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

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

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 Even in 22q11.2 deletion syndrome (22qDS), our group (unpublished) and Murphy et al.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

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

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

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

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

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary Reid

While some have expressed frustration over the lack of clear reproducibility of linkage and association findings in schizophrenia, the importance of the chromosome 22q11 deletion syndrome (22q11DS) as a real and significant genetic risk factor for schizophrenia has often been overlooked. While the deletion syndrome is present in a minority of individuals with schizophrenia (estimates of approximately 1 percent), presence of the deletion increases risk of developing schizophrenia some 30-fold, making this one of the clearest known genetic risk factors for a psychiatric illness. As multiple genes are deleted in 22q11DS, it can be a challenge to determine which gene or genes are involved in specific phenotypic elements of this syndrome.

The May 11, 2008, paper by Stark et al. highlights the utility of engineered animals for dissecting the individual effects of multiple genes within a deletion region and provides an important clue into the mechanism likely responsible for at least some of the behavioral aspects of the phenotype....  Read more

View all comments by Linda Brzustowicz

The common theory held until recently regarding the genetic underpinning of neuropsychiatric disorders was based on the “common disease-common variant” model. According to that theory, multiple common alleles in the population contribute small-to-moderate additive or multiplicative effects to the predisposition to neuropsychiatric disorders. With the advances in genetic screening technologies this theory is now being challenged. Recent findings indicate that rare copy number variations (CNVs) may account for a substantial fraction of the overall genetic risk for neuropsychiatric disorders including schizophrenia and autism (Consortium, 2008; Stefansson et al., 2008; Mefford et al., 2008). The 22q11.2 microdeletion was the most common CNV identified in patients with schizophrenia in a recent large scale study of patients with schizophrenia (Consortium, 2008). The 22q11.2 microdeletion is also...  Read more

View all comments by Doron Gothelf

The answer is unequivocally, “yes”
In co-highlighting the papers from Need et al., 2009, and Tomppo et al., 2009, you pose the question “CNV’s, interacting loci or both?” to which my immediate answer is an unequivocal “yes,” but it actually goes further than that. These two studies, interesting in their own rights, add just two more pieces of evidence now accumulated from case only, case-control, and family-based linkage on the genetic architecture of schizophrenia. Thus, we can reject with confidence a single evolutionary and genetic origin for schizophrenia. If it were so, it would have been found already by the plethora of genomewide studies now completed, studies specifically designed to detect causal variants, should they exist, which are both common to most if not all subjects and ancient in origin—the Common Disease, Common Variant (CDCV) hypothesis.

Moreover, for DISC1, NRG1, NRXN1, and a few others, the criteria for causality are met in some subjects, but none of these is the sole cause of schizophrenia. Their net contributions to individual and...  Read more

View all comments by David J. Porteous

The results reported by Tomppo et al. and Need et al. collectively instantiate the complexities of the genetic architecture underlying risk for psychiatric illness. Paradoxically, however, while the results of Need et al. suggest that the answer to the complex question of risk genes for schizophrenia (SZ) may be found by searching a very select population for rare changes in genetic sequence, the results of Tomppo et al. suggest that the answer may be found by searching for common variants in large heterogeneous populations. So which is it? Is SZ the result of rare, novel genetic mutations or an accumulation of common ones? Such a conundrum is not a novel predicament in the process of scientific inquiry and such conundrums are often resolved by the reconciliation of both opposing views. Thus, if we allow history to serve as our guide it seems reasonable that the answer to the current question of what genetic mechanisms are responsible for SZ, is that SZ is caused by both rare and common variants.

Although considerable efforts, by our lab and others, are currently being...  Read more

View all comments by Pamela DeRosse
View all comments by Anil Malhotra

Has anyone considered the possibility that the CNVs found to be elevated in schizophrenia versus controls could be a peripheral effect and perhaps not present in brain tissue? For example, the diet of the typical schizophrenia patient is poor, and it is conceivable that chronic folate deficiency could predispose to problems in DNA structure or repair in lymphocytes. Thus, the CNVs could be an effect of the illness, and not a cause. Someone needs to do the experiment that compares CNVs in blood to those in the brain of the same individual. And then we need studies of the stability of CNVs over the lifetime of an individual.

View all comments by James Kennedy

The papers by Need et al. and Tomppo et al. seem to present conflicting evidence for the involvement of common or rare variants in the etiology of schizophrenia.

On the one hand, Need et al., in a very large and well-powered sample, find no evidence for involvement of any common SNPs or CNVs. Importantly, they show that while any one SNP with a small effect and modest allelic frequency might be missed by their analysis, the likelihood that all such putative SNPs would be missed is vanishingly small. They come to the reasonable conclusion that common variants are unlikely to play a major role in the etiology of schizophrenia, except under a highly specific and implausible genetic model. Does this sound the death knell for the common variants, polygenic model of schizophrenia? Yes and no. These and other empirical data are consistent with theoretical analyses which show that the currently popular purely polygenic model, without some gene(s) of large effect, cannot explain familial risk patterns (Hemminki et al., 2007;   Read more

View all comments by Kevin J. Mitchell

If schizophrenia and autism are on a spectrum, how can there be people who are both autistic and schizophrenic? I know of a few people who suffer from both diseases.

View all comments by Katie Rodriguez

One Hundred Years of Insanity: The Relationship Between Schizophrenia and Autism
The great Colombian author Gabriel García Márquez reified the cyclical nature of history in his Nobel Prize-winning 1967 book, One Hundred Years of Solitude. Eugen Bleuler’s less-famous book Dementia Præcox or the Group of Schizophrenias, originally published in 1911, saw first use of the term “autism,” a form of solitude manifest as withdrawal from reality in schizophrenia. This neologism, about to celebrate its centenary, epitomizes an astonishing cycle of reification and change in nosology, a cycle only now coming into clear view as molecular-genetic data confront the traditional, age-old categories of psychiatric classification.

The term autism was, of course, redefined by Leo Kanner (1943) for a childhood psychiatric condition first considered as a subset of schizophrenia, then regarded as quite distinct (Rutter, 1972) or even opposite to it (Rimland, 1964; Crespi and Badcock, 2008), and most recently seen by some researchers as returning to its original...  Read more

View all comments by Bernard Crespi

The Diametric Opposition of Autism and Psychosis: Support From a Study of Cognition
As has been noted previously, Crespi and Badcock’s (2008) theory that autism and schizophrenia are diametrically opposed disorders is certainly a novel and somewhat controversial one. In his recent blog on Psychology Today, Badcock states that the theory stands on two completely different foundations: one in evolution and genetics, and one in psychiatry and cognitive science (Badcock, 2010). While most of the comments posted before ours have addressed the relationship between autism and schizophrenia from a genetic perspective, coming from a psychology background, we note that it is the aspects of Crespi and Badcock’s theory that relate to cognition which have particularly caught our attention. While we can therefore contribute little to the discussion of a relationship between autism and schizophrenia...  Read more

View all comments by Suzanna Russell-Smith
View all comments by Donna Bayliss
View all comments by Murray Maybery