and Education, VU University Amsterdam, Amsterdam, The Netherlands.
⁵ 1] Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland [2] Departments of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA.
⁶ Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁷ Institute of Psychiatry, King's College London, London, UK.
⁸ Institute of Neuroscience and Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
⁹ Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany.
¹⁰ 1] Institute of Psychiatry, King's College London, London, UK [2] Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada.
¹¹ 1] Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany [2] Department of Addictive Behaviour and Addiction Medicine, Heidelberg University, Heidelberg, Germany.
¹² Neurospin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Paris, France.
¹³ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Department of Physics and Astronomy, University of Nottingham, Nottingham, UK.
¹⁵ Physikalisch-Technische Bundesanstalt (PTB), Braunschweig und Berlin, Berlin, Germany.
¹⁶ School of Psychology, University of Nottingham, Nottingham, UK.
¹⁷ 1] Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 'Imaging & Psychiatry', University Paris Sud, Orsay, France [2] AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France.
¹⁸ Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
¹⁹ 1] School of Psychology, University of Nottingham, Nottingham, UK [2] Rotman Research Institute, University of Toronto, Toronto, ON, Canada [3] Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
²⁰ The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
²¹ Behavioural and Clinical Neurosciences Institute, Department of Experimental Psychology, University of Cambridge, Cambridge, UK.
²² Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.

PMID: 24820538
PMCID: PMC4207335
DOI: 10.1038/npp.2014.107

Abstract

Catecholamine-0-methyl-transferase (COMT) gene variation effects on prefrontal blood oxygenation-level-dependent (BOLD) activation are robust; however, despite observations that COMT is estrogenically catabolized, sex differences in its prefrontal repercussions remain unclear. Here, in a large sample of healthy adolescents stratified by sex and Val(158)Met genotype (n=1133), we examine BOLD responses during performance of the stop-signal task in right-hemispheric prefrontal regions fundamental to inhibitory control. A significant sex-by-genotype interaction was observed in pre-SMA during successful-inhibition trials and in both pre-SMA and inferior frontal cortex during failed-inhibition trials with Val homozygotes displaying elevated activation compared with other genotypes in males but not in females. BOLD activation in the same regions significantly mediated the relationship between COMT genotype and inhibitory proficiency as indexed by stop-signal reaction time in males alone. These sexually dimorphic effects of COMT on inhibitory brain activation have important implications for our understanding of the contrasting patterns of prefrontally governed psychopathology observed in males and females.

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Figures

**Figure 1**
Conditional process analysis conceptual model. The horizontal line from COMT to hyperactivity represents the direct pathway; by contrast, the indirect pathway is indicated by the dotted line via BOLD activation. Conditional effects of sex were assessed on the pathways shown in grey.

**Figure 2**
Regions significantly activated during stop-success (left) and stop-fail (right) trials overlaid on a standardized T1-weighted image. Color bar denotes T-scale. Voxels are thresholded at a family-wise error corrected P-value of 0.05.

**Figure 3**
Group-averaged activation in pre-supplementary motor area (pre-SMA) and inferior frontal cortex (IFC) during stop trials for sex-genotype groups. Error bars denote SEM.

See this image and copyright information in PMC

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References

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Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence

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Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence

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