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Annotation

Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AL. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci . 2005 Nov 1 ; 8(11):1500-2. PubMed Abstract

Comments on Paper and Primary News
Primary News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 5 November 2005 Posted 5 November 2005

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


Primary News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Caterina Merendino
Submitted 5 November 2005 Posted 5 November 2005
  I recommend this paper

Comment by:  Jeffrey Lieberman, SRF Advisor
Submitted 6 November 2005 Posted 6 November 2005
  I recommend this paper

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


Primary News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Leboyer Marion
Submitted 6 November 2005 Posted 6 November 2005
  I recommend this paper

Primary News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Anne Bassett
Submitted 7 November 2005 Posted 7 November 2005
  I recommend this paper

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...  Read more


View all comments by Anne Bassett

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 14 November 2005 Posted 14 November 2005

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   Read more


View all comments by Daniel Weinberger

Comment by:  Doron GothelfAllan Reiss
Submitted 18 November 2005 Posted 18 November 2005

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...  Read more


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

Comment by:  Carrie Bearden
Submitted 21 November 2005 Posted 21 November 2005
  I recommend this paper

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...  Read more


View all comments by Carrie Bearden

Comment by:  Patricia Estani
Submitted 23 November 2005 Posted 23 November 2005
  I recommend this paper

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


Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 27 December 2005 Posted 27 December 2005
  I recommend this paper
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