No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome

Article

Reference

No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome

GLASER, Bronwyn, et al.

Abstract

OBJECTIVE: Previous studies linking the catechol O-methyltransferase (COMT) functional polymorphism to the specific phenotype in 22q11.2 deletion syndrome (22q11.2DS) have yielded inconsistent results. The goal of the present study was to replicate a recent finding that executive function is higher in individuals hemizygous for the Met allele. METHOD:

Thirty-four children and young adults with a 22q11.2 microdeletion, hemizygous for the Val (N=14) or Met (N=20) polymorphism, were tested on measures of executive function, IQ, and memory. RESULTS: No significant differences were detected between Met- and Val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. CONCLUSIONS:

These results suggest either a small effect of the COMT polymorphism on executive function in 22q11.2DS or no effect at all. Further research is needed to characterize the implications of hemizygosity of COMT in 22q11.2DS for cognitive function.

GLASER, Bronwyn, et al . No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome. American Journal of Psychiatry , 2006, vol.

163, no. 3, p. 537-539

DOI : 10.1176/appi.ajp.163.3.537 PMID : 16513880

Available at:

http://archive-ouverte.unige.ch/unige:5369

Disclaimer: layout of this document may differ from the published version.

1 / 1

Am J Psychiatry 163:3, March 2006

537

BRIEF REPORTS

ajp.psychiatryonline.org lase is reduced without loss of neurons in prefrontal cortex of

schizophrenics. Arch Gen Psychiatry 1995; 52:258–266 2. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA: De-

creased GAD₆₇ mRNA expression in a subset of prefrontal cor- tical GABA neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000; 57:237–245

3. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, Sampson AR, Lewis DA: Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 2003; 23:6315–6326

4. Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6:312–324 5. Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear

MF, Maffei L, Tonegawa S: BDNF regulates the maturation of in- hibition and the critical period of plasticity in mouse visual cor- tex. Cell 1999; 98:739–755

6. Cotrufo T, Viegi A, Berardi N, Bozzi Y, Mascia L, Maffei L: Effects of neurotrophins on synaptic protein expression in the visual cortex of dark-reared rats. J Neurosci 2003; 23:3566–3571 7. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR,

Kleinman JE: Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychia- try 2003; 8:592–610

8. Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA: Relationship of brain-

derived neurotrophic factor and its receptor TrkB to altered in- hibitory prefrontal circuitry in schizophrenia. J Neurosci 2005;

25:372–383

9. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Wein- berger DR: The BDNF Val66Met polymorphism affects activity- dependent secretion of BDNF and human memory and hip- pocampal function. Cell 2003; 112:257–269

10. Hayashi M, Yamashita A, Shimizu K: Somatostatin and brain- derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging. Brain Res 1997; 749:283–289

11. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM: BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psy- chiatry 2005; 10:208–212

12. Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, Bobb A, Greenstein D, Lenane M, Gochman P, Baker N, Balkissoon R, Vakkalanka RK, Weinberger DR, Rapoport JL, Straub RE: GAD1 (2q31.1), which encodes glutamic acid decar- boxylase (GAD₆₇), is associated with childhood-onset schizo- phrenia and cortical gray matter volume loss. Mol Psychiatry 2005; 10:581–588

Brief Report

No Evidence for an Effect of COMT Val158Met Genotype on Executive Function in Patients With 22q11 Deletion Syndrome

Bronwyn Glaser, M.A.

Martin Debbane, M.A.

Christine Hinard, Ph.D.

Michael A. Morris, Ph.D.

Sophie P. Dahoun, M.D.

Stylianos E. Antonarakis, M.D.

Stephan Eliez, M.D.

Objective: Previous studies linking the catechol O-methyl- transferase (COMT) functional polymorphism to the specific phenotype in 22q11.2 deletion syndrome (22q11.2DS) have yielded inconsistent results. The goal of the present study was to replicate a recent finding that executive function is higher in

individuals hemizygous for the Met allele.

Method: Thirty-four children and young adults with a 22q11.2 microdeletion, hemizygous for the Val (N=14) or Met (N=20) polymorphism, were tested on measures of executive function, IQ, and memory.

Results: No significant differences were detected between Met- and Val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory.

Conclusions: These results suggest either a small effect of the COMT polymorphism on executive function in 22q11.2DS or no effect at all. Further research is needed to characterize the implications of hemizygosity of COMT in 22q11.2DS for cogni- tive function.

(Am J Psychiatry 2006; 163:537–539)

2 2q11.2 deletion syndrome (22q11.2DS) is a congenital disorder caused by an interstitial deletion on chromosome 22q11.2, associated with frequent psychiatric problems (1) and learning disabilities. The phenotype includes specific weaknesses in executive functions, such as working mem- ory and information sequencing (2), and attentional ca-

pacities (3). It has been suggested that haploinsufficiency

of the catechol O-methyltransferase (COMT) gene, within

the 22q11.2 region, may contribute to the psychiatric phe-

notype associated with the disorder (4). The COMT gene

confirms a functional polymorphism determining high

and low activity of the COMT enzyme and associated with

538

ajp.psychiatryonline.org

dopamine degradation (5). Individuals affected by 22q11.2DS are hemizygous for either the COMT158Met (M158), associated with very low COMT activity, or the COMT158Val variant (V158), which would be expected to be associated with enzymatic activity comparable to that of nondeleted heterozygotes (Val-Met) (6).

There is an increasing body of literature investigating links between COMT enzyme activity and the 22q11.2DS psychiatric phenotype, given reports linking the COMT gene to dopamine dysfunction in schizophrenia (7). How- ever, the results of such studies have been inconsistent.

Some investigations have found no association between COMT activity and schizophrenia in 22q11.2DS (1, 8), but others propose a relationship between psychiatric mani- festations in the disease and low-activity COMT, postulat- ing that M158 may be related to dopamine excess (4, 9).

By contrast, a recent study (10) showed higher executive function in a Met-hemizygous than a Val-hemizygous group of patients with 22q11.2DS, suggesting that pa- tients hemizygous for M158 may be at lower risk for pre- frontal degradation.

The goal of the current report was to test the hypotheses presented by Bearden et al. (10) that 1) executive function is higher in patients hemizygous for M158 and 2) full-scale IQ is likely to be higher in patients who are hemizygous for V158. Given the controversy in the literature relating COMT to 22q11.2DS, our aim was to test for the same group differences in 22q11.2DS patients using compara- ble measures of executive function as well as global indi- ces of intelligence and memory.

Method

Thirty-four participants (21 female, 13 male) with 22q11.2DS, from 6 to 37 years of age (mean=16.49, SD=8.37), participated in the study. Participants were recruited through announcements in patient association newsletters. All participants were Caucasian.

Written informed consent was received from all of the subjects’

parents under protocols approved by the Institutional Review

Board of Geneva University Hospital. Presence of the 22q11.2 mi- crodeletion was confirmed by fluorescence in situ hybridization with probes D0832 (COMT) and N48C12 (D22S264) and by geno- typing for microsatellites D22S941, D22S944, D22S264, and D22S611 (11). COMT genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analy- sis with the restriction enzyme NlaIII (12).

One-way analysis of variance (ANOVA) was used to detect group differences between M158 and V158 subjects for a battery of neuropsychological measures. First, to test the previously hy- pothesized difference between the COMT genotype and execu- tive function (10), the following measures of executive function were used as dependent variables: verbal fluency animal naming score, Wechsler (WISC-III and WAIS-III) Digit Span and Arith- metic subtests, and Stroop interference score. Second, to test for overall differences in executive function, the standard scores on each measure were converted to z scores and an executive func- tion composite score was calculated by averaging the z scores (10). Finally, to explore related differences in cognitive and mne- monic functioning, we used main index scores from Wechsler measures of IQ (WISC-III and WAIS-III) and memory (Children’s Memory Scale and Wechsler Memory Scale, 3rd ed.). Only those measures common to both child and adult batteries were in- cluded in the analyses (Table 1).

Results

V158 and M158 and all employed neuropsychological measures were tested for the basic assumptions of ANOVA.

ANOVA performed on the measures of executive function and the executive function composite score yielded no sig- nificant differences between M158 and V158 participants (Table 1); the groups did not differ on full-scale, perfor- mance, and verbal IQ or on verbal and visual memory. To control for the (nonsignificant) difference in age between the M158 and V158 groups, we separated the children and adults and repeated the analyses. Separating the groups yielded no significant differences on any of the measures.

Discussion

The primary goal of the current report was to test a hy- pothesis linking M158 to superior executive function in

Measure

Met-Hemizygous Group (N=20)

Val-Hemizygous Group (N=14)

Analysis of Variance (df=1, 32)

Mean SD Mean SD F p

Executive function

Verbal fluency in animal naming 13.90 4.80 13.29 4.05 0.153 0.698

Stroop task interference 50.05 6.57 51.07 7.73 0.172 0.681

Arithmetic 5.15 1.81 4.71 2.56 0.339 0.564

Digit Span 7.50 2.50 6.79 3.66 0.458 0.503

Executive function composite 15.39 2.28 15.20 1.91 0.062 0.805

General IQ

Full-scale 70.45 9.82 69.57 14.06 0.046 0.831

Performance 72.10 11.55 70.86 10.83 0.100 0.754

Verbal 73.90 11.94 75.57 17.33 0.111 0.741

Memory Visual

Immediate 77.85 15.22 73.43 15.22 0.695 0.411

Delayed 82.55 12.77 78.07 11.39 1.105 0.301

Verbal

Immediate 91.70 10.65 85.86 14.60 1.826 0.186

Delayed 91.70 11.21 82.57 17.32 3.493 0.071

Am J Psychiatry 163:3, March 2006

539

BRIEF REPORTS

ajp.psychiatryonline.org

22q11.2DS. ANOVA showed no differences between M158

and V158 groups on individual measures of executive function, a composite measure of executive function, ver- bal and performance IQ, and verbal and visual memory.

Globally, our findings suggest that the effect of COMT al- lele status on intellectual functioning of 22q11.2DS pa- tients may be small compared with the overall cognitive impairments associated with the deletion.

Our executive function measure included the Stroop task instead of the Trails B test used in the previous report (10), which may explain why M158 individuals did not demonstrate superior executive function in the current study. Trails B and Digit Span were the two measures that were related to COMT status in the earlier study (10), sug- gesting a difference in working memory between Val and Met hemizygosity. In the current study, however, we were unable to delineate a relationship between performance and COMT status on measures related to working memory or short-term memory, such as the Digit Span and Arith- metic subtests and the verbal and visual immediate mem- ory indices. Given that previous research has shown an ef- fect of COMT homozygosity or heterozygosity on measures of working memory and executive function not used in the current study (i.e., n-back task and the Wisconsin Card Sorting Test) (13, 14), it will be important for future studies of 22q11.2DS to use alternate executive function measures for which Val-Val, Met-Met, and Val-Met comparison groups are available in order to explore the specific effect of COMT hemizygosity on prefrontal cognition.

The inconsistencies between findings from initial stud- ies on COMT in 22q11.2DS imply that the relationship be- tween gene expression and cognitive expression in 22q11.2DS is complex. It may be that overall cognitive def- icits resulting from the deletion are severe enough that a functional effect of the COMT polymorphism is either not detectable or would be consistently detectable only in large samples.

Received Nov. 1, 2004; revisions received Jan. 18 and April 18, 2005; accepted April 26, 2005. From the Department of Child Psychi- atry and the Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals, Geneva. Address correspondence and reprint requests to Dr. Eliez, Service médico-pédagogique, Bd St-Georges 16-18, Case postale 50, CH-1211 Geneva 8, Switzerland; stephan.eliez@medecine.unige.ch (e-mail).

Supported in part by Swiss National Research Funds (grants 3200- 063135.00/1, 3232-063134.00/1, and PP00B-102864) (Dr. Eliez) and by the National Alliance for Research on Schizophrenia and Depres- sion (Dr. Eliez).

The authors thank Verane Braissand for her assistance with data processing, as well as the families in Génération 22, the French 22q11.2DS association, for their support.

References

1. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940–945

2. Wang PP, Woodin MF, Kreps-Falk R, Moss EM: Research on be- havioral phenotypes: velocardiofacial syndrome (deletion 22q11.2). Dev Med Child Neurol 2000; 42:422–427

3. Gothelf D, Presburger G, Levy D, Nahmani A, Burg M, Berant M, Blieden LC, Finkelstein Y, Frisch A, Apter A, Weizman A: Ge- netic, developmental, and physical factors associated with at- tention deficit hyperactivity disorder in patients with velocar- diofacial syndrome. Am J Med Genet B Neuropsychiatr Genet 2004; 126:116–121

4. Papolos DF, Veit S, Faedda GL, Saito T, Lachman HM: Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 1998; 3:346–349

5. Weinshilboum RM, Raymond FA: Inheritance of low erythro- cyte catechol-O-methyltransferase activity in man. Am J Hum Genet 1977; 29:125–135

6. Syvanen AC, Tilgmann C, Rinne J, Ulmanen I: Genetic polymor- phism of catechol-O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and com- parison of the allele frequencies in the normal population and parkinsonian patients in Finland. Pharmacogenetics 1997; 7:

65–71

7. Herken H, Erdal ME: Catechol-O-methyltransferase gene poly- morphism in schizophrenia: evidence for association between symptomatology and prognosis. Psychiatr Genet 2001; 11:

105–109

8. Tunbridge E, Burnet PW, Sodhi MS, Harrison PJ: Catechol-O-me- thyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression. Synapse 2004; 51:

112–118

9. Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G, Goldberg R, Kucherlapati R, Papolos DF: Association of codon 108/158 catechol-O-methyltransferase gene poly- morphism with the psychiatric manifestations of velo-cardio- facial syndrome. Am J Med Genet 1996; 67:468–472

10. Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald- McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ: Effects of a functional COMT polymor- phism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry 2004; 161:1700–

1702

11. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK: Schizo- phrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995; 92:7612–

7616

12. 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

13. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR: Executive subpro- cesses in working memory: relationship to catechol-O-methyl- transferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60:889–896

14. 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 2002; 159:652–654