Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence - PubMed (original) (raw)

Multicenter Study

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

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

Eva Loth 2, Katya Rubia 3, Lydia Krabbendam 4, Robert Whelan 5, Tobias Banaschewski 6, Gareth J Barker 7, Arun L W Bokde 8, Christian Büchel 9, Patricia Conrod 10, Mira Fauth-Bühler 11, Herta Flor 6, Vincent Frouin 12, Jürgen Gallinat 13, Hugh Garavan 5, Penny Gowland 14, Andreas Heinz 13, Bernd Ittermann 15, Claire Lawrence 16, Karl Mann 6, Marie-Laure Paillère 17, Frauke Nees 18, Tomas Paus 19, Zdenka Pausova 20, Marcella Rietschel 6, Trevor Robbins 21, Michael N Smolka 22, Sukhwinder S Shergill 1, Gunter Schumann 2; IMAGEN Consortium

Affiliations

Multicenter Study

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

Thomas P White et al. Neuropsychopharmacology. 2014 Oct.

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

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

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

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.

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