Article

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

Children's Hospital of Philadelphia, Department of Child Development, USA.
American Journal of Psychiatry (Impact Factor: 13.56). 10/2004; 161(9):1700-2. DOI: 10.1176/appi.ajp.161.9.1700
Source: PubMed

ABSTRACT 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.

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    • "Similar results were reported by Shashi et al. (2006) and Bearden et al. (2004): Met-hemizygous 22q11.2DS children outperformed Val carriers on a composite measure of EF. "
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals. Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age.
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    1 edited by Prof. Dr. Maria Puiu Department of Medical Genetics, University of Medicine and Pharmacy Victor Babes Timisoara, Romania, 12/2012; Intech., ISBN: 980-953-307-751-7
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    • "Recent work has quantified nonverbal learning impairments in the 22q11.2DS by evaluating the behavioral endophenotypes predicted by the spatial and temporal attention model (Bearden et al., 2001, 2004a, 2005; Bish et al., 2005, 2007; Gothelf et al., 2010a; Karayiorgou et al., 2010; Kiehl et al., 2009; Simon, 2008; Simon et al., 2005a, 2005b, 2008a, 2008b; Stoddard et al., 2010; Takarae et al., 2009; Xu et al., 2010; Yamagishi and Srivastava, 2003). Individuals with the 22q11.2DS "
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