Effects of a Functional COMT Polymorphism on Prefrontal Cognitive Function in Patients With 22q11.2 Deletion Syndrome
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
14. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Alu-
wahlia S: A Children’s Global Assessment Scale (CGAS). Arch Gen
Psychiatry 1983; 40:1228–1231
15. Bird HR, Gould MS, Staghezza B: Aggregating data from multi-
ple informants in child psychiatry epidemiological research. J
Am Acad Child Adolesc Psychiatry 1992; 31:78–85
16. Hinds DA, Risch N: The ASPEX package: affective sib-pair exclu-
sion mapping, 1996. http://aspex.sourceforge.net
17. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M: Se-
quence variants of the brain-derived neurotrophic factor
(BDNF) gene are strongly associated with obsessive-compulsive
disorder. Am J Hum Genet 2003; 73:370–376
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
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 Children’s 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
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,
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; email@example.com (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.
1. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Wein-
shilboum RM: Human catechol-O-methyltransferase pharma-
cogenetics: description of a functional polymorphism and its
potential application to neuropsychiatric disorders. Pharmaco-
genetics 1996; 6:243–250
2. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM,
Straub RE, Goldman D, Weinberger DR: Effect of COMT Val108/
158Met genotype on frontal lobe function and risk for schizo-
phrenia. Proc Natl Acad Sci USA 2001; 98:6917–6922
3. Graf WD, Unis AS, Yates CM, Sulzbacher S, Dinulos MB, Jack RM,
Dugaw KA, Paddock MN, Parson WW: Catecholamines in pa-
tients with 22q11.2 deletion syndrome and the low-activity
COMT polymorphism. Neurology 2001; 57:410–416
4. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Gold-
man D: A functional polymorphism in the COMT gene and per-
formance on a test of prefrontal cognition. Am J Psychiatry
5. Grossman MH, Emanuel BS, Budarf ML: Chromosomal map-
ping of the human catechol-O-methyltransferase gene to
22q11.1----q11.2. Genomics 1992; 12:822–825
6. McDonald-McGinn DM, LaRossa D, Randall P, Emanuel BS, Zac-
kai EH: The 22q11.2 deletion: screening, diagnostic workup,
and outcome. Genet Test 1997; 1:99–108
7. Woodin M, Wang PP, Aleman D, McDonald-McGinn D, Zackai E,
Moss E: Neuropsychological profile of children and adolescents
with the 22q11.2 microdeletion. Genet Med 2001; 3:34–39
8. Bearden CE, Woodin M, Wang PP, Moss E, McDonald-McGinn D,
Zackai E, Emanuel B, Cannon TD: Neuropsychological function
in the 22q deletion syndrome. J Clin Exp Neuropsychol 2001;
9. Bassett AS, Chow EW: 22q11 deletion syndrome: a genetic sub-
type of schizophrenia. Biol Psychiatry 1999; 46:882–891
10. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in
adults with velo-cardio-facial syndrome. Arch Gen Psychiatry
11. Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherla-
pati R, Shprintzen RJ: Bipolar spectrum disorders in patients di-
agnosed with velo-cardio-facial syndrome: does a hemizygous
deletion of chromosome 22q11 result in bipolar affective dis-
order? Am J Psychiatry 1996; 153:1541–1547
12. Lynch DR, Mozley D, Sokol S, Maas NMC, Balcer LJ, Siderowf AD:
Lack of effect of polymorphisms in dopamine metabolism re-
lated genes on imaging of TRODAT-1 in striatum of asymptom-
atic volunteers and patients with Parkinson’s disease. Move-
ment Disord 2003; 18:804–812
13. Lezak M: Neuropsychological Assessment. New York, Oxford
University Press, 1995
14. Karayiorgou M, Gogos JA, Galke BL, Wolyniec PS, Nestadt G,
Antonarakis SE, Kazazian HH, Housman DE, Pulver AE: Identifi-
cation of sequence variants and analysis of the role of the
catechol-O-methyl-transferase gene in schizophrenia suscepti-
bility. Biol Psychiatry 1998; 43:425–431