Effects of a Functional COMT Polymorphism on Prefrontal Cognitive Function in Patients With 22q11.2 Deletion Syndrome

Article (PDF Available)inAmerican Journal of Psychiatry 161(9):1700-2 · October 2004with96 Reads
DOI: 10.1176/appi.ajp.161.9.1700 · Source: PubMed
The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for schizophrenia. These behavioral manifestations of 22q11.2 deletion syndrome could result from haploinsufficiency of the catechol O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype as a predictor of prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Patients with confirmed 22q11.2 deletions (N=44) underwent neurocognitive testing following Val(158)Met genotyping (Met hemizygous: N=16; Val hemizygous: N=28). Analyses of covariance revealed that Met-hemizygous patients performed significantly better on a composite measure of executive function (comprising set-shifting, verbal fluency, attention, and working memory) than did Val-hemizygous patients. These data are consistent with those of previous studies in normal individuals, suggesting that a functional genetic polymorphism in the 22q11 region may influence prefrontal cognition in individuals with COMT haploinsufficiency.
1700 Am J Psychiatry 161:9, September 2004
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Brief Report
Effects of a Functional COMT Polymorphism on Prefrontal
Cognitive Function in Patients With 22q11.2 Deletion Syndrome
Carrie E. Bearden, Ph.D.
Abbas F. Jawad, Ph.D.
David R. Lynch, M.D., Ph.D.
Set Sokol, B.A.
Steven J. Kanes, M.D., Ph.D.
Donna M. McDonald-McGinn, M.S.
Sulagna C. Saitta, M.D., Ph.D.
Stacy E. Harris, B.S.
Edward Moss, Ph.D.
Paul P. Wang, M.D.
Elaine Zackai, M.D.
Beverly S. Emanuel, Ph.D.
Tony J. Simon, Ph.D.
Objective: The 22q11.2 deletion syndrome (DiGeorge/velocar-
diofacial syndrome) is associated with attentional problems and
executive dysfunction, and is one of the highest known risk fac-
tors for schizophrenia. These behavioral manifestations of
22q11.2 deletion syndrome could result from haploinsuffi-
ciency of the catechol O-methyltransferase (COMT) gene, lo-
cated within the 22q11 region. The goal of the present study
was to examine COMT genotype as a predictor of prefrontal cog-
nitive function in patients with 22q11.2 deletion syndrome.
Method: Patients with confirmed 22q11.2 deletions (N=44)
underwent neurocognitive testing following Val
Met genotyp-
ing (Met hemizygous: N=16; Val hemizygous: N=28).
Results: Analyses of covariance revealed that Met-hemizygous
patients performed significantly better on a composite measure
of executive function (comprising set-shifting, verbal fluency, at-
tention, and working memory) than did Val-hemizygous pa-
Conclusions: These data are consistent with those of previous
studies in normal individuals, suggesting that a functional ge-
netic polymorphism in the 22q11 region may influence pre-
frontal cognition in individuals with COMT haploinsufficiency.
(Am J Psychiatry 2004; 161:1700–1702)
The enzyme catechol O-methyltransferase (COMT) is
critical in the metabolic degradation of synaptic dopam-
ine and norepinephrine (1), key neurotransmitters hy-
pothesized to influence human cognitive function (2). The
COMT gene contains a functional polymorphism
Met) that determines high and low activity of this
enzyme (1). Homozygosity for the low-activity (Met) allele
is associated with a three- to fourfold reduction of COMT
enzyme activity compared with homozygotes for the high-
activity (Val) variant, resulting in reduced degradation of
synaptic catecholamines in individuals with the Met allele
(3). Recent evidence suggests that in both healthy volun-
teers and schizophrenia patients, the Met allele is associ-
ated with superior performance on measures of prefrontal
cortical function (2, 4).
The 22q11.2 deletion syndrome (DiGeorge/velocardio-
facial syndrome) results from a hemizygous deletion in
chromosome 22 (5) and is characterized by dysmorphia,
cleft palate, and cardiac anomalies (6). Patients also dis-
play a unique behavioral phenotype involving particular
deficits in executive function, attention, and abstraction
(7); visuospatial cognition (8); and elevated rates of ADHD
and psychosis (9–11). Because the COMT gene maps to
the deleted region, the characteristic behavioral manifes-
tations of this syndrome may be related to dopamine dys-
regulation resulting from COMT haploinsufficiency (3).
Moreover, it is unknown whether COMT genotype in the
intact chromosome in patients with 22q11.2 deletion syn-
drome has a similar influence on executive cognition to
that observed in other populations. While prior research
has suggested an association between the Met allele and
psychopathology in patients with 22q11.2 deletions (11),
no previous work has investigated the effect of COMT
polymorphism on neurocognitive function in this popula-
tion. Thus, the goal of this research was to assess prefron-
Am J Psychiatry 161:9, September 2004 1701
tal cognition in relation to COMT genotype in patients
with the 22q11.2 deletion syndrome.
Participants were recruited through the Clinical Genetics Cen-
ter at the Childrens Hospital of Philadelphia. Genetic diagnosis
was confirmed by fluorescence in situ hybridization with the
N25(D2S75) molecular probe. Complete neuropsychological and
genotype data were available for 44 patients with 22q11.2 dele-
tion syndrome (27 female, 17 male; mean age=11.1 years [SD=
3.2]; Val hemizygous: N=28 [64%], Met hemizygous: N=16 [36%]).
Forty-two participants were Caucasian, one was black, and one
was Asian. All provided written informed consent/assent.
The neurocognitive battery included measures of general intel-
lectual function, memory, language, attention, executive func-
tions, and visuomotor skills. A complete description of the battery
and test results are published in detail elsewhere (7, 8).
COMT genotype was determined by polymerase chain reac-
tion/restriction fragment length polymorphism analysis, as de-
scribed previously (1, 12).
The objective of our statistical analysis was to examine the as-
sociation of COMT genotype with measures of prefrontal cogni-
tion. We selected the following executive function measures from
our larger battery on the basis of previous factor analytic studies
(13): verbal category fluency (animal naming), Trails B, WISC-3
Arithmetic, and Digit Span tasks. Variables were rescaled to z
score equivalents, and an executive function domain score was
computed by averaging the z scores on contributing variables.
Two-tailed analysis of covariance (ANCOVA) was used to com-
pare the two genotype groups (Met hemizygous versus Val hemi-
zygous). Secondly, we examined individual executive function
tests as predictors of allele status. Because there was a tendency
toward higher full-scale IQ in Val-hemizygous patients than in
Met-hemizygous patients (mean=77.6 [SD=10.5] versus 71.8 [SD=
11.4], respectively; F=2.98, df=1, 42, p=0.09), statistical analyses
controlled for full-scale IQ.
Met-hemizygous and Val-hemizygous subjects were
similar with regard to age, sex, and race. In the ANCOVA for
executive function composite score, IQ was a highly signif-
icant covariate (F=32.48, df=1, 41, p<0.001). Notably, geno-
type remained a significant predictor of executive function
score after effects of IQ were controlled, with Met-hemi-
zygous patients performing better than Val-hemizygous
patients (Figure 1). Met allele was associated with signifi-
cantly better performance (after IQ was controlled) on the
digit span task and superior performance on the Trails B
test. Performance on verbal fluency and arithmetic tasks
did not differ between groups. There was no main effect of
gender nor a genotype-by-gender interaction.
In addition, because the digit span and arithmetic tasks
contribute to the full-scale IQ measure, we recalculated
our composite using only those tests unrelated to full-
scale IQ (Trails B, verbal fluency) and obtained a similar
result (F=3.40, df=1, 41, p=0.07).
The principal finding of this study is that Met-hemi-
zygous patients performed significantly better than Val-
hemizygous patients on a composite measure of executive
cognition. Post hoc analyses indicated that this difference
was principally driven by performance on the digit span
and Trails B tests. This finding appears qualitatively simi-
lar to that observed in individuals with no 22q11.2 dele-
tion. However, because our executive function measure
involved a broader range of tests than those used in previ-
ous studies, which examined the Wisconsin Card Sort as
the only dependent measure (2, 4), it is unclear if COMT
genotype explains a greater portion of variance in execu-
tive cognition in patients with 22q11.2 deletion syndrome.
In this study group there was a tendency toward higher
full-scale IQ in Val-hemizygous patients. Because this re-
lationship was not observed in previous studies of normal
subjects (2, 4), we opted to control for it statistically. How-
ever, it is conceivable that this difference is representative
of the 22q11.2 deletion syndrome population and thus
worth considering in future samples.
To our knowledge, no previous study has investigated
cognitive measures in relation to COMT genotype in pa-
tients with 22q11.2 deletion syndrome. Investigators have
reported increased prevalence of schizophrenia associated
with the deletion (9, 10) and identified schizophrenia sus-
FIGURE 1. Executive Functioning in 44 Patients With
22q11.2 Deletion Syndrome Categorized by Genotype at
the Val
Met Locus of the COMT Gene
Values represent least estimate mean z-scores (with 95% confidence
intervals) after full-scale IQ was controlled.
Significant between-group difference (F=5.03, df=1, 41, p<0.05).
Significant between-group difference (F=4.38, df=1, 41, p<0.05).
Difference between groups approached significance (F=3.57, df=1,
41, p=0.07).
z Score
Trails B
Met hemizygous (N=16)
Val hemizygous (N=28)
1702 Am J Psychiatry 161:9, September 2004
ceptibility loci within the 22q11 region (14), although Mur-
phy et al. (10) detected no association between COMT gen-
otype and schizophrenia diagnosis in adults with 22q11.2
deletion syndrome. The functional implications of COMT
haploinsufficiency are unclear, although patients should
be particularly susceptible to the development of psycho-
sis (via increased brain dopamine levels) if the nondeleted
chromosome encodes the low-activity (Met) variant of
COMT (3). This is in contrast with the reported association
of Val allele load with impaired prefrontal function, and in-
creased risk of schizophrenia (2). However, the actual ef-
fects of 22q11.2 deletion on catecholamine neurotransmis-
sion are not known. Future research should examine more
direct measures of catecholaminergic turnover in order to
quantify prefrontal dopamine uptake as a function of gen-
otype in patients with 22q11.2 deletion syndrome.
Presented in part at the ninth International Congress for Schizo-
phrenia Research, Colorado Springs, Colo., March 30–April 2, 2003.
Received April 30, 2003; revision received Dec. 2, 2003; accepted
Dec. 15, 2003. From the Children’s Hospital of Philadelphia Depart-
ments of Child Development, Biostatistics, Human Genetics and Mo-
lecular Biology, and Neurology; and the Department of Psychiatry,
Hospital of the University of Pennsylvania, Philadelphia. Address re-
print requests to Dr. Bearden, UCLA Department of Psychiatry and
Biobehavioral Sciences, 300 UCLA Medical Plaza, Room 2265, Los An-
geles, CA 90095; cbearden@mednet.ucla.edu (e-mail).
Supported in part by NIH grant PO1-DC-02027 (Dr. Emanuel) and a
Beeson Award from the American Federation for Aging Research (Dr.
The authors thank M.F. Woodin for assistance with data collection,
J.R. Monterosso for comments on the manuscript, and the 22q11.2
deletion syndrome patients for their participation in the study.
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    • "A functional single nucleotide polymorphism, Val158Met of the COMT gene (Val/Met), has been suggested to lead to a 40 % reduction in enzyme activity and has been shown to affect cortical DA metabolism levels, with Val carriers displaying lower extracellular DA levels than Met-carriers [15]. This polymorphism contributes to measurable individual differences in human cognitive function [16][17][18] . Moreover, fMRI studies in healthy participants have shown that frontal and striatal activation during anticipation of reward is dependent on COMT genotype with Met homozygotes showing larger brain response than Val homozygotes [19, 20]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: 22q11.2 deletion syndrome (22q11DS) is caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk to develop psychosis. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in disrupted dopaminergic neurotransmission in 22q11DS, which may contribute to the increased vulnerability for psychosis. A dysfunctional motivational reward system is considered one of the salient features in psychosis and thought to be related to abnormal dopaminergic neurotransmission. The functional anatomy of the brain reward circuitry has not yet been investigated in 22q11DS. Methods: This study aims to investigate neural activity during anticipation of reward and loss in adult patients with 22q11DS. We measured blood-oxygen-level dependent (BOLD) activity in 16 patients with 22q11DS and 12 healthy controls during a monetary incentive delay task using a 3T Philips Intera MRI system. Data were analysed using SPM8. Results: During anticipation of reward, the 22q11DS group alone displayed significant activation in bilateral middle frontal and temporal brain regions. Compared to healthy controls, significantly less activation in bilateral cingulate gyrus extending to premotor, primary motor and somatosensory areas was found. During anticipation of loss, the 22q11DS group displayed activity in the left middle frontal gyrus and anterior cingulate cortex, and relative to controls, they showed reduced brain activation in bilateral (pre)cuneus and left posterior cingulate. Within the 22q11DS group, COMT Val hemizygotes displayed more activation compared to Met hemizygotes in right posterior cingulate and bilateral parietal regions during anticipation of reward. During anticipation of loss, COMT Met hemizygotes compared to Val hemizygotes showed more activation in bilateral insula, striatum and left anterior cingulate. Conclusions: This is the first study to investigate reward processing in 22q11DS. Our preliminary results suggest that people with 22q11DS engage a fronto-temporal neural network. Compared to healthy controls, people with 22q11DS primarily displayed reduced activity in medial frontal regions during reward anticipation. COMT hemizygosity affects responsivity of the reward system in this condition. Alterations in reward processing partly underlain by the dopamine system may play a role in susceptibility for psychosis in 22q11DS.
    Full-text · Article · Jul 2016
    • "One possible explanation for differences in modulation of social brain regions by different types and intensity of facial expression may be variation in dopamine metabolism—for example, associated with variation in catechol- O-methyl transferase (COMT), a methylation enzyme that metabolizes catecholamines (including dopamine) [118] . In other words, dopamine levels in social brain regions could be abnormal in people with 22q11DS who have haploinsufficiency in COMT119120121122 . We will address this issue in future larger studies. "
    [Show abstract] [Hide abstract] ABSTRACT: 22q11.2 deletion syndrome (22q11DS, velo-cardio-facial syndrome [VCFS]) is a genetic disorder associated with interstitial deletions of chromosome 22q11.2. In addition to high rates of neuropsychiatric disorders, children with 22q11DS have impairments of face processing, as well as IQ-independent deficits in visuoperceptual function and social and abstract reasoning. These face-processing deficits may contribute to the social impairments of 22q11DS. However, their neurobiological basis is poorly understood. We used event-related functional magnetic resonance imaging (fMRI) to examine neural responses when children with 22q11DS (aged 9-17 years) and healthy controls (aged 8-17 years) incidentally processed neutral expressions and mild (50%) and intense (100%) expressions of fear and disgust. We included 28 right-handed children and adolescents: 14 with 22q11DS and 14 healthy (including nine siblings) controls. Within groups, contrasts showed that individuals significantly activated 'face responsive' areas when viewing neutral faces, including fusiform-extrastriate cortices. Further, within both groups, there was a significant positive linear trend in activation of fusiform-extrastriate cortices and cerebellum to increasing intensities of fear. There were, however, also between-group differences. Children with 22q11DS generally showed reduced activity as compared to controls in brain regions involved in social cognition and emotion processing across emotion types and intensities, including fusiform-extrastriate cortices, anterior cingulate cortex (Brodmann area (BA) 24/32), and superomedial prefrontal cortices (BA 6). Also, an exploratory correlation analysis showed that within 22q11DS children reduced activation was associated with behavioural impairment-social difficulties (measured using the Total Difficulties Score from the Strengths and Difficulties Questionnaire [SDQ]) were significantly negatively correlated with brain activity during fear and disgust processing (respectively) in the left precentral gyrus (BA 4) and in the left fusiform gyrus (FG, BA 19), right lingual gyrus (BA 18), and bilateral cerebellum. Regions involved in face processing, including fusiform-extrastriate cortices, anterior cingulate gyri, and superomedial prefrontal cortices (BA 6), are activated by facial expressions of fearful, disgusted, and neutral expressions in children with 22q11DS but generally to a lesser degree than in controls. Hypoactivation in these regions may partly explain the social impairments of children with 22q11DS.
    Full-text · Article · Jan 2015
    • "Previous studies of COMT genotype in 22q11.2DS have yielded differential results, with some studies reporting Met hemizygosity of COMT to be related to poorer outcome on tasks requiring executive control (Baker et al., 2005; Takarae et al., 2009), and others reporting better outcomes (Bearden et al., 2004; Shashi et al., 2006 ). Additional studies have found no relationship between COMT genotype and measures of cognitive control in 22q11.2DS "
    [Show abstract] [Hide abstract] ABSTRACT: Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD) were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT), a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ). When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures.
    Full-text · Article · Jun 2014
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