The fact that the PRODH alteration studied in Gogos et al. leads to alterations in glutamate release, and this corresponds to deficits in associative learning and response to psychotomimetics, provides a nice parallel to the human condition. The Reiss paper examines humans with the 22q11.2 deletion, and shows that the COMT low-activity allele of this deletion syndrome correlates with cognitive decline, PFC volume, and development of psychotic symptoms. This is a nice addition to the Weinberger and Bilder papers about how COMT can lead to psychosis vulnerability.

View all comments by Anthony Grace

  I recommend the Primary Papers

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Isn't the association of the low-activity COMT allele with development of psychotic symptoms in the paper by Gothelf et al. inconsistent with the finding of Egan et al. and subsequent replications? The latter's findings of decreased cortical information processing efficiency and vulnerability to schizophrenia was with the high-activity allele. How is this apparent inconsistency in the 22q11.2 deletion subjects reconciled?

View all comments by Jeffrey Lieberman

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I echo Jeff Lieberman's comment regarding previous reports of a weak association between the Val COMT functional allele and schizophrenia. Notably, the most recent meta-analysis (Munafo et al., 2005) shows no significant association. Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al. (1999) have reported that there is no association between COMT genotype and schizophrenia, and Bearden et al. reported that Val-hemizygous patients performed significantly worse than Met-hemizygous patients on executive cognition ( 2004) and childhood behavioral problems (2005). Though important as an initial prospective study, there is a risk in the Gothelf et al. small sample size and multiple testing for type 1 errors. Certainly, there is little evidence, even in 22qDS, for COMT (or PRODH) as “key” risk factors for schizophrenia. There may be some evidence for small effects on cognitive or other measures. Regardless, there is not “extreme deficiency” in COMT activity in the many individuals with Met-hemizygosity in 22qDS, or Met-Met homozygosity in the general population.

Regarding the news item, there are a few widely held misconceptions about 22qDS. Our recent article (Bassett et al., 2005) shows that, accounting for ascertainment bias, the rate of schizophrenia was 23 percent, and congenital heart defects was 26 percent. Of the other 41 common lifetime features of 22qDS (found in 5 percent or more patients), neuromuscular palatal anomalies were common but overt cleft palate was so rare it did not meet inclusion criteria; intellectual disabilities ranged from severe mental retardation (rare) to average intellect (rare) with most patients falling in the borderline range of intellect; and on average, patients had nine of 43 common features. We propose clinical practice guidelines for adults with 22qDS which may be directly applicable to the 1-2 percent of patients with a 22qDS form of schizophrenia.

References:
Bassett AS, Chow EWC, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A. 2005 Nov 1;138(4):307-13. Abstract

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 polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry . 2004 Sep;161(9):1700-2. Abstract

Bearden CE, Jawad AF, Lynch DR, Monterossso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Feb;11(1):109-17. Abstract

Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005 Aug;10(8):765-70. Abstract

Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct 1;56(10):940-5. Abstract

View all comments by Anne Bassett

Drs. Lieberman and Basset raise an important question about why the met allele in the VCFS early adult cases is associated with cognitive decline and risk for psychosis, while the val allele tends to be associated with both characteristics when there is a positive association to COMT in adult subjects. I believe that the data of Gothelf and colleagues are entirely consistent with predictions about what would be expected in VCFS based on evidence that dopamine signaling in prefrontal cortex relates to prefrontal function as an inverted U-shaped dose-response curve. Too little dopamine, as might be seen in normal aging, in Parkinson's disease and possibly in schizophrenia, is associated with relatively abnormal prefrontal function, and too much dopamine, as might be seen in amphetamine or other acute psychotic states, also is associated with relatively abnormal prefrontal function. Landmark experiments from the laboratory of the late Patricia Goldman-Rakic at Yale demonstrated this in the monkey, and Mattay et al., 2003 showed similar effects in normal human beings.

In the study of Gothelf et al., in late childhood, val hemizygous individuals with VCFS were more impaired on cognitive testing compared to met hemizygous individuals (consistent with other VCFS studies of children), but the reverse relationships emerged later in adolescence. What explains this? The evidence that dopaminergic innervation of the primate prefrontal cortex increases during adolescence is well established (e.g., Lambe et al., 2000), and this developmental enhancement of cortical dopaminergic activity would be expected to move everyone further to the right on the inverted U-shaped dopamine cortical response curve.

What would this mean for individuals hemizygous for COMT? As dopamine activity goes up, val individuals are rescued by being hemizygous, because their normally increased COMT activity (i.e., reduced synaptic DA) is compensated by the null COMT chromosome. In contrast, COMT met hemizygous individuals are compromised by having one low-activity COMT chromosome and one null activity chromosome, and pushed to the far downslope of the curve. The study of Gothelf et al. illustrates that the critical factor in genetic risk for abnormal brain function is the biologic state of the gene, not necessarily a particular allele or haplotype, and how this biologic state relates to the biologic context of the neural functions involved.

View all comments by Daniel Weinberger

Reply to comments by Lieberman and Bassett

I have just seen Dr. Weinberger's reply and our reply follows the same vein.

22q11.2DS subjects are unique in that they are hemizygous for the COMT gene, that is, have half the dosage of the gene and are thus different from the general population and from non-22q11.2DS schizophrenia patients. The model we think best integrates our "met" findings with the "val" findings in non-22q11.2DS schizophrenia is that of the hypothetical inverted U-shape relationship between prefrontal dopamine levels and cognitive functioning/neuropsychiatric risk. Too much dopamine, as presumably occurs in the prefrontal cortex of the 22q11.2DS "met" subgroup, or too little prefrontal dopamine, as presumably occurs in the general schizophrenia population, puts subjects outside the “optimal” dopamine range and in a less favorable state in terms of cognitive functioning and risk for psychosis. As Dr. Bassett noted, there are indeed studies that found higher cognitive performance in 22q11.DS children with the "val" as compared to "met." In our study, the same trend was evident when we looked only at Time-1 evaluations conducted during childhood. However, during adolescence, those with "met" had a more robust decline in VIQ and expressive language. Thus, it was the longitudinal follow-up of subjects during adolescence that enabled us to identify this intriguing developmental trend.

Dr. Bassett suggests that 22q11.2DS met subjects are not in extreme deficiency of COMT enzyme activity. There is no definite information about this because there are no measures of enzyme activity in this population. However, in the COMT knockout model published by Gogos et al. (1998), a 100-200 percent increase in prefrontal dopamine was measured in males, and this was accompanied by aggressive behavior. We think that the state of the COMT knockout mouse may resemble that of 22q11.2DS as these subjects are “knocked-out” of the COMT gene by virtue their deletion in this region. As to Dr. Bassett’s remark about sample size, we strongly ascribe to the principle that “more is better,” particularly in genetic association studies where samples tend to be biologically heterogeneous and where the variance of key measures is often relatively large. However, in contrast to the study of persons with phenomenologically (i.e., DSM-IV) defined “schizophrenia,” our investigation focuses on a group where a specific genetic risk factor for schizophrenia can be identified (22q11.2DS), and is shared amongst affected individuals. Thus, relative to a DSM-IV defined sample, a 22q11.2DS group would be likely to demonstrate less variance in key cognitive, neuropsychiatric, and biological measures, with smaller sample size requirements for demonstrating effects of interest. Accordingly, we believe that 22q11.2DS is a powerful model from which to discern genetic and pathophysiological mechanisms associated with schizophrenia.

In our longitudinal study, the met allele was robustly associated with three pivotal phenotypic features of schizophrenia: 1) emergence of psychotic symptoms, 2) decline in cognitive abilities, and 3) reduction in prefrontal gray matter volumes. Each of these phenotypic features has been linked with dopamine dysregulation. Thus, it is logical to presume that a unique hyperdopaminergic state, induced by severe deficiency of COMT activity in 22s11.2DS, would trigger a series of pathophysiological events that increase risk for schizophrenia. We believe that the likelihood of a type 1 error in our study is greatly reduced by the homogeneity of our sample (with respect to shared “risk” for psychosis), the consistency of our findings across core phenotypic features of schizophrenia, and the consistency of our findings within a rigorous neurobiological framework. Of course, we agree that replication should be tested in larger, independent samples of subjects, including those with different ethnicities.

View all comments by Doron Gothelf
View all comments by Allan Reiss

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Gothelf and colleagues present a novel study (the first longitudinal investigation of psychopathology, cognition, and brain volume in adolescents with 22q11.2 deletions) with a very interesting result. As they correctly assert in their manuscript, their baseline finding of a trend toward better cognitive function in the COMT H (Val) subgroup is consistent with our previous finding of a tendency toward higher full-scale IQ in Val-hemizygous patients with 22q11.2 deletions versus 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; Bearden et al., 2004). Despite this, as Dr. Bassett described above, we also found that Met-hemizygous patients performed significantly better than Val-hemizygous patients on measures of executive function (specifically Digit Span and Trailmaking B), after controlling for overall effects of IQ. In addition, we found that Val genotype was associated with a greater-than-fourfold increase in risk for clinically significant behavior problems, as measured by the Child Behavior Checklist (CBCL), in 38 children (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions. While inconsistent with the findings of Gothelf et al. of increased rates of schizophrenia in 22q11.2DS patients with the low-activity (Met) allele, our data are nonetheless consistent with previous findings of increased psychopathology associated with the Val genotype in normal adults. Clearly, this is a complicated story, though, and much of the puzzle still awaits to be solved, as at least two published studies (Baker et al., 2005; Murphy et al., 1999) have found no association between COMT genotype and psychopathology in 22q11.2DS. Thus, it is not clear whether COMT genotype in the intact chromosome in patients with 22q11.2 deletion syndrome has a similar influence on executive cognition and psychiatric symptoms to that observed in other populations.

While intriguing, several questions remain regarding the findings presented in Gothelf et al. First, what is the mechanism by which one would predict that COMT would cause verbal IQ and prefrontal volume decline over time in 22q11DS patients with the low-activity (Met) allele? Dr. Weinberger eloquently elaborates on the idea of the hypothetical U-shaped dose-response curve, in which relatively abnormal prefrontal function may be seen at both ends of the curve. However, if developmental enhancement of cortical dopaminergic activity does indeed move everyone further to the right on the inverted U-shaped dopamine cortical response curve, I am not sure this explains why cognitive performance (and prefrontal cortical volume) would remain stable in the Val-hemizygotes over time.

In addition, it is not clear whether Gothelf and colleagues mean to suggest that somehow COMT exerts independent effects on cognition and psychotic symptoms (as implied by their statement that VIQ decline precedes development of psychosis). Clearly, further study would be needed in order to address that question.

The finding of concomitant declines in verbal IQ and expressive language are quite unusual, as these measures of crystallized knowledge/verbal abilities are highly unlikely to truly decompensate over time—it is not clear that the decline over time observed in both cognition (on VIQ and CELF-E scores) and prefrontal volume is not entirely accounted for by the greater rate of development of psychotic disorder in the Met allele subgroup. I assume that the significantly higher BPRS scores at follow-up for the Met patients would correspond to this (although data regarding rates of psychotic disorder in low- versus high-activity COMT subgroups were not specifically reported). While this in itself would not detract from the importance of the finding, it seems that acute psychiatric symptomatology may be the best explanation for the IQ/cognitive decline witnessed in the 22q11 L group. This type of decline on such highly stable measures is quite atypical except under unusual circumstances, and is rare even in typical young adult patients who develop psychotic illness (e.g., Kurtz, 2005).

Finally, I am curious as to the reason that the authors would a priori hypothesize that verbal IQ and expressive language (CELF-E) would be associated with COMT genotype, and not the complementary measures (performance IQ and receptive language; CELF-R), which most likely also were administered at the same time.

Nevertheless, this study represents a very important step toward a better understanding of the effects of specific genetic influences on human cognition, and pathophysiological mechanisms associated with the development of psychosis.

References:
Baker K, Baldeweg T, Sivagnanasundaram S, Scambler P, Skuse D. COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11deletion syndrome. Biol Psychiatry. 2005 Jul 1;58(1):23-31. Abstract

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 polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry . 2004 Sep;161(9):1700-2. Abstract

Bearden CE, Jawad AF, Lynch DR, Monterosso JR, Sokol S, McDonald-McGinn DM, Saitta SC, Harris SE, Moss E, Wang PP, Zackai E, Emanuel BS, Simon TJ. Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome. Neuropsychol Dev Cogn C Child Neuropsychol. 2005 Feb;11(1):109-17. Abstract

Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res. 2005 74(1):15-26. Abstract

Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct 1;56(10):940-5. Abstract

View all comments by Carrie Bearden

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I agree with the comments of Dr. Weinberger about the COMT gene and schizophrenia. This relationships is consistent with the data of Gothelf et al. More experiments must be carried out to separate these variables.

View all comments by Patricia Estani

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