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Influence of the COMT Genotype on Working Memory and Brain Activity Changes During Development
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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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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43 Own result · 41 Not checked yet · 10 Own interpretation · 8 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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)”
plainn = 81- Asserted: passes — The authors put it forward as true.
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In the paper
“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)”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“as well as slower to respond (correct trials only, WM: 1277 ms ± 360; Control: 738 ms ± 215) ( t (124) = 25.11, p < .001).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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 ).”
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In the paper
“and that these participants also showed a positive correlation between IFG activation and Dot Matrix performance.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the IPS, the main effect of genotype tended to be greater in males”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Only the Val dominance model led to a significantly improved fit of the data compared with the age and sex only model (likelihood-ratio test, D = 9.77, 4 degrees of freedom, p = .045).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“while in the IFG the interaction between age and genotype tended to be greater in males ( Table 2 ).”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“There was a weak trend in the largest cluster for a genotype by age interaction, with a steeper decrease in GM with age in the Val/Val individuals than Met carriers.”
hedgedcorrelationaln = 84 ·- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 23
- Probably not a substantial claim. 25
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
plaincorrelationaln = 322- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“however there was no main effect of genotype or age by genotype interaction (all p s > 0.29).”
plainn = 81- Asserted: passes — The authors put it forward as true.
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In the paper
“Neither sex, nor interactions between sex and other variables had a significant effect on behavior.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The main effect of genotype but not the age x genotype interaction was significant in both clusters.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites [17] Mechelli, 2009, Genetic vulnerability to affective psychopathology in childhood: A combined voxel-based morphometry and functional magnetic resonance imaging study, Biol Psychiatry source
- Not checked yetcites [18] Shaw, 2009, Effects of the Val158Met catechol-O-methyltransferase polymorphism on cortical structure in children and adolescents, Mol Psychiatry source
- Not checked yetcites [19] Thomason, 2010, COMT genotype affects prefrontal white matter pathways in children and adolescents, Neuroimage source
- Not checked yetcites [20] Thomason, 2009, COMT genotype and resting brain perfusion in children, Neuroimage source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“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).”
What the sources say
- Not checked yetcites [1] Craddock, 2006, The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: Evidence and lessons, Mol Psychiatry source
- Not checked yetcites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This lack of consistency may arise from age differences in the effect of COMT genotype on cognition.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
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In the paper
“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).”
What the sources say
- Not checked yetcites [28] Goldman-Rakic, 1982, Postnatal development of monoamine content and synthesis in the cerebral cortex of rhesus monkeys, Brain Res source
- Not checked yetcites [29] Goldman-Rakic, 1981, Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys, Neuroscience source
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In the paper
“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).”
What the sources say
- Not checked yetcites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source
- Not checked yetcites [26] Giakoumaki, 2008, Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism, Neuropsychopharmacology source
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
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In the paper
“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)).”
What the sources say
- Not checked yetcites [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
- Not checked yetcites [48] Hersrud, 2009, Epistatic interaction between COMT and DAT1 genes on eating behavior: A pilot study, Eat Behav source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“To reduce potential age or genotype differences in behavior, the task included load 2 (two dots) and 4 (four dots) trials only.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, behavior may reflect more complex and global dopamine effects on brain activity and structure in a wide network of brain regions.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Contrasts were inclusively masked by the WM-Control main effect previously defined.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites [21] Barnett, 2007, Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children, Am J Psychiatry source
- Not checked yetcites [22] Diamond, 2004, Genetic and neurochemical modulation of prefrontal cognitive functions in children, Am J Psychiatry source
- Not checked yetcites [23] Wahlstrom, 2007, Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents, Biol Psychiatry source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Total GM volumeZ was included as an additional covariate to permit the study of regional rather than global effects.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The best model was identified using Akaike's (AIC) and Schwartz's information criteria (SBC or BIC) (45,46).”
What the sources say
- Not checked yetcites [45] Akaike, 1974, A new look at the statistical model identification, IEEE Trans Automat Contr source
- Not checked yetcites [46] Schwartz, 1978, Estimating the dimension of a model, Ann Stat
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
What the sources say
- Not checked yetcites [38] McCulloch, 2001
- Not checked yetcites [39] Molenberghs, 2001, A review on linear mixed models for longitudinal data, possibly subject to dropout, Stat Model source
- Not checked yetcites [40] Starr, 2007, COMT genotype and cognitive ability: A longitudinal aging study, Neurosci Lett source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Note however that substance use was not recorded in this study and is a potential confound of the age effect observed here (55).”
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“and the COMT Val allele has been shown to be a small risk factor (odds ratio 1.12) for smoking (58).”
What the sources say
- Not checked yetcites [58] Tammimäki, 2010, Are genetic variants of COMT associated with addiction?, Pharmacogenet Genomics source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The present study did not evaluate pubertal state.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“correcting for multiple comparison across all voxels within the brain, with a false discovery rate (FDR) threshold of p < 0.05”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This permitted the inclusion in a single analysis of participants with and without longitudinal data.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Smoking is associated with lower WM in adults, while the evidence is mixed in younger samples (59).”
What the sources say
- Not checked yetcites [59] Durazzo, 2010, Chronic cigarette smoking: Implications for neurocognition and brain neurobiology, Int J Environ Res Public Health source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [21] Barnett, 2007, Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children, Am J Psychiatry source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
What the sources say
- Not checked yetcites [64] Shaw, 2007, Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation, Proc Natl Acad Sci U S A source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [24] Vijayraghavan, 2007, Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory, Nat Neurosci source
- Not checked yetcites [2] Meyer-Lindenberg, 2006, Intermediate phenotypes and genetic mechanisms of psychiatric disorders, Nat Rev Neurosci source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“There is widespread but weak evidence of an interaction between sex and rs4680 on behavior, brain structure and the incidence of psychiatric disorders (47).”
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the locations of the observed effects differ between studies, which may be due to differences in methodology and age of the participants.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [23] Wahlstrom, 2007, Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents, Biol Psychiatry source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [68] Fischer, 2010, Simulating neurocognitive aging: Effects of a dopaminergic antagonist on brain activity during working memory, Biol Psychiatry source
- Not checked yetcites [69] Landau, 2009, Striatal dopamine and working memory, Cereb Cortex source
- Not checked yetcites [70] Nyberg, 2009, Striatal dopamine D2 binding is related to frontal BOLD response during updating of long-term memory representations, Neuroimage source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Estrogens have been implicated to explain these sex differences, as they are thought to down-regulate COMT activity (47).”
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 yetcites [66] Slifstein, 2008, COMT genotype predicts cortical-limbic D1 receptor availability measured With [11C]NNC112 and PET, Mol Psychiatry source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredIn the citing paper
“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)
In the citing paper
“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”
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.
Citations
Cites
A new look at the statistical model identification
Akaike, H. (1974) · IEEE Transactions on Automatic Control · doi:10.1109/tac.1974.1100705 · Cited by 51,879
Estimating the Dimension of a Model
Schwarz, G. (1978) · The Annals of Statistics · doi:10.1214/aos/1176344136 · Cited by 47,033
Multiple regression: testing and interpreting interactions
(1992) · Choice Reviews Online · doi:10.5860/choice.29-3352 · Cited by 36,647
A fast diffeomorphic image registration algorithm
Ashburner, J. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.07.007 · Cited by 8,122
ANew Look at the Statistical Model Identification
AKAlKE, H. (2011) · Cited by 4,177
Effect size, confidence interval and statistical significance: a practical guide for biologists
Nakagawa, S., & Cuthill, I. C. (2007) · Biological Reviews · doi:10.1111/j.1469-185x.2007.00027.x · Cited by 3,835
Why do many psychiatric disorders emerge during adolescence?
Paus, T., Keshavan, M., & Giedd, J. N. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2513 · Cited by 3,123
Generalized, Linear, and Mixed Models
McCulloch, C. E., & Searle, S. R. (2000) · Wiley series in probability and statistics · doi:10.1002/0471722073 · Cited by 3,057
The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway
Howes, O. D., & Kapur, S. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp006 · Cited by 2,693
McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A. S., Zackai, E. H., Emanuel, B. S., Vermeesch, J. R., Morrow, B. E., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.71 · Cited by 2,236
Cited by
Sorted by citations
The attentive brain: insights from developmental cognitive neuroscience
Amso, D., & Scerif, G. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn4025 · Cited by 369
Dumontheil, I. (2016) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2016.04.012 · Cited by 186
Self-citationDarki, F., & Klingberg, T. (2015) · Cerebral Cortex · doi:10.1093/cercor/bht352 · Cited by 212
“Participants performed 10 min of visuo-spatial WM task (Dumontheil et al. 2011) in the scanner.”
MethodInfluentialSelf-citationCommon Variants in Psychiatric Risk Genes Predict Brain Structure at Birth
Knickmeyer, R. C., Wang, J., Zhu, H., Geng, X., Woolson, S., Hamer, R. M., Konneker, T., Lin, W., Styner, M., & Gilmore, J. H. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhs401 · Cited by 149
“Our finding of increased parietal volumes in Val/Val homozygotes is also consistent with a previous report (Dumontheil et al. 2011).”
ResultDarki, F., Peyrard‐Janvid, M., Matsson, H., Kere, J., & Klingberg, T. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.05.008 · Cited by 158
Self-citation
Metadata
- 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
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 70
- Issue
- 3
- Pages
- 222-229
- ISSN
- 0006-3223 (ISSN-L)
- 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
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Vetenskapsrådet
- 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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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