COMT and anxiety and cognition in children with chromosome 22q11.2 deletion syndrome
By: Vandana Shashi, Timothy D. Howard, Matcheri S. Keshavan, Jessica Kaczorowski,
Margaret N. Berry, Kelly Schoch, Edward J. Spence, Thomas R. Kwapil
Shashi, V., Howard, T., Keshavan, M.S., Kaczorowski, J., Berry, M.N., Schoch, K., Spence, E.,
& Kwapil, T.R. (2010). COMT and anxiety and cognition in children with chromosome 22q11.2
deletion syndrome. Psychiatry Research, 178, 433-436.
http://dx.doi.org/10.1016/j.psychres.2010.04.048
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Abstract:
The COMT gene is thought to contribute to the cognitive/psychiatric phenotypes in 22q11.2
deletion syndrome. We measured these manifestations against the Val/Met alleles of the COMT
gene, in 40 nonpsychotic 22q11DS children. The Val allele was associated with poor IQ,
processing speed, executive function and a higher frequency of anxiety disorders, underscoring
the importance of the COMT gene in the childhood psychopathology in 22q11DS.
elocardiofacial syndrome | COMT Val/Met | psychopathology | psychology Keywords: v
Article:
1. Introduction
Chromosome 22q11.2 deletion syndrome (22q11DS) also known as DiGeorge/velocardiofacial
syndrome, is associated with childhood deficits in attention, working memory and executive
functioning; anxiety disorders are also common ( [Gerdes et al., 1999], [Moss et al.,
1999], [Swillen et al., 1997] and [Woodin et al., 2001]). These childhood impairments are
thought to be related to the 25–40% risk of psychotic disorders in late adolescence/adulthood
( [Gothelf et al., 2008] and [Shprintzen, 2008]).
The catechol-O-methyltransferase (COMT) gene located in the 22q11.2 interval has a functional
polymorphism (Val
158
Met); homozygosity for Met is associated with 1/3 the enzyme activity in
Val homozygotes (Chen et al., 2004) and is correlated with better neurocognition in the general
population ( [Egan et al., 2001] and [Malhotra et al., 2002]) and in schizophrenia ( [Kremer et
al., 2003] and [Shifman et al., 2002]). Studies of COMT and psychological function in 22q11DS
individuals have been variable. Met has been reported with decline in verbal ability and working
memory, AD/HD, obsessive compulsive disorder and bipolar illness ( [Baker et al.,
2005], [Gothelf et al., 2005], [Gothelf et al., 2006], [Lachman et al., 1996] and [Michaelovsky et
al., 2008]); others report no differences between the Val and Met groups (Glaser et al., 2006).
Note, however that the above reports included children and adults, as well as psychotic and
nonpsychotic participants in the same study. Studies including only children with 22q11DS
found that Val correlated with poor performance in executive function (Kates et al., 2006),
sustained attention ( [Bearden et al., 2004] and [Shashi et al., 2006]) and more internalizing and
externalizing behaviors (Bearden et al., 2005). A recent study reported impaired attention with
the Met allele (Takarae et al., 2009); thus there is a need for further study of these associations.
We purposefully restricted our study to nonpsychotic children. Based on our previous study
(Shashi et al., 2006) we hypothesized that children with Met would demonstrate better cognitive
functioning and behavior relative to Val children. Our preliminary data as well as reports in the
literature show a high rate (∼ 50%) of anxiety disorders in 22q11DS ( [Baker and Skuse,
2005], [Gothelf et al., 2007] and [Jolin et al., 2009]) and since anxiety disorders have been
associated with Val/Met in the general population (Hettema et al., 2008), we examined the
relationship between these and Val/Met in our cohort. It is to be noted that anxiety disorders are
a heterogeneous group of disorders and in this manuscript the term anxiety refers to the entire
group of disorders.
2. Methods
The participants were 40 children with 22q11DS, aged 7–16 years. The mean ages of the Met
and Val groups were 9.3 years (S.D. = 2.3) and 9.8 years (S.D. = 2.8) respectively. All had a
22q11.2 deletion on FISH testing. A portion of the participants were part of a previous study on
COMT and cognition (Shashi et al., 2006).
Neurocognitive assessments included the Wechsler Intelligence Scale for Children, 4th edition
(Wechsler, 2003) (some of the earlier participants were administered the 3rd edition (Wechsler,
1999)), Wechsler Individual Achievement Test 2nd edition (Wechsler, 2001), the Continuous
Performance Test (CPT_IP and _AX) (Cornblatt et al., 1988), the Wisconsin Card Sorting Test
(WCST) (Harris, 1988), and the California Verbal Learning Test, Children's Version (CVLT)
(Delis et al., 1994).
Parents rated their child's behavior using the Child Behavior Checklist (CBCL) (Achenbach and
Ruffle, 2000) and the Social Skills Rating System (SSRS) (Gresham and Elliot, 1990). The
Computerized Diagnostic Interview for Children (C-DISC) (NIMH-CDISC, 2004) was
administered by a licensed clinical psychologist to each child's caregiver. Note that the
examiners were unaware of the genotype status.
The COMT Val/Met alleles were ascertained by SNP mapping, using the MassArray system and
the iPLEX assay from Sequenom, Inc. Statistical analyses were carried out by a t-test, Fisher's
exact test and Mann–Whitney test. The Val and Met groups were compared with respect to the
neurocognitive, behavioral and psychiatric manifestations.
3. Results
The Met hemizygotes (n = 22) and the Val hemizygotes (n = 18) did not differ in age, gender or
ethnic composition. Note that corrections for multiple comparisons were not employed given that
analyses were based on a priori hypotheses.
Table 1 displays the comparisons of the Val and Met groups on quantitative measures of
neurocognition and behavior. Reanalyzing the data as 2 (group) × 2 (sex) ANOVAs did not
change the results; thus gender did not have an effect upon the associations. Furthermore, the
results were unchanged after excluding the three African-Americans in the study.
Table 1. Comparison of neuropsychological and behavioral manifestations in the Val and Met
groups (independent samples t-test).
Test
Val/Met
n
Mean
SD
t-
value
Cohen's d
P value
WISC full scale IQ
Met
Val
21
18
76.24
68.00
9.55
11.95
2.39
0.76
< 0.05
WISC verbal
comprehension factor
Met
Val
21
17
79.52
73.71
11.91
10.99
1.55
0.51
0.13
WISC working
memory
Met
Val
20
16
82.95
75.06
10.41
15.19
1.85
0.60
0.07
WISC processing
speed factor
Met
Val
21
16
85.00
72.88
15.13
12.02
2.61
0.88
< 0.05
WISC perceptual
organization factor
Met
Val
22
17
78.73
71.24
10.72
15.59
1.77
0.55
0.08
WCST conceptual
level response
Met
Val
22
17
84.36
80.41
7.73
14.31
117.5
a
< 0.05
CBCL social t-score
Met
Val
17
14
45.35
38.14
7.19
8.82
2.39
0.85
< 0.05
CBCL
anxious/depressed
(III) t-score
Met
Val
18
14
56.17
64.35
6.24
9.33
− 2.98
1.03
< 0.01
CBCL internalizing t-
score
Met
Val
18
14
53.61
64.07
15.54
12.74
− 2.04
0.74
< 0.05
Parent SSRS total
standard score
Met
Val
18
16
102.11
82.5
13.50
28.62
2.60
0.88
0.01
C-DISC any anxiety
disorder
Met
Val
5/22
13/18
Fisher's exact test P = < 0.01
a Due to violation of the assumption of homogeneity of variance, Mann–
Whitney U statistic computed. Please note that not all tests were performed on all the subjects.
None of the participants had a psychotic disorder, but 25/40 subjects had at least one DSM-IV
diagnosis (APA, 2000) on the C-DISC. The Val group exceeded the Met group on the rate of any
diagnosis (P = 0.02). Anxiety disorders were significantly higher with Val (P = <0.01). These
included in order of Met and Val: specific phobia (n = 5 and n = 9), obsessive compulsive
disorder (n = 2 and n = 3), separation anxiety (n = 2 and n = 1), social phobia (n = 0 and n = 3),
generalized anxiety (n = 2 and n = 0), panic disorder (n = 1 andn = 0) and post-traumatic stress
disorder (n = 0 and n = 6). However, there is no difference between Val and Met groups when
we tested these anxiety disorders individually. Five of the Met and six of the Val subjects had
more than one disorder. Note that there is a discrepancy in the number of individuals with Met
who are listed to have anxiety based on the CBCL in Table 1, compared to those with Met
(n = 12) who had an anxiety disorder on the C-DISC. Since the C-DISC is a structured
diagnostic interview, compared to the CBCL which is a parent questionnaire, the results on the
C-DISC would be more valid. We have formal medical reports as well as verbal confirmation of
these diagnoses from physicians and parents. There were no differences between Val and Met
groups in the occurrence of depression or AD/HD, or in medication status for anxiety disorder or
AD/HD.
4. Discussion
The relation of COMT with psychological functioning in children with 22q11DS has been
equivocal. We found that children who are hemizygous for Met have superior cognitive
functioning and diminished behavioral problems relative to children hemizygous for Val.
Additionally, we are the first to report that the Val allele is associated with anxiety disorders in
22q11DS children.
Within the general population, Met homozygosity is often reported to confer a cognitive
advantage in healthy individuals and in schizophrenia ( [Bilder et al., 2002], [Diamond et al.,
2004], [Egan et al., 2001], [Enoch et al., 2009], [Houlihan et al., 2009], [Joober et al.,
2002] and [Malhotra et al., 2002]) . For 22q11DS patients, associations of the Val/Met genotype
and psychological deficits have been contradictory, with reports of Met being advantageous on
intelligence and higher neurocognition ( [Bearden et al., 2004], [Kates et al., 2006] and [Shashi
et al., 2006]); reports of no association with intelligence ( [Baker et al., 2005], [Glaser et al.,
2006] and [van Amelsvoort et al., 2008]) and reports of Met being associated with a decline in
verbal IQ (Gothelf et al., 2005). We found that Met hemizygosity is associated with better
cognitive performance in 22q11DS children. It may be that this relation changes with age, such
that the Met becomes associated with poorer cognition, consistent with the proposed inverted U-
shaped relationship between PFC dopamine levels and function ( [Barnett et al.,
2009], [Goldman-Rakic et al., 2000] and [Mattay et al., 2003]). Indeed, most studies of 22q11DS
children less than 16 years found that neurocognition is superior with Met ( [Bearden et al.,
2004], [Kates et al., 2006] and [Shashi et al., 2006]). Studies including older 22q11DS subjects
reported that Val posed a cognitive advantage ( [Baker et al., 2005] and [Bassett et al., 2007]).
Other factors that could account for such varying reports include small sample sizes, inclusion of
both psychotic and nonpsychotic individuals, differences in neuropsychological measures,
effects of linkage disequilibrium with another genetic variant in this interval, interactions
between COMT and other genes (Vorstman et al., 2009), impact of stress upon frontal dopamine
levels and ethnicity differences in genotypes. We did not see differences on tests of sustained
attention and verbal learning between Val and Met in our study. This may be because these are
not pure tests of prefrontal cognition, with the anterior cingulate modulating sustained attention
and verbal memory involving the temporal lobe.
The relation between Val/Met and childhood psychiatric diagnoses in 22q11DS is poorly
delineated. Met was associated with elevated rates of AD/HD (Gothelf et al., 2006); in the same
subjects AD/HD and OCD were associated with a larger haplotype within COMT, including Met
(Michaelovsky et al., 2008). However, these samples included subjects 6–26 years in age and a
mix of psychotic and nonpsychotic participants. We found no evidence of an association between
Val/Met and AD/HD in our cohort, similar to a meta-analysis in the general population (Cheuk
and Wong, 2006).
Our finding of an association between Val and anxiety disorders may suggest that similar to
neurocognition, the influence of COMT on anxiety disorders in 22q11DS may be age dependent,
consistent with a report that Val was associated with higher internalizing behaviors in 22q11DS
children (Bearden et al., 2005). A definite association of the Val allele with anxiety disorders in
children in the general population has not been established (Gadow et al., 2009) while in adults
the Met allele is often found to be associated with anxiety (Drabant et al., 2006). Nevertheless,
our finding provides an important baseline indicator that warrants replication and longitudinal
study.
The strengths of our study include the use of nonpsychotic children with 22q11DS, a reasonable
sample size given the difficulty of recruiting from this population and the inclusion of
neurocognitive measures recommended by the NIMH-MATRICS task force ( [Kern et al.,
2004] and [Nuechterlein, 2006]). The limitations of the study are that it is possible that our
results may be related to linkage disequilibrium with other genetic variants in this interval and
due to our sample size the power was 62%.
In conclusion, we demonstrated that the Met allele is associated with better neurocognition and
lower frequency of anxiety disorders in nonpsychotic children with 22q11DS. Longitudinal
studies of this cohort should facilitate understanding of the developmental trajectories associated
with Val/Met hemizygosity.
Acknowledgements
This work was supported by grant R01MH78015, PI: Shashi, V.
We are very grateful to the subjects with 22q11DS and the control participants for their
involvement in the study.
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