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Cited by 165Neurotransmitter Receptor Influence on BehaviorCognitive Abilities and TestingNeural and Behavioral Psychology Studies

Influence of the COMT genotype on working memory and brain activity changes during development

Dumontheil, Iroise, Roggeman, Chantal, Ziermans, Tim, Peyrard-Janvid, Myriam, Matsson, Hans, Kere, Juha, Klingberg, Torkel·2011·Biological Psychiatry
DOI 10.1016/j.biopsych.2011.02.027
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Abstract

Background The Valine158Methionine (Val158Met) polymorphism of the COMT gene leads to lower enzymatic activity and higher dopamine availability in Met carriers. The Met allele is associated with better performance and reduced prefrontal cortex activation during working memory (WM) tasks in adults. Dopaminergic system changes during adolescence may lead to a reduction of basal dopamine levels, potentially affecting Met allele benefits during development.Methods We investigated the association of COMT genotype with behavioral (n = 322) and magnetic resonance imaging data (n = 81-84) collected during performance of a visuospatial WM task and potential changes in these effects during development (reflected in age × genotype interactions). Data were collected from a cross-sectional and longitudinal typically developing sample of 6- to 20-year-olds.Results Visuospatial WM capacity exhibited an age × genotype interaction, with a benefit of the Met allele emerging after 10 years of age. There was a parallel age × genotype interaction on WM-related activation in the right inferior frontal gyrus and intraparietal sulcus (IPS), with increases in activation with age in the Val/Val group only. Main effects of COMT genotype were also observed in the IPS, with greater gray matter volumes bilaterally and greater right IPS activation in the Val/Val group compared with the Met carriers.Conclusions These results suggest that COMT genotype effects on WM brain activity and behavior are not static during development. The full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations.

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Written from the paper’s full text.

TL;DR

In a developmental sample, COMT Val158Met genotype effects on visuospatial working memory and related brain activity were not static: Met/Met individuals were poorer performers in childhood but became better performers from mid-adolescence, while Val/Val individuals showed age-related increases in right frontal and parietal activation. The authors interpret this as evidence that the adult pattern of COMT effects emerges during adolescence, possibly reflecting developmental decreases in basal dopamine.

Key findings

  • Behavioral data (N=322, including 260 with longitudinal data) showed an age × genotype interaction: the Val dominance model improved fit over age/sex only (likelihood-ratio test, D=9.77, 4 df, p=.045), with a significant genotype × age⁻¹ interaction (F(1,500.1)=4.40, p=.036). Met/Met individuals switched from poorer performance in childhood to better performance from mid-adolescence, with model-estimated cross-over at 10.2 years.
  • fMRI data (N=81, including 44 longitudinal) showed age × genotype interactions in right inferior frontal gyrus and right intraparietal sulcus/angular gyrus: activation increased with age in Val/Val participants only (parietal: F(1,22.5)=21.5, p<.001; frontal: F(1,20.3)=25.9, p<.001), while Met carriers showed no significant age effect (p>.2 and p>.4). The parietal cluster also showed greater activation in Val/Val than Met carriers.
  • In-scanner performance was high but lower in WM than Control (accuracy 90.6% ± 10.6 vs. 98.4% ± 3.5, t(124)=9.52, p<.001; correct-trial RT 1277 ms ± 360 vs. 738 ms ± 215, t(124)=25.11, p<.001), with no main effect of genotype or age × genotype interaction on WM vs. Control performance (all ps > 0.29).
  • VBM data (N=84, including 47 longitudinal) showed Met dominance clusters in bilateral lateral bank of the IPS, with greater gray matter volumes in Val/Val participants than Met carriers; the largest cluster showed only a weak trend for genotype × age, and genotype effects were greater in males than females bilaterally.

Methods

  • Participants were from the Swedish “Brainchild” study, recruited by random sampling from the population registry in Nynäshamn; age groups were 6, 8, 10, 12, 14, 16, 18, 20, and 25 years. DNA was extracted from blood or saliva, and COMT rs4680 was genotyped.
  • Visuospatial WM was assessed with the Dot Matrix task from the AWMA battery; behavioral analyses used linear mixed models with age transformations (age, age⁻¹, ln(age)), sex, COMT genotype, and interactions, comparing additive, Val dominance, and Met dominance models.
  • MRI analyses used SPM5: fMRI WM–Control contrasts were analyzed with flexible factorial second-level models, and VBM gray matter data were processed with DARTEL and analyzed similarly, with FDR p<.05 and inclusive masking by the WM–Control main effect for fMRI.

Limitations

  • The paper states that pubertal state was not evaluated, substance use was not recorded and could confound the age effect, and small age groups when split by sex plus lack of pubertal stage information prevented detailed investigation of sex differences during development.
  • The paper notes that the fMRI task included only relatively low WM loads and a control task, whereas the behavioral score reflected performance up to each participant’s maximum WM load level; it also notes that the locations of gray matter effects differ across studies and that it remains unclear what greater parietal gray matter volumes in Val/Val individuals precisely reflect.
  • The text also makes evident that the complicated non-independent design did not allow calculation of standardized effect statistics, and effect sizes from round 1 only are reported in supplementary information.

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Crossref · 10.1016/j.biopsych.2011.02.027

Cites

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Statistics

Claims the paper makes

0 of 77 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Effect of COMT genotype on the WM-Control contrast · p. 10

    Activations in the IFG and IPS clusters were more strongly correlated in the Val/Val group.

    “Further analyses (see Supplemental Information, Figures S2, S3) indicated that activations in the IFG and IPS clusters were more strongly correlated in the Val/Val group”
    Quote in the paperNot a substantial claim
  • Findingown data
    § In-scanner performance · p. 9

    Participants were less accurate in the WM condition than in the Control condition (WM mean 90.6% ± SD 10.6; Control 98.4% ± 3.5; t(124)=9.52, p<.001).

    “Participants were less accurate in the WM condition (WM: mean 90.6 % ± SD 10.6; Control: 98.4 % ± 3.5) ( t (124) = 9.52, p < .001)”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Influence of COMT genotype on WM capacity development · p. 8

    In the behavioral model, there was a main effect of age^-1 Z (F(1,502.7)=171.01, p<.001).

    “The only significant effects observed in this full model were a main effect of age -1 Z ( F (1,502.7) = 171.01, p < .001)”
    Quote in the paperNot a substantial claim
  • Findingown data
    § In-scanner performance · p. 9

    Participants were slower to respond in the WM condition than in the Control condition (correct trials only, WM: 1277 ms ± 360; Control: 738 ms ± 215; t(124)=25.11, p<.001).

    “as well as slower to respond (correct trials only, WM: 1277 ms ± 360; Control: 738 ms ± 215) ( t (124) = 25.11, p < .001).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Effect of COMT genotype on the WM-Control contrast · p. 9

    Only the Met dominance model resulted in significant clusters for the WM-Control contrast, located in the right inferior frontal gyrus (IFG) and posterior right intraparietal sulcus (IPS)/angular gyrus.

    “Only the Met dominance model resulted in significant clusters, located in the right inferior frontal gyrus (IFG) and in the posterior section of the right intraparietal sulcus (IPS)/angular gyrus ( Table 2, Figure 3b and Figure S1 ).”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 25

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    Findingown data
    § WM capacity development · p. 8

    Visuospatial WM capacity was best modeled by age^-1 Z, with steeper change over younger ages and flattening to an asymptote.

    “The best model was where WM capacity was explained by age -1 Z , with a steeper change in WM capacity over younger ages and then flattening to an asymptote.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Effect of COMT genotype on the WM-Control contrast · p. 10

    The main effect of genotype and age x genotype interaction remained significant (ps ≤ .001) when including genotype x sex, age x sex, and genotype x age x sex interactions in the model.

    “The main effect of genotype and age x genotype interaction remained significant ( p s ≤ .001) when including genotype x sex, age x sex, and genotype x age x sex interactions in the model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § In-scanner performance · p. 9

    There was no main effect of genotype or age by genotype interaction on in-scanner WM vs Control performance (all ps > 0.29).

    “however there was no main effect of genotype or age by genotype interaction (all p s > 0.29).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Influence of COMT genotype on WM capacity development · p. 8

    Neither sex nor interactions between sex and other variables had a significant effect on behavior.

    “Neither sex, nor interactions between sex and other variables had a significant effect on behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Figure legends · p. 22

    8 year-olds showed a detrimental effect of the Met allele, while 18 year-olds showed the typical adult pattern of a beneficial effect of the Met allele, with higher WM capacity and lower brain activity in the frontal cortex.

    “8 year-olds showed a detrimental effect of the Met allele, while 18 year-olds showed the typical adult pattern of a beneficial effect of the Met allele, with higher WM capacity and lower brain activity in the frontal cortex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Figure legends · p. 21

    In the VBM gray matter data, the main effect of genotype but not the age x genotype interaction was significant in both clusters.

    “The main effect of genotype but not the age x genotype interaction was significant in both clusters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Introduction · p. 3

    In children and adolescents, COMT genotype effects have been reported on brain structure, resting brain perfusion, and brain activation in response to emotional stimuli.

    “In children and adolescents effects of COMT genotype in specific age groups have been reported on brain structure (17-19), resting brain perfusion (20) and brain activation in response to emotional stimuli (17).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Mechelli, 2009, Genetic vulnerability to affective psychopathology in childhood: A combined voxel-based morphometry and functional magnetic resonance imaging study, Biol Psychiatry source

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    • cites [18] Shaw, 2009, Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents, Mol Psychiatry source

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    • cites [19] Thomason, 2010, COMT genotype affects prefrontal white matter pathways in children and adolescents, Neuroimage source

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    • cites [20] Thomason, 2009, COMT genotype and resting brain perfusion in children, Neuroimage source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Introduction · p. 3

    In fMRI studies, Val/Val adults tend to exhibit greater prefrontal cortex activation during working memory tasks than Met/Met individuals.

    “In functional magnetic resonance imaging (fMRI) studies Val/Val adults tend to exhibit greater prefrontal cortex (PFC) activation during WM tasks than Met/Met individuals (12,13).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Dickinson, 2009, Genes, cognition and brain through a COMT lens, Neuroscience source

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    • cites [13] Mier, 2010, Neural substrates of pleiotropic action of genetic variation in COMT: A meta-analysis, Mol Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction · p. 3

    The COMT enzyme mediates the degradation of catecholamines, in particular dopamine.

    “The gene coding for the catechol-O-methyltransferase (COMT) enzyme, which mediates the degradation of catecholamines, in particular dopamine, has attracted considerable attention as a promising candidate gene for studying variance in cognitive function and mental illness (1,2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Craddock, 2006, The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: Evidence and lessons, Mol Psychiatry source

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    • cites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source

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    Premisecitation
    § Introduction · p. 3

    Dopamine effects on behavior follow an inverted U-shaped dose-response curve, with both deficient and excessive dopamine activity predicting poor cognitive task performance.

    “Dopamine effects on behavior follow an inverted U-shaped dose-response curve, with both deficient and excessive amounts of dopamine activity predicting poor cognitive tasks performance (24,25).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Vijayraghavan, 2007, Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory, Nat Neurosci source

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    • cites [25] Arnsten, 1997, Catecholamine regulation of the prefrontal cortex, J Psychopharmacol (Oxford) source

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    Interpretationreasoning
    § Introduction · p. 3

    The lack of consistency in COMT genotype effects may arise from age differences in the effect of COMT genotype on cognition.

    “This lack of consistency may arise from age differences in the effect of COMT genotype on cognition.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning
    § Introduction · p. 4

    A decrease in basal dopamine level between childhood and adulthood could affect the position of the Val158Met genotypes on the inverted U-shaped curve and lead to a differential effect of rs4680 during development.

    “A decrease in basal dopamine level between childhood and adulthood could affect the position of the Val 158 Met genotypes on the inverted U-shaped curve and lead to a differential effect of rs4680 during development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Introduction · p. 4

    In rhesus monkeys, dopamine concentration in the PFC and dopamine synthesis in the PFC and parietal cortex peak around puberty (2-3 years), while dopamine concentration in the parietal cortex remains stable from 5 months of age.

    “In the rhesus monkey, dopamine concentration in the PFC and dopamine synthesis in the PFC and parietal cortex peak around puberty (2-3 years), while dopamine concentration in the parietal cortex remains stable from 5 months of age (28,29).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Goldman-Rakic, 1982, Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys, Brain Res source

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    • cites [29] Goldman-Rakic, 1981, Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys, Neuroscience source

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    Premisecitation
    § Introduction · p. 3

    Met/Met adults are thought to be near the apex of the inverted U curve, while Val carriers lie towards the lower end because of the increased dopamine metabolism rate associated with the Val allele.

    “Met/Met adults are thought to be near the apex of this curve, while Val carriers lay towards the lower end because of the increased dopamine metabolism rate associated with the Val allele (2,26,27).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source

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    • cites [26] Giakoumaki, 2008, Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism, Neuropsychopharmacology source

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    • cites [27] Mattay, 2003, Catechol O-methyltransferase val158–met genotype and individual variation in the brain response to amphetamine, Proc Natl Acad Sci U S A source

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    Study design and conductreasoning
    § Dot Matrix statistical analyses · p. 6

    Both additive and dominance models were evaluated to allow detection of non-linear effects.

    “In order to allow the detection of such effects, we evaluated both additive (0=Met/Met, 1=Val/Met, 2=Val/Val) and dominance models (Val dominance: 0=Met/Met, 1=Val carriers; Met dominance: 0=Met carriers, 1=Val/Val) (similarly to (9,48)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Barnett, 2007, Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: A meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls, Mol Psychiatry source

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    • cites [48] Hersrud, 2009, Epistatic interaction between COMT and DAT1 genes on eating behavior: A pilot study, Eat Behav source

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    Study design and conductreasoning
    § Brain imaging (fMRI) · p. 6

    The fMRI task included load 2 and 4 trials only to reduce potential age or genotype differences in behavior.

    “To reduce potential age or genotype differences in behavior, the task included load 2 (two dots) and 4 (four dots) trials only.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Discussion · p. 12

    Behavior may reflect more complex and global dopamine effects on brain activity and structure in a wide network of brain regions.

    “In addition, behavior may reflect more complex and global dopamine effects on brain activity and structure in a wide network of brain regions.”
    Quote in the paperNot a substantial claim

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    Study design and conductnone given
    § Brain imaging (fMRI) · p. 7

    Contrasts were inclusively masked by the WM-Control main effect previously defined.

    “Contrasts were inclusively masked by the WM-Control main effect previously defined.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Discussion · p. 12

    Previous studies of children and adolescents observed inconsistent COMT genotype effects and were restricted by either a small age range or a small sample size.

    “Previous studies of children and adolescents observed inconsistent COMT genotype effects and were restricted by either a small age range (21) or a small sample size (22,23).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Barnett, 2007, Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children, Am J Psychiatry source

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    • cites [22] Diamond, 2004, Genetic and neurochemical modulation of prefrontal cognitive functions in children, Am J Psychiatry source

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    • cites [23] Wahlstrom, 2007, Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents, Biol Psychiatry source

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    Interpretationreasoning
    § Discussion · p. 12

    The increasingly poorer WM performance in Val carriers compared to Met/Met individuals may thus partly reflect increased smoking during adolescence particularly in Val carriers.

    “The increasingly poorer WM performance in Val carriers compared to Met/Met individuals may thus partly reflect increased smoking during adolescence particularly in Val carriers.”
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    Study design and conductreasoning
    § Voxel-based morphometry · p. 10

    Total GM volume was included as an additional covariate to permit the study of regional rather than global effects.

    “Total GM volumeZ was included as an additional covariate to permit the study of regional rather than global effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation
    § Dot Matrix statistical analyses · p. 6

    Genotype x sex and genotype x age x sex interactions were included to test for potential sex differences in the effect of COMT genotype.

    “Genotype x sex and genotype x age x sex interactions were also included to test for potential sex differences in the effect of COMT genotype (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Harrison, 2008, Catechol-O-methyltransferase (COMT): A gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders, Neuropsychopharmacology source

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    Study design and conductcitation
    § Dot Matrix statistical analyses · p. 5

    The best model was identified using Akaike's (AIC) and Schwartz's information criteria (SBC or BIC).

    “The best model was identified using Akaike's (AIC) and Schwartz's information criteria (SBC or BIC) (45,46).”
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    • cites [45] Akaike, 1974, A new look at the statistical model identification, IEEE Trans Automat Contr source

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    • cites [46] Schwartz, 1978, Estimating the dimension of a model, Ann Stat

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    Study design and conductcitation
    § Dot Matrix statistical analyses · p. 5

    Linear mixed model analyses allow inclusion of data from participants who have not attended all testing waves and adjust for inter-correlation between testing waves.

    “Linear mixed model analyses, which allow the inclusion of data from participants who have not attended all testing waves and adjust for inter-correlation between testing waves (38-40), were performed using the PASW 18.0 statistical package (41).”
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    • cites [38] McCulloch, 2001

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    • cites [39] Molenberghs, 2001, A review on linear mixed models for longitudinal data, possibly subject to dropout, Stat Model source

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    • cites [40] Starr, 2007, COMT genotype and cognitive ability: A longitudinal aging study, Neurosci Lett source

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    Study design and conductcitation
    § Discussion · p. 12

    Substance use was not recorded in this study and is a potential confound of the age effect observed here.

    “Note however that substance use was not recorded in this study and is a potential confound of the age effect observed here (55).”
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    • cites [55] Saraceno, 2009, Genetic and non-genetic influences on the development of co-occurring alcohol problem use and internalizing symptomatology in adolescence: A review, Addiction source

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    Premisecitation
    § Discussion · p. 12

    The COMT Val allele has been shown to be a small risk factor (odds ratio 1.12) for smoking.

    “and the COMT Val allele has been shown to be a small risk factor (odds ratio 1.12) for smoking (58).”
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    • cites [58] Tammimäki, 2010, Are genetic variants of COMT associated with addiction?, Pharmacogenet Genomics source

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    Interpretationreasoning
    § Discussion · p. 12

    Smoking rate is low, the associations between the Val allele and smoking, and between smoking and WM, are weak and therefore unlikely to explain the entire effect observed here.

    “However, smoking rate is low, the associations between the Val allele and smoking, and between smoking and WM, are weak and therefore unlikely to explain the entire effect observed here.”
    Quote in the paperSubstantial claim

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    Study design and conductnone given
    § Discussion · p. 12

    The present study did not evaluate pubertal state.

    “The present study did not evaluate pubertal state.”
    Quote in the paperSubstantial claim

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    Study design and conductown data
    § Brain imaging (fMRI) · p. 7

    The fMRI analysis corrected for multiple comparisons across all voxels within the brain with a false discovery rate (FDR) threshold of p < 0.05.

    “correcting for multiple comparison across all voxels within the brain, with a false discovery rate (FDR) threshold of p < 0.05”
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    Study design and conductreasoning
    § Brain imaging (fMRI) · p. 6

    The flexible factorial design permitted inclusion in a single analysis of participants with and without longitudinal data.

    “This permitted the inclusion in a single analysis of participants with and without longitudinal data.”
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    Premisecitation
    § Discussion · p. 12

    Smoking is associated with lower WM in adults, while the evidence is mixed in younger samples.

    “Smoking is associated with lower WM in adults, while the evidence is mixed in younger samples (59).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Durazzo, 2010, Chronic cigarette smoking: Implications for neurocognition and brain neurobiology, Int J Environ Res Public Health source

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    § Discussion · p. 12

    Barnett et al. (21) reported a greater effect of COMT genotype on verbal IQ in 8-year-old boys who were pubertal at age 9 compared to prepubertal boys or girls.

    “Barnett et al. (21) reported a greater effect of COMT genotype on verbal IQ in 8 year-old boys who were pubertal at age 9 compared to prepubertal boys or girls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Barnett, 2007, Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children, Am J Psychiatry source

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    Premisecitation
    § Discussion · p. 14

    Delayed peaks in cortical thickness in ADHD lead to increased cortical thickness in ADHD during late childhood and early adolescence.

    “For example, delayed peaks in cortical thickness in Attention-Deficit/Hyperactivity Disorder (ADHD) (64), a disorder associated with visuospatial WM impairments (65), lead to increased cortical thickness in ADHD during late childhood and early adolescence.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Shaw, 2007, Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation, Proc Natl Acad Sci U S A source

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    Premisecitation
    § Discussion · p. 14

    PFC functioning and WM performance have been suggested to follow an inverted-U curve function of dopamine levels, with adult rs4680 Met/Met individuals near the apex of this curve.

    “PFC functioning and WM performance have been suggested to follow an inverted-U curve function of dopamine levels (24), with adult rs4680 Met/Met individuals near the apex of this curve (2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Vijayraghavan, 2007, Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory, Nat Neurosci source

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    • cites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source

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    Premisecitation
    § Discussion · p. 13

    There is widespread but weak evidence of an interaction between sex and rs4680 on behavior, brain structure and the incidence of psychiatric disorders.

    “There is widespread but weak evidence of an interaction between sex and rs4680 on behavior, brain structure and the incidence of psychiatric disorders (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Harrison, 2008, Catechol-O-methyltransferase (COMT): A gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders, Neuropsychopharmacology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given
    § Discussion · p. 13

    The locations of the observed rs4680 effects differ between studies, which may be due to differences in methodology and age of the participants.

    “However, the locations of the observed effects differ between studies, which may be due to differences in methodology and age of the participants.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning
    § Discussion · p. 15

    Our findings are compatible with a decrease in basal dopamine levels during adolescence, providing indirect evidence for the development of the dopamine system in humans.

    “Thus our findings are compatible with a decrease in basal dopamine levels during adolescence (23), providing indirect evidence for the development of the dopamine system in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Wahlstrom, 2007, Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents, Biol Psychiatry source

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    § Discussion · p. 14

    Recent multimodal PET and fMRI studies in adults have repeatedly identified parietal and lateral PFC regions similar to the clusters observed in the present study and provide independent evidence that these regions are sensitive to basal dopamine levels and dopamine levels in interconnected subcortical regions.

    “Recent multimodal studies combining positron emission tomography (PET) and fMRI data to study the dopamine system in adults have repeatedly identified parietal and lateral PFC regions similar to the clusters observed in the present study and provide independent evidence that these regions are sensitive to basal dopamine levels and dopamine levels in interconnected subcortical regions (68-70).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [68] Fischer, 2010, Simulating neurocognitive aging: Effects of a dopaminergic antagonist on brain activity during working memory, Biol Psychiatry source

      Not checked in the free run.

    • cites [69] Landau, 2009, Striatal dopamine and working memory, Cereb Cortex source

      Not checked in the free run.

    • cites [70] Nyberg, 2009, Striatal dopamine D2 binding is related to frontal BOLD response during updating of long-term memory representations, Neuroimage source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion · p. 13

    Estrogens have been implicated to explain sex differences in COMT effects, as they are thought to down-regulate COMT activity.

    “Estrogens have been implicated to explain these sex differences, as they are thought to down-regulate COMT activity (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Harrison, 2008, Catechol-O-methyltransferase (COMT): A gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion · p. 14

    Dopamine D1 receptor availability and the correlation between D1 receptor availability and COMT genotype are similar throughout the cortex.

    “In line with these results, dopamine D1 receptors availability (34) and correlation between D1 receptors availability and COMT genotype (66) are similar throughout the cortex, and dopamine D1 receptors density and change in WM capacity after training are correlated in both prefrontal and parietal cortex (67).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Jucaite, 2010, Age-related reduction in dopamine D1 receptors in the human brain: From late childhood to adulthood, a positron emission tomography study, Neuroscience source

      Not checked in the free run.

    • cites [66] Slifstein, 2008, COMT genotype predicts cortical-limbic D1 receptor availability measured With [11C]NNC112 and PET, Mol Psychiatry source

      Not checked in the free run.

40 of 40

  • The paper relies on this without support.

    Participants were typically developing.

    “Data were collected from a cross-sectional and longitudinal typically developing sample of 6 to 20 year-olds.”

  • The paper relies on this without support.

    Genotype variations are associated with the incidence of developmental psychiatric disorders.

    “and that genotype variations have been associated with the incidence of developmental psychiatric disorders”

  • The paper relies on this without support.

    rs4680 is a functional variant.

    “rs4680 is a functional variant and could be thought to affect brain function but not brain structure.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Working memory performance in psychotic and healthy subjects relies on dopamine levels within the prefrontal cortex.

    “Studies have shown that WM performance in psychotic and healthy subjects rely on dopamine levels within the PFC (Dumontheil et al., 2011; Mattay et al., 2003; Okubo et al., 1997).”

    From Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits (2023) · cites this paper as Dumontheil et al., 2011

    The Discussion (p. 14) says PFC functioning and working-memory performance have been suggested to vary with dopamine levels, supporting the general relationship. The paper examines developmental effects of COMT genotype, however, and does not establish this relationship in psychotic subjects; its Discussion (p. 15) mentions psychiatric populations only as a context for interpreting developmental findings. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The unique basal level of dopamine in every individual that causes differences in personality trait scores might cause WM performance variation between persons.

    “The unique basal level of dopamine in every individual that causes differences in personality trait scores, in turn by transitivity, might cause WM performance variation between persons”

    From Systematic reviews of the acute effects of amphetamine on working memory and other cognitive performances in healthy individuals, with a focus on the potential influence of personality traits (2023) · cites this paper as Dumontheil et al., 2011

    The Introduction (p. 4) proposes that changes in basal dopamine levels could alter COMT-genotype effects on working memory, and the Figure 4 legend (p. 22) relates working-memory capacity to hypothetical dopamine concentrations. The paper does not support the claim that individuals’ dopamine levels cause differences in personality trait scores; its reported scores concern working-memory capacity. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • During a visuo-spatial working memory task in individuals aged 6 to 20, activation in frontal and parietal regions increased across development in val/val homozygotes but not met carriers, suggesting delayed development of cognitive function in individuals with the val allele.

    “During a visuo-spatial working memory task in individuals between the ages of 6 and 20,Dumontheil et al. (2011), demonstrated that activation in frontal and parietal regions increased across development in individuals homozygous for the val allele, but not met carriers, suggesting delayed development of cognitive function in individuals with the val allele.”

    From Developmental imaging genetics: Linking dopamine function to adolescent behavior (2014) · cites this paper as Dumontheil et al. (2011)

  • Limited developmental imaging genetics research has suggested that the direction of gene effects on brain function may change over development as brain systems reorganize.

    “The limited developmental imaging genetics research (i.e. (Dumontheil, Roggeman et al. 2011) has suggested that the direction of gene effects on brain function may change over development as brain systems reorganize.”

    From Developmental imaging genetics: Linking dopamine function to adolescent behavior (2014) · cites this paper as Dumontheil, Roggeman et al. 2011

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 502.7) = 171.01reported p < .001 · recomputed p < .001

    “F (1,502.7) = 171.01, p < .001”

  • ConsistentF(1, 500.1) = 4.4reported p = .036 · recomputed p = .036

    “F (1,500.1) = 4.40, p = .036”

  • Consistentt(124) = 9.52reported p < .001 · recomputed p < .001

    “t (124) = 9.52, p < .001”

  • Consistentt(124) = 25.11reported p < .001 · recomputed p < .001

    “t (124) = 25.11, p < .001”

  • ConsistentF(1, 87.8) = 10.06reported p = .002 · recomputed p = .002

    “F (1,87.8) = 10.06, p = .002”

  • ConsistentF(1, 97.1) = 32.05reported p < .001 · recomputed p < .001

    “F (1,97.1) = 32.05, p < .001”

  • ConsistentF(1, 22.5) = 21.5reported p < .001 · recomputed p < .001

    “F (1,22.5) = 21.5, p < .001”

  • ConsistentF(1, 20.3) = 25.9reported p < .001 · recomputed p < .001

    “F (1,20.3) = 25.9, p < .001”

8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Dumontheil, I., Roggeman, C., Ziermans, T., Peyrard-Janvid, M., Matsson, H., Kere, J., & Klingberg, T.
Affiliations
  • Karolinska Institutet (SE)
  • University of Helsinki (FI)
Corresponding author
Dumontheil, Iroise
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2011-08
Volume
70
Issue
3
Pages
222-229
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2011.02.027
OpenAlex
W2111880168
Semantic Scholar
193187535a862c55f293cfadedd75b72ce1d3187
Cited by
165
References
70
Citations by year
2025: 5 · 2024: 4 · 2023: 6 · 2022: 10 · 2021: 5 · 2020: 8 · 2019: 14 · 2018: 9 · 2017: 8 · 2016: 18 · 2015: 18 · 2014: 14 · 2013: 23 · 2012: 18
FWCI
7.82
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • BIROn (Birkbeck, University of London) (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • VetenskapsrÃ¥det
  • Knut och Alice Wallenbergs Stiftelse
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords
COMT gene, COMT Val158Met polymorphism, working memory, visuospatial working memory, brain development, adolescence, dopamine availability, prefrontal cortex activation, intraparietal sulcus, inferior frontal gyrus, gray matter volume, genetic polymorphism
MeSH terms
Adolescent, Alleles, Brain, Brain Mapping, Catechol O-Methyltransferase, Child, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Memory, Short-Term, Neuropsychological Tests, Polymorphism, Single Nucleotide, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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