Association of the low-activity COMT 158 Met allele with ADHD and OCD in subjects with velocardiofacial syndrome

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1 International Journal of Neuropsychopharmacology (2007), 10, Copyright f 2006 CINP doi: /s Association of the low-activity COMT 158 Met allele with ADHD and OCD in subjects with velocardiofacial syndrome ARTICLE CINP Doron Gothelf 1,2 *, Elena Michaelovsky 2,3 *, Amos Frisch 2,3, Ada H. Zohar 4, Gadi Presburger 1, Merav Burg 1, Ayala Aviram-Goldring 5, Moshe Frydman 2,5, Josepha Yeshaya 6, Mordechai Shohat 2,6, Michael Korostishevsky 2, Alan Apter 1,2 and Abraham Weizman 2,3,7 1 The Behavioral Neurogenetics Center, Feinberg Child Study Center, Schneider Children s Medical Center of Israel, Petah Tiqwa, Israel 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Felsenstein Medical Research Center, Tel Aviv University, Petah Tiqwa, Israel 4 Behavioral Sciences Department, Ruppin Academic Center, Emek Hefer, Israel 5 The Danek Gertner Institute of Human genetics, Sheba Medical Center, Tel Hashomer, Israel 6 Department of Medical Genetics, Rabin Medical Center, Petah Tiqwa, Israel 7 Research Unit, Geha Mental Health Center, Petah Tiqwa, Israel Abstract Velocardiofacial syndrome (VCFS) is caused by a microdeletion in chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. The catechol-o-methyltransferase (COMT), residing in the 22q11.2 microdeletion region, is a major candidate gene for genetic susceptibility to neuropsychiatric disorders in VCFS. Individuals with VCFS carrying the low-activity allele (COMT L ) are expected to have the lowest possible COMT activity since they have only a single copy of the gene. We explored the possibility that COMT L is associated with psychiatric disorders commonly found in VCFS. Fifty-five unrelated individuals with VCFS underwent psychiatric evaluation and were genotyped for the COMT 158 Val/Met polymorphism coding for COMT high/low-activity alleles. The COMT L allele was significantly more prevalent in VCFS subjects with attention deficit hyperactivity disorder (ADHD) (73.9% vs. 33.3%, OR 5.67, x 2 =7.76, p=0.005) and obsessive compulsive disorder (OCD) (78.6% vs. 33.3%, OR 7.33, x 2 =7.24, p=0.007) than in the control group (VCFS subjects without OCD, ADHD and schizophrenia/schizoaffective (SZ/SZaff) disorder). The results of this study suggest that greatly reduced COMT activity, as expected in VCFS COMT L individuals may be a risk factor for psychiatric sequelae in this population. Future longitudinal studies focusing on additional COMT polymorphic sites and other candidate genes from the deleted region will elucidate the molecular pathways leading to schizophrenia and other psychiatric disorders in VCFS. Received 31 January 2006; Reviewed 10 March 2006; Revised 10 March 2006; Accepted 1 April 2006; First published online 31 May 2006 Key words: Attention deficit hyperactivity disorder, obsessive compulsive disorder, polymorphism, schizophrenia, 22q11.2 deletion. Introduction Velocardiofacial syndrome (VCFS), also known as DiGeorge syndrome and 22q11.2 deletion syndrome, Address for correspondence : D. Gothelf, Department of Child Psychiatry, Schneider Children s Medical Center of Israel, 14 Kaplan St, PO Box 559, Petah Tiqwa, 49202, Israel. Tel. : Fax : gothelf@post.tan.ac.il * Both authors contributed equally to this work. This work was performed in partial fulfilment of the requirements for the Ph.D. degree of Elena Michaelovsky, Sackler Faculty of Medicine, Tel Aviv University. is caused by a microdeletion in the long arm of chromosome 22 (Carlson et al., 1997). The incidence is estimated to be at least 1 in 5000 live births (Botto et al., 2003). The exact incidence of the syndrome is still uncertain as there are yet no screening studies assessing the prevalence of VCFS microdeletion in the general population. Thus, currently there are only rough estimates based on selected cases referred to cardiologic and genetic clinics, or registries of congenital defects (for review see Botto et al., 2003). VCFS is the most common microdeletion syndrome known in humans and probably the second most common genetic defect after Down syndrome (Bassett and Chow, 1999). The

2 302 D. Gothelf et al. syndrome was initially described independently by Angelo DiGeorge and Robert Shprintzen (Kirkpatrick and DiGeorge, 1968; Shprintzen et al., 1978). The Shprintzen syndrome, later renamed VCFS, was defined as including palate anomalies ( velo ), congenital cardiovascular defects ( cardio ) and mild facial dysmorphism ( facial ) (Shprintzen et al., 1978). The DiGeorge syndrome was defined as being composed of immunological deficiencies, hypocalcaemia, and congenital cardiac anomalies (Kirkpatrick and DiGeorge, 1968). In the early 1990s it was discovered that the same 22q11.2 deletion is the cause of both VCFS and also of the DiGeorge manifestations (Carey et al., 1992). It has also been discovered that the phenotypic expression of VCFS is extremely broad and includes more than 180 physical anomalies, in addition to cognitive deficits, and psychiatric manifestations (Shprintzen, 2000). Most subjects with VCFS have learning disabilities and the mean IQ in this population is in the borderline range (mid-seventies) (Swillen et al., 1997). VCFS is also characterized by a high rate of psychiatric disorders. About 25% of individuals with VCFS develop a schizophrenia-like psychotic disorder placing individuals with this condition in the highest risk group for schizophrenia next to an identical twin or offspring of two parents with schizophrenia (Gottesman and Shields, 1976; Murphy et al., 1999). High frequency of chromosome 22q11.2 deletions was found in children (Usiskin et al., 1999) and adults with schizophrenia (Karayiorgou et al., 1995). The frequency of the 22q11 deletion is especially high in schizophrenia patients with one (20%) or two (53%) major physical symptoms of VCFS (Bassett et al., 1998; Gothelf et al., 1997). In addition to a high rate of psychotic disorders evolving by early adulthood, children and adolescents with VCFS have a high rate of non-psychotic psychiatric disorders including attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, anxiety and affective disorders, obsessive compulsive disorder (OCD) and autism spectrum disorders (Arnold et al., 2001; Feinstein et al., 2002; Fine et al., 2005; Gothelf et al., 2004; Papolos et al., 1996). The molecular defect in VCFS subjects, namely the haploinsufficiency of numerous genes in the 22q11.2 region, offers the opportunity of focusing on a specific region in the genome in search of candidate genes for susceptibility to psychiatric disorders. One of the most relevant candidate genes in this region is catechol-o-methyltransferase (COMT) that codes for the enzyme which is involved in metabolic inactivation of catecholamines including dopamine in the brain, particularly in the prefrontal cortex (PFC) (Mannisto and Kaakkola, 1999). Dysregulation of dopaminergic neurotransmission has been implicated in the pathophysiology of schizophrenia (Winterer and Weinberger, 2004), ADHD (Biederman and Faraone, 2002) and OCD (Denys et al., 2004) and during the last decade, the association between the COMT genotype and susceptibility to these disorders was intensively investigated (Azzam and Mathews, 2003; Glatt et al., 2003; Qian et al., 2003). The COMT genotype is also known to affect PFC-related cognitive functions in psychiatric patients and normal individuals (Egan et al., 2001). The 158 Val/Met polymorphism in the COMT gene codes for high- and low-enzymatic-activity alleles (COMT H and COMT L respectively). In erythrocytes and liver there is a 3- to- 4-fold higher COMT enzymatic activity in subjects homozygous for COMT H than in subjects homozygous for COMT L (Chen et al., 2004; Lotta et al., 1995), and COMT enzymatic activity in post-mortem human dorsolateral prefrontal cortex (DLPFC) is y40% higher in COMT H vs. COMT L homozygotes (Chen et al., 2004; Lotta et al., 1995). Because COMT is within the 22q11 deletion, all VCFS subjects carry only one copy of the COMT gene (Carlson et al., 1997). VCFS subjects who carry the COMT L variant of the gene are supposedly particularly deficient in COMT activity since they carry a single copy of an allele with reduced enzymatic activity. Consequently, VCFS individuals with COMT L are expected to have a dopamine overload in the brain, particularly in the PFC. This is because the PFC has very low level of dopamine transporter that is crucial for reuptake of dopamine to the presynaptic neurons (Sesack et al., 1998). Thus, the presynaptic mechanism of dopamine degradation by MAO, is ineffective in the PFC. A recent study followed subjects with VCFS longitudinally from childhood early adolescence to late adolescence early adulthood. The study found that in comparison to subjects hemizygous for COMT H, subjects hemizygous for COMT L demonstrated a more significant decline in verbal IQ and expressive language abilities as well as a more robust decline in PFC grey-matter volume and evolution of more severe psychotic symptoms (Gothelf et al., 2005). In the present study we sought to further explore the association between the COMT 158 Val/Met polymorphism and psychiatric disorders in VCFS. Since the age of many of the VCFS subjects in our sample was below the age of onset of schizophrenia spectrum disorders, the rate of patients with these disorders was relatively low. The most common psychiatric diagnoses found in our sample were ADHD and OCD

3 COMT and psychiatric disorders in VCFS 303 (Gothelf et al., 2003, 2004). Thus, we investigated the association of the COMT gene 158 Val/Met polymorphism with ADHD, OCD and also schizophrenia in order to test the hypothesis that COMT L is a risk factor for the emergence of these neuropsychiatric disorders in VCFS. Material and methods Subjects Fifty-five unrelated subjects with VCFS (mean age S.D.: yr; males/females: 34/21) were studied. Only VCFS individuals aged o6 yr were included in the study. In familial cases only the oldest family member was included. Subjects were recruited from a Behavioral Neurogenetics Centre located at a major tertiary medical centre. The centre coordinates all the medical and psychosocial treatment of subjects with VCFS and their families. The major sources of referrals to the centre are clinical genetic departments. We believe that our sample is not biased towards more severely affected subjects as about 90% of the subjects diagnosed in the major clinical genetic departments of two major hospitals participated in the study. All participants were Jews living in Israel to minimize stratification effects on the association analysis. Ashkenazi and non-ashkenazi Jews have no statistical difference in COMT 158 Val/Met allelic frequency (Frisch et al., 1999). Out of the 43 subjects described in our previous publication (Gothelf et al., 2004), 34 are included in the present study. Five subjects with Arabic ethnicity and four familial cases were excluded from the study. The presence of the 22q11.2 deletion was confirmed in all subjects by the fluorescent in situ hybridization (FISH) assay using a commercial probe (Vysis, Downers Grove, IL). The study protocol was approved by the Rabin Medical Center Review Board. Written informed consent was obtained from adult and adolescent subjects and in minors, assent was obtained from the subjects and written consent from their parents. Psychiatric and cognitive assessments Comprehensive and structured psychiatric evaluation was performed on all subjects according to a standard protocol, which we have described elsewhere (Gothelf et al., 2004). All subjects were evaluated using the Hebrew version of the Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime (K-SADS-PL; Shanee et al., 1997) and the Yale Brown Obsessive Compulsive Scale (YBOCS, Goodman et al., 1989). Subjects >18 years were also evaluated with the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-P; First et al., 2004). Full scale, verbal and performance IQ (FSIQ, VIQ, PIQ) were measured with the Hebrew version of the Wechsler Intelligence Scale for Children 3rd edn (WISC-III) for subjects aged f17 years (Wechsler, 1991) and with the Hebrew version of the Wechsler Adult Intelligence Scale 3rd edn (WAIS-III) for subjects aged >17 years (Wechsler, 1997). Genotyping DNA was isolated from leukocytes by a commercial kit (Roche Diagnostics, Mannheim, Germany). All subjects were genotyped for the COMT 158 Val/Met polymorphism (472G/472A, rs165688) as described previously (Daniels et al., 1996). Briefly, a 169-bp fragment was amplified using primers 5k-ACT- GTGGCTAGCAGCTGTG-3k and 5k-CCTTTTCCAG- GTCTGACAA-3k. PCR protocol included: initial denaturation (2 min at 95 xc) followed by 35 cycles of 95 xc for 40 s, 56 xc for 40 s, and 72 xc for 1 min; final extension was performed at 72 xc for 5 min. PCR products were digested with NlaIII (New England Biolabs, Beverly, MA, USA) and electrophoresed on a 4% agarose gel composed of 2% SeaKem LE and 2% NuSieve GTG low-melting agarose (both from Cambrex, Rockland, ME, USA). Digestion yielded two DNA fragments (138 and 31 bp) for the 472G allele ( 158 Val) and three (120, 31 and 18 bp) for the 472A allele ( 158 Met). Data analysis Genotype and allele distribution of the COMT 158 Val/ Met polymorphism was determined by direct counting. Possible differences in genotype or allele frequency between the samples were estimated using the x 2 test. Bonferroni corrections were performed by the SISA online procedure ( bonfer.htm). Age and IQ scores were compared using one-way analysis of variance (ANOVA) for differences between psychiatric subgroups and by t tests for differences between 158 Met and 158 Val carriers. Results Of the 55 subjects with VCFS 23 (41.8%) met DSM-IV criteria for ADHD (61.5% combined type and 38.5% inattentive type), 14 (25.5%) for OCD and seven (12.7%) for both ADHD and OCD. Five subjects (9.1%) met diagnostic criteria of schizophrenia/ schizoaffective (SZ/SZaff) disorder. Two of them had

4 304 D. Gothelf et al. Table 1. Clinical and demographic data of the study VCFS subjects Psychiatric diagnosis n Age (yr) (average S.D.) Gender IQ scores (average S.D.) Male Female FSIQ VIQ PIQ ADHD OCD SZ/SZaff Control a ADHD, Attention deficit hyperactivity disorder ; OCD, obsessive compulsive disorder; SZ/SZaff, schizophrenia/schizoaffective disorder; FSIQ, full scale IQ; VIQ, verbal IQ; PIQ, performance IQ. a VCFS subjects without ADHD, OCD, SZ/SZaff comorbid OCD and two had a history of ADHD. The 24 VCFS subjects (45.4%) without ADHD, OCD or SZ/ SZaff served as the control group for phenotypic and genetic analyses. The demographic and clinical characteristics of all participants, divided into subgroups according to psychiatric diagnoses, are given in Table 1. Although the subjects with SZ/SZaff tended to be older than the other groups, the differences in mean age between diagnostic subgroups were not statistically significant (F=1.94, d.f.=3, p=0.13). There were also no significant differences among the diagnostic subgroups on FSIQ (F=0.37, d.f.=3, p=0.78), VIQ (F=0.82, d.f.=3, p=0.49), and PIQ (F=0.22, d.f.=3, p=0.88). Similarly, there were no significant differences in gender distribution among ADHD, OCD and control groups (po0.14). The SZ/SZaff group (consisting of only five females) was different from each of the other groups (pf0.03). The distribution of COMT L /COMT H alleles in the total sample of VCFS subjects was 56%/44% which is not statistically different (x 2 =1.54, p=0.20) from that found in the general population of Jews in Israel (Frisch et al., 1999). When all VCFS subjects were compared according to genotype, COMT L and COMT H carriers were similar in mean age ( vs yr, p=0.74) and IQ scores: FSIQ ( vs , p=0.37), VIQ ( vs , p=0.79), and PIQ ( vs , p=0.23). The association of COMT L /COMT H with ADHD, OCD and SZ/SZaff in the VCFS cohort is presented in Table 2. The COMT L allele was significantly more common in subjects affected with ADHD than in the control group (p=0.005). Similarly, subjects with OCD had higher frequency of COMT L in comparison with controls (p=0.007). The prevalence of COMT L in subjects affected by both OCD and ADHD (n=7) was significantly elevated (85.7% vs. 33.3%, OR 12.00, x 2 =6.00, p=0.014). Out of the five subjects with SZ/ SZaff, four (80%) carried the COMT L allele but difference from controls was not statistically significant. When subjects affected by ADHD, OCD, or SZ/SZaff (n=31) were analysed together and compared to controls, association with COMT L was highly significant (74.2% vs. 33.3%, OR 5.75, x 2 =9.12, p=0.0024). There was no statistically significant deviation in COMT allele frequency between males and females in ADHD, OCD or the control groups (p=0.42) suggesting that the association of COMT L with ADHD and OCD in VCFS subjects is not gender related. The interaction between gender and COMT alleles could not be evaluated for SZ/SZaff as all subjects in this group were females. Discussion The main finding of this study is that VCFS subjects who suffer from either ADHD or OCD have significantly (p=0.005 and p=0.007 respectively) higher frequency of the COMT L allele compared with those who are not affected. Patients with SZ/SZaff show the same trend but results were not significant (p=0.053), probably due to the small number of individuals affected. A relatively high comorbidity was found in our VCFS subjects between OCD and ADHD. Other studies of VCFS found a high comorbidity between OCD and psychotic symptoms (Bassett et al., 2003; Pulver et al., 1994). The high comorbidity between psychiatric disorders in VCFS suggests that shared biological mechanisms, such as reduced COMT activity, may be involved in the pathophysiology of neuropsychiatric disorders in VCFS. The results of the present study complement a recent report from a different cohort suggesting that the COMT L allele is a risk factor for the development of

5 COMT and psychiatric disorders in VCFS 305 Table 2. Association of the COMT L /COMT H polymorphism with ADHD, OCD and SZ/SZaff comorbidities in subjects with velocardiofacial syndrome Psychiatric diagnosis n COMT L n (%) COMT H n (%) x 2 (1) a OR 95% CI p ADHD (73.9) 6 (26.1) b OCD (78.6) 3 (21.4) b SZ/SZaff 5 4 (80.0) 1 (20.0) Control c 24 8 (33.3) 16 (66.7) ADHD, attention-deficit/hyperactivity disorder; OCD, obsessive-compulsive disorder; SZ/SZaff, schizophrenia/schizoaffective disorder. a Diagnostic group vs. control. b Remains significant following Bonferroni correction. c VCFS subjects without ADHD, OCD, SZ/SZaff. psychotic symptoms and decline in both verbal abilities and PFC volumes in VCFS adolescents (Gothelf et al., 2005). An earlier study (Papolos et al., 1996) reported an association of the COMT L allele with rapid-cycling bipolar affective disorder in VCFS subjects. In the Papolos et al. cohort the COMT L allele was also overrepresented, although not statistically significant, in the ADHD subgroup. It should be noted that in one cohort of children with VCFS the COMT H allele was associated with higher scores on parent report of the Child Behavior Checklist subscales (Bearden et al., 2005) and lower achievements on a composite measure of executive functioning (Bearden et al., 2004). Another study with older adolescents and young adults found that VCFS subjects carrying the COMT L allele had significantly poorer achievements than matched-iq controls on verbal working memory and expressive language performance but a similar rate of psychiatric disorders (Baker et al., 2005). Yet another study reported no association between COMT and schizophrenia in VCFS (Murphy et al., 1999). The mixed findings among studies could be related to several factors. First, the sample size in all previous studies was relatively small, which could lead to both type I and type II errors. Second, the one study that found the COMT H allele to be associated with the severity of psychiatric symptoms (Bearden et al., 2005) relied solely on parent reports without obtaining categorical DSM-IV diagnostic criteria. Psychiatric manifestations, such as psychotic symptoms, could be underdiagnosed when relying solely on parent reports. Another possible explanation for the mixed findings could be the different age range of the cohorts. In the study of Bearden et al. (2005) the sample consisted mainly of pre-adolescent subjects. The present study and the longitudinal study (Gothelf et al., 2005) both consisted of older subjects including young adults. It is possible that the increased psychiatric morbidity in VCFS adolescents and young adults is mediated by neurodevelopmental increase in brain dopamine levels beginning at adolescence. Studies with primates indicate that there is indeed a dramatic increase in dopamine levels during adolescence (Lambe et al., 2000). It is likely that VCFS adolescents and adults with the COMT L allele fail to adjust for the increased load in dopamine and as a result develop certain psychiatric disorders. This is supported by the longitudinal follow-up of VCFS subjects that found that the COMT L allele was a risk factor for psychosis and cognitive decline, in adolescents and young adults but not in children (Gothelf et al., 2005). Theoretically, there might be gender differences in the effect of COMT on dopamine levels in VCFS subjects. Oestrogen inhibits the COMT promoter and reduces the transcription of COMT in females (Jiang et al., 2003). Conversely, in mice knocked-out of the COMT gene only males showed increase in PFC dopamine levels and exhibited aggressive behavior (Gogos et al., 1998). Although we did not find gender differences in the COMT 158 Val/Met association with ADHD and OCD, it should be noted that our sample size was probably not large enough to detect gender differences with small effect size. It is tempting to infer from our data on the role of the COMT L allele in the susceptibility to ADHD and OCD in the general population. However, the situation in VCFS patients carrying a single allele is unique and even homozygotes for this allele in the general population are expected to have higher COMT enzymatic activity. In the general population, there were some reports on an association of the COMT L allele with OCD in males (Alsobrook et al., 2002; Karayiorgou et al., 1997; Poyurovsky et al., 2005) and

6 306 D. Gothelf et al. females (Alsobrook et al., 2002). However, there were several other reports of no association (Azzam and Mathews, 2003). Association studies between ADHD and COMT 158 Val/Met in the general population were mostly negative (Jiang et al., 2003; Qian et al., 2003). We believe that VCFS, being defined aetiologically by its well-characterized genetic defect, is an alternative approach for contending with the aetiological heterogeneity of psychiatric disorders. As such, VCFS is a promising model to learn about the effect of decreased dosage of pivotal genes, such as COMT, on psychiatric morbidity and cognitive function. The results of the present study suggest that the COMT L allele is a risk factor for ADHD and OCD, which are common psychiatric disorders in VCFS. Longitudinal studies of large cohorts of VCFS children followed to adulthood will further elucidate the role of COMT in VCFS schizophrenia. Besides the COMT 158 Val/Met polymorphism, other polymorphisms and haplotypes within the COMT gene have been associated with schizophrenia (Shifman et al., 2002), and their role in VCFS-related mental disorders merits further investigation. Moreover, other genes from the 22q11.2 deletion region, such as PRODH, that may contribute separately or synergistically to the psychiatric phenotype of VCFS should be explored (Paterlini et al., 2005). We suggest that future studies in VCFS will focus on the association between COMT genotype and specific endophenotypes. These candidate endophenotypes should include prefrontal dopaminedependent working memory and inhibition tasks, that were recently found to be associated with COMT 158 Val/Met polymorphism in schizophrenia (Diamond et al., 2004; Egan et al., 2001) and were also reported to be deficient in VCFS (Reif et al., 2004; Woodin et al., 2001). Acknowledgements The authors are grateful to the National Institute for Psychobiology in Israel (grant no ). Statement of Interest None. References Alsobrook 2nd JP, Zohar AH, Leboyer M, Chabane N, Ebstein RP, Pauls DL (2002). Association between the COMT locus and obsessive-compulsive disorder in females but not males. American Journal of Medical Genetics 114, Arnold PD, Siegel-Bartelt J, Cytrynbaum C, Teshima I, Schachar R (2001). Velo-cardio-facial syndrome: implications of microdeletion 22q11 for schizophrenia and mood disorders. American Journal of Medical Genetics 105, Azzam A, Mathews CA (2003). Meta-analysis of the association between the catecholamine-o-methyltransferase gene and obsessive-compulsive disorder. American Journal of Medical Genetics. B : Neuropsychiatric Genetics 123, Baker K, Baldeweg T, Sivagnanasundaram S, Scambler P, Skuse D (2005). COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. Biological Psychiatry 58, Bassett AS, Chow EW (1999). 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biological Psychiatry 46, Bassett AS, Chow EW, Abdel Malik P, Gheorghiu M, Husted J, Weksberg R (2003). The schizophrenia phenotype in 22q11 deletion syndrome. American Journal of Psychiatry 160, Bassett AS, Hodgkinson K, Chow EW, Correia S, Scutt LE, Weksberg R (1998). 22q11 deletion syndrome in adults with schizophrenia. American Journal of Medical Genetics 81, Bearden CE, Jawad AF, Lynch DR, Monterossso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, et al. (2005). Effects of COMT genotype on behavioral symptomatology in the 22q11.2 deletion syndrome. Neuropsychology Devevlopment and Cognition, Section C: Child Neuropsychology 11, Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, et al. (2004). Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. American Journal of Psychiatry 161, Biederman J, Faraone SV (2002). Current concepts on the neurobiology of Attention-Deficit/Hyperactivity Disorder. Journal of Attention Disorder 6 (Suppl. 1), S7 16. Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O Leary LA, Wong LY, Elixson EM, et al. (2003). A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112, Carey AH, Kelly D, Halford S, Wadey R, Wilson D, Goodship J, Burn J, Paul T, Sharkey A, Dumanski J, et al. (1992). Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. American Journal of Human Genetics 51, Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, Wadey R, Patanjali SR, Weissman SM, Anyane-Yeboa K, Warburton D, et al. (1997). Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients. American Journal of Human Genetics 61, Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud

7 COMT and psychiatric disorders in VCFS 307 J, et al. (2004). Functional analysis of genetic variation in catechol-o-methyltransferase (COMT): effects on mrna, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics 75, Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC, Spurlock G, Riley B, Scambler P, Asherson P, et al. (1996). No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. American Journal of Psychiatry 153, Denys D, Zohar J, Westenberg HG (2004). The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. Jornal of Clinical Psychiatry 65 (Suppl. 14), Diamond A, Briand L, Fossella J, Gehlbach L (2004). Genetic and neurochemical modulation of prefrontal cognitive functions in children. American Journal of Psychiatry 161, Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences USA 98, Feinstein C, Eliez S, Blasey C, Reiss AL (2002). Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biological Psychiatry 51, Fine SE, Weissman A, Gerdes M, Pinto-Martin J, Zackai EH, McDonald-McGinn DM, Emanuel BS (2005). Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome. Journal of Autism and Developmental Disorders 35, First M, Spitzer R, Gibbon M, Williams J (2004). Stuctured Clinical Interview for Axis I DSM-IV. New York: New York State Psychiatric Institute. Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S, Birman E, Laor N, Rauchverger B, Kreinin A, Poyurovsky M, et al. (1999). Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. Molecular Psychiatry 4, Glatt SJ, Faraone SV, Tsuang MT (2003). Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of casecontrol and family-based studies. American Journal of Psychiatry 160, Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M (1998). Catechol-Omethyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proceedings of the National Academy of Sciences USA 95, Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS (1989). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry 46, Gothelf D, Eliez S, Thompson T, Penniman L, Feinstein C, Kwon H, Jo B, Hinard C, Morris MA, Antonarakis SA, Reiss AL (2005). COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience 8, Gothelf D, Frisch A, Munitz H, Rockah R, Aviram A, Mozes T, Birger M, Weizman A, Frydman M (1997). Velocardiofacial manifestations and microdeletions in schizophrenic inpatients. American Journal of Medical Genetics 72, Gothelf D, Gruber R, Presburger G, Dotan I, Brand- Gothelf A, Burg M, Inbar D, Steinberg T, Frisch A, Apter A, Weizman A (2003). Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome : an open-label study. Journal of Clinical Psychiatry 64, Gothelf D, Presburger G, Zohar AH, Burg M, Nahmani A, Frydman M, Shohat M, Inbar D, Aviram-Goldring A, Yeshaya J, et al. (2004). Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. American Journal of Medical Genetics B Neuropsychiatric Genetics 126, Gottesman II, Shields J (1976). A critical review of recent adoption, twin, and family studies of schizophrenia: behavioral genetics perspectives. Schizophrenia Bulletin 2, Jiang H, Xie T, Ramsden DB, Ho SL (2003). Human catechol- O-methyltransferase down-regulation by estradiol. Neuropharmacology 45, Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA (1997). Genotype determining low catechol-o-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proceedings of the National Academy of Sciences USA 94, Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, et al. (1995). Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proceedings of the National Academy of Sciences USA 92, Kirkpatrick Jr. JA, DiGeorge AM (1968). Congenital absence of the thymus. American Journal of Roentgenology, Radium Therapy & Nuclear Medicine 103, Lambe EK, Krimer LS, Goldman-Rakic PS (2000). Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey. Journal of Neuroscience 20, Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995). Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34, Mannisto PT, Kaakkola S (1999). Catechol-Omethyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new

8 308 D. Gothelf et al. selective COMT inhibitors. Pharmacological Reviews 51, Murphy KC, Jones LA, Owen MJ (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Archives of General Psychiatry 56, Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen RJ (1996). Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? American Journal of Psychiatry 153, Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, Westphal KG, Olivier B, Sulzer D, Pavlidis P, et al. (2005). Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophreniarelated phenotypes in mice. Nature Neuroscience 8, Poyurovsky M, Michaelovsky E, Frisch A, Knoll G, Amir I, Finkel B, Buniak F, Hermesh H, Weizman R (2005). COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study. Neuroscience Letters 389, Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS, Morrow B, Karayiorgou M, Antonarakis SE, Housman D, et al. (1994). Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. Journal of Nervous and Mental Disease 182, Qian Q, Wang Y, Zhou R, Li J, Wang B, Glatt S, Faraone SV (2003). Family-based and case-control association studies of catechol-o-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. American Journal of Medical Genetics B Neuropsychiatric Genetics 118, Reif A, Fallgatter AJ, Ehlis AC, Lesch KP (2004). Altered functioning of the cingulate gyrus in two cases of chromosome 22q11 deletion syndrome. Psychiatry Research 132, Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI (1998). Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. Journal of Neuroscience 18, Shanee N, Apter A, Weizman A (1997). Psychometric properties of the K-SADS-PL in an Israeli adolescent clinical population. Israel Journal of Psychiatry and Related Sciences 34, Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, et al. (2002). A highly significant association between a COMT haplotype and schizophrenia. American Journal of Human Genetics 71, Shprintzen RJ (2000). Velo-cardio-facial syndrome : a distinctive behavioral phenotype. Mental Retardation and Developmental Disabilities Research Reviews 6, Shprintzen RJ, Goldberg RB, Lewin ML, Sidoti EJ, Berkman MD, Argamaso RV, Young D (1978). A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities : velocardio-facial syndrome. Cleft Palate Journal 15, Swillen A, Devriendt K, Legius E, Eyskens B, Dumoulin M, Gewillig M, Fryns JP (1997). Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. Journal of Medical Genetics 34, Usiskin SI, Nicolson R, Krasnewich DM, Yan W, Lenane M, Wudarsky M, Hamburger SD, Rapoport JL (1999). Velocardiofacial syndrome in childhood-onset schizophrenia. Journal of the American Academy of Child and Adolescent Psychiatry 38, Wechsler D (1991). Wechsler Intelligence Scale for Children Third Edition Manual. San Antonio, TX: The Psychological Corporation Wechsler D (1997). Wechsler Adult Intelligence Scale Third Edition. Administration and Scoring Manual. San Antonio, TX : The Psychological Corporation Winterer G, Weinberger DR (2004). Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends in Neuroscience 27, Woodin M, Wang PP, Aleman D, McDonald-McGinn D, Zackai E, Moss E (2001). Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genetics in Medicine 3,