Schizophrenia Research Forum - A Catalyst for Creative Thinking

Chromosome 22 Link to Schizophrenia Strengthened

4 November 2005. There is now overwhelming evidence that genetic inheritance plays a major role in susceptibility to schizophrenia. And though no schizophrenia genes have yet been confirmed, there are plenty of candidates. Multiple lines of evidence, for example, suggest that a region in the small arm of chromosome 22 (22q11.2) might confer susceptibility to the disease. Two recent Nature Neuroscience papers bolster that connection.

The link between schizophrenia and chromosome 22q11.2 is particularly interesting because that segment of DNA harbors genes for two enzymes that can influence neurotransmission—catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH). COMT, of course, is crucial for dopamine metabolism, so any genetic variance that alters the activity of this enzyme could tip the balance toward too much, or too little, of this neurotransmitter. The PRODH link is less obvious, but again, loss or reduction of PRODH activity could lead to an increase in the level of proline, and it was recently shown that this amino acid accumulates in glutamatergic synapses where it probably modulates glutamate transmission (see, for example, Renick et al., 1999). Now, together, the two papers add weight to the COMT/PRODH link.

Allan Reiss and colleagues at Stanford University, California, together with collaborators at Tel Aviv University, Israel; the University of Geneva, Switzerland; and the University of Washington, Seattle, report on a study of adolescents with 22q11.2 deletion syndrome. The disorder is often referred to as velocardiofacial syndrome (VCFS), a term that encompasses some of the most common early childhood manifestations such as cleft palate, heart defects, characteristic facial appearance, minor learning problems, and speech and feeding problems. The constellation of some 30 different identifying features, not all of which appear in any given child, are traceable to the deletion of that region of chromosome 22. About one third of all babies born with these deletions will go on to later develop schizophrenia (see, for example, Murphy et al., 1999).

First author Doron Gothelf and colleagues considered whether polymorphisms, or variations, in the undeleted copy of COMT may help to explain why some with the 22q11.2 deletion will develop schizophrenia, while others do not. They followed patients known to have the deletion, correlating the emergence of the disease with a known single nucleotide polymorphism—one that results in a methionine amino acid instead of a valine at position 158 and that ablates about one third of the enzyme’s activity.

Gothelf and colleagues tested 24 patients with 22q11.2 deletion syndrome. During childhood, none showed evidence of a psychotic disorder, but in early adulthood, seven did. The authors found that the COMT variant with low enzyme activity (COMTL) correlated with lower verbal IQ and language skills and lower prefrontal cortex volume in these seven adolescents. The results suggest that “extreme deficiency in COMT activity, as present in the COMTL subjects with 22q11.2DS, is an important neurodevelopmental risk factor for decline in PFC [prefrontal cortex] volume and cognition and for the emergence of psychotic symptoms during adolescence,” write the authors.

In the second paper, Maria Karayiorgou's group at Rockefeller University, New York, and Joseph Gogos's group at Columbia University, New York, collaborated to model the effect of altering the expression of PRODH. First author Marta Paterlini and colleagues found that in mice, loss of the enzyme leads to increases in neuronal proline and that this, in turn, increases the probability that glutamate will be released into synapses in the hippocampus. In addition, the authors discovered that synaptic plasticity, as defined by the ability of neurons to modulate their activity in response to the activity of other nearby neurons, is compromised. They found, for example, that both paired-pulse facilitation and long-term potentiation, two commonly used measures of plasticity, were inhibited. The authors also found that loss of PRODH and increases in proline were accompanied by behavioral changes—the mice were generally less active, exploring about 25 percent less than normal mice, and they reacted less frequently in conditioned responses to stimuli such as mild shock. The animals also had a poorer response to psychotomimetic drugs, such as MK801, which increase glutamate release (this could be because the PRODH-deficiency already causes more release of glutamate than normal), but when given amphetamine, locomotor activity increased almost twofold more than in normal animals. “This is reminiscent of the increased susceptibility to the disorganizing effects of D-amphetamine observed in individuals with schizophrenia,” note the authors.

Gothelf and colleagues, in their 22q11.2 deletion paper, emphasize that many other genes in the vicinity of COMT and PRODH should be evaluated, and Paterlini and colleagues do just this, using a transcriptional profiling method to evaluate what genes may be turned on or off by the loss of PRODH in their animal model. And one of the genes that interacts most strongly with PRODH was none other than COMT, which was upregulated in the prefrontal cortex of the PRODH-deficient animals. This not only buttresses the argument for COMT and PRODH as key risk factors for schizophrenia, but also suggests that the two genes may interact.—Tom Fagan.

References:
Paterlini M, Zakharenko SS, Lai W-S, Qin J, Zhang H, Mukai J, Westphal KGC, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005 Nov;8(11):1586-1594. Epub 2005 Oct 23. Abstract

Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Einstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AI. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. Abstract

Comments on News and Primary Papers
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 GraceComment by:  Caterina Merendino
Submitted 5 November 2005
Posted 5 November 2005
  I recommend the Primary Papers

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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 LiebermanComment by:  Leboyer Marion
Submitted 6 November 2005
Posted 6 November 2005
  I recommend the Primary PapersComment by:  Anne Bassett
Submitted 7 November 2005
Posted 7 November 2005
  I recommend the Primary Papers

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

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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 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

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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 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

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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 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

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

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

Comments on Related News


Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Mary Reid
Submitted 28 September 2006
Posted 29 September 2006

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

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Patricia Estani
Submitted 5 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

Related News: 22q11 and Schizophrenia: New Role for microRNAs and More

Comment by:  Linda Brzustowicz
Submitted 21 May 2008
Posted 21 May 2008

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. While some may argue about the full validity of animal models of complex human behavior disorders, these systems do have an advantage in manipulability that cannot be achieved in work with human subjects. A key feature of this paper is the comparison of the phenotype of mice engineered to contain a 1.3 Mb deletion of 27 genes with mice engineered to contain a disruption of only one gene in the region, DGCR8. The ability to place both of these alterations on the same genetic background and then do head-to-head comparisons on a number of behavioral, neuropathological, and gene expression assays allows a clear assessment of which components of the mouse phenotype may be attributed specifically to DGCR8 haploinsufficiency. Perhaps not surprisingly, DGCR8 seems to play a role in some, but not all, of the behavioral and neuropathological changes seen in the animals with the 1.3 Mb deletion. The fact that the DGCR8 disruption was able to recapitulate certain elements of the full deletion in the mice does raise its profile as an important candidate gene for some of the neurocognitive elements of 22q11DS, and makes it a potential candidate gene for contributing to schizophrenia risk in individuals without 22q11DS.

Also of great interest is the known function of DGCR8. While the gene name simply stands for DiGeorge syndrome Critical Region gene 8, it is now known that this gene plays an important role in the biogenesis of microRNAs, small non-coding RNAs that regulate gene expression by targeting mRNAs for translational repression or degradation. As miRNAs have been predicted to regulate over 90 percent of genes in the human genome (Miranda et al., 2006), a disruption in a key miRNA processing step could have profound regulatory impacts. Indeed, as reported in the Stark et al. paper and elsewhere (Wang et al., 2007), homozygous deletion of DGCR8 function is lethal in mice. What perhaps seems to be the most surprising result is that haploinsufficiency of DGCR8 function does not induce a more profound phenotype, given the large number of genes that would be expected to be affected if miRNA processing were globally impaired. The Stark et al. paper determined that while the pre-processed form of miRNAs may be elevated in haploinsufficient mice, perhaps only 10-20 percent of all mature miRNAs show altered levels, suggesting that some type of compensatory mechanism may be involved in regulating the final levels of the other miRNAs. Still, the 20-70 percent decrease in the abundance of these altered miRNAs could have a profound effect on multiple cellular processes, given the regulatory nature of miRNAs. In the context of the recent evidence for altered levels of some miRNA in postmortem samples from individuals with schizophrenia (Perkins et al., 2007), the Stark et al. paper adds further support for studying miRNAs as potential candidate genes in all individuals with schizophrenia, not just those with 22q11DS. This paper should serve as an important reminder of how careful analysis of a biological subtype of a disorder can reveal important insights that will be relevant to a much broader set of affected individuals.

References:

1. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 May 11; Abstract

2. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006 Sep 22;126(6):1203-17. Abstract

3. Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet. 2007 Mar 1;39(3):380-5. Abstract

4. Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J, Hammond SM. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 2007 Jan 1;8(2):R27. Abstract

View all comments by Linda Brzustowicz

Related News: Are Membrane Molecules Unmoored in 22q11DS Mouse?

Comment by:  Doron Gothelf
Submitted 27 October 2008
Posted 27 October 2008

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 the most common microdeletion occurring in humans and up to one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia by adulthood. Thus the syndrome serves as an important model from which to learn the path leading from a well defined genetic defect to brain development and eventually to the evolution of schizophrenia.

It is still uncertain whether the neuropsychiatric phenotype associated with 22q11.2DS is a result of a strong effect of haploinsufficiency of one or a few genes from the microdeletion region as some studies suggested (Gothelf et al., 2005; Paterlini et al., 2005; Raux et al., 2007; Vorstman et al., 2008), or the result of cumulative small effects of haploinsufficiency of multiple genes, each contributing a small effect, as other studies suggested (Maynard et al., 2003; Meechan et al., 2006).

The current very elegant study by Mukai and colleagues suggests that haploinsufficiency of a single gene from the 22q11.2 deleted region, Zdhhc8, is responsible for the microscopic neural hippocampal abnormalities present in a mouse model of the disease. Remarkably, these abnormalities were prevented with the reintroduction of enzymatically active ZDHHC8 protein. The works of Gogos and his colleagues (Paterlini et al., 2005; Stark et al., 2008) are consistently and brilliantly getting us closer to revealing the complex association between genes from the 22q11.2 region and the neuropsychiatric phenotype. If indeed haploinsuffiency of single genes like Zdhhc8, COMT, or Dgcr8 have a strong effect on abnormal brain development and the eruption of schizophrenia, it conveys an enormous potential for developing novel pathophysiologically based treatments for this refractory disease. Such treatments will target the enzymatic deficit conveyed by the genetic mutation.

References:

[No authors listed]. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Sep 11;455(7210):237-41. Abstract

Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Sep 11;455(7210):232-6. Abstract

Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008 Oct 16;359(16):1685-99. Abstract

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. Abstract

Paterlini M, Zakharenko SS, Lai WS, Qin J, Zhang H, Mukai J, Westphal KG, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005 Nov 1;8(11):1586-94. Abstract

Raux G, Bumsel E, Hecketsweiler B, van Amelsvoort T, Zinkstok J, Manouvrier-Hanu S, Fantini C, Brévière GM, Di Rosa G, Pustorino G, Vogels A, Swillen A, Legallic S, Bou J, Opolczynski G, Drouin-Garraud V, Lemarchand M, Philip N, Gérard-Desplanches A, Carlier M, Philippe A, Nolen MC, Heron D, Sarda P, Lacombe D, Coizet C, Alembik Y, Layet V, Afenjar A, Hannequin D, Demily C, Petit M, Thibaut F, Frebourg T, Campion D. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome. Hum Mol Genet. 2007 Jan 1;16(1):83-91. Abstract

Vorstman JA, Chow EW, Ophoff RA, van Engeland H, Beemer FA, Kahn RS, Sinke RJ, Bassett AS. Association of the PIK4CA schizophrenia-susceptibility gene in adults with the 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 21; Abstract

Maynard TM, Haskell GT, Peters AZ, Sikich L, Lieberman JA, LaMantia AS. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8. Abstract

Meechan DW, Maynard TM, Wu Y, Gopalakrishna D, Lieberman JA, LaMantia AS. Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome. Mol Cell Neurosci. 2006 Dec 1;33(4):412-28. Abstract

Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008 Jun 1;40(6):751-60. Abstract

View all comments by Doron Gothelf

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  David J. Porteous, SRF Advisor
Submitted 11 February 2009
Posted 12 February 2009

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 population risk remain uncertain and await large scale resequencing as well as SNP and CNV studies to capture the totality of genetic variation and how that contributes to the incidence of major mental illness. Meanwhile, nosological and epidemiological evidence has also forced a re-evaluation of the categorical distinction between schizophrenia and bipolar disorder, let alone schizoaffective disorder (Lichtenstein et al., 2009).

In this regard, DISC1 serves again as an instructive paradigm, with good evidence for genetic association to schizophrenia, BP, schizoaffective disorder, and beyond (Chubb et al., 2008). The study by Hennah et al. (2008) added a further nuance to the DISC1 story by demonstrating intra-allelic interaction. Tomppo et al. (2009) now build upon their earlier evidence to show that DISC1 variants affect subcomponents of the psychiatric phenotype, treated now as a quantitative than a dichotomous trait. In much the same way and just as would be predicted, DISC1 variation also contributes to normal variation in human brain development and behavior (e.g., Callicott et al., 2005). Self-evidently, different classes of genetic variants (SNP or CNV, regulatory or coding) will have different biological and therefore psychiatric consequences (Porteous, 2008).

That Need et al. (2009) failed to replicate previous genomewide association studies (or find support for DISC1, NRG1, and the rest) is just further proof, if any were needed, that there is extensive genetic heterogeneity and that common variants of ancient origin are not major determinants of individual or population risk (Porteous, 2008). Variable penetrance, expressivity, and gene-gene interaction (epistasis) all need to be considered, but these intrinsic aspects of genetic influence are best addressed by family studies (currently lacking for CNV studies) and poorly addressed by large-scale case-control genomewide association studies. Power to test the CDCV hypothesis may increase with increasing numbers of subjects, but so does the inherent heterogeneity, both genetic and diagnostic.

That said, genetics is without doubt the most incisive tool we have to dissect the etiology of major mental illness. The criteria for success (and certainly for causality, rather than mere correlation) must be less about the number of noughts after the “p” and much more about the connection between candidate gene, gene variant, and the biological consequences for brain development and function. In this regard, both studies have something to say and offer.

References:

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. 2009 Lancet 373:234-9. Abstract

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. Mol Psychiatry. The DISC locus in psychiatric illness. 2008 Jan;13(1):36-64. Epub 2007 Oct 2. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA,Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. 2005 Proc Natl Acad Sci U S A. 2005 102:8627-32. Abstract

Porteous D. Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. 2008 Curr Opin Genet Dev. 18:229-34. Abstract

View all comments by David J. Porteous

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Pamela DeRosseAnil Malhotra (SRF Advisor)
Submitted 19 February 2009
Posted 22 February 2009

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 directed towards seeking the type of rare variants that Need et al. suggest may be responsible for risk for SZ, a less concerted effort is being directed towards parsing the effects of more specific, common genetic variations. To date, there are limited data seeking to elucidate the effects of previously identified risk variants for SZ on phenotypic variation within the diagnostic group. The data that are available, however, suggest that risk variants do influence phenotypic variation. Our work with DISC1, for example, has produced relatively robust, and replicated findings linking variation in the gene to cognitive dysfunction (Burdick et al., 2005) as well as an increased risk for persecutory delusions in SZ (DeRosse et al., 2007). Similarly, our work with DTNBP1 indicates a strong association between variants in the gene and both cognitive dysfunction (Burdick et al., 2006) and negative symptoms in SZ (DeRosse et al., 2006). Moreover, the risk for cognitive dysfunction associated with the DTNBP1 risk genotype was also observed in a sample of healthy individuals. Thus, it seems conceivable that genetic variation associated with phenotypic variation within a diagnostic group may also be associated with similar, sub-syndromal phenotypes in non-clinical samples.

The data reported by Tomppo et al. provide support for the utility of parsing the specific effects of genetic variants on phenotypic variation and extend this approach to populations with sub-syndromal psychiatric symptoms. Such an approach is attractive in that it allows us to study the effects of genotype on phenotype without the confound imposed by psychotropic medications. Although the current data linking genes to specific dimensions of psychiatric illness are provocative, the study groups utilized are comprised of patients undergoing varying degrees of pharmacological intervention. Thus, in these analyses quantitative assessment of psychosis is to some extent confounded by treatment history and response. By measuring lifetime history of symptoms, which for most patients includes substantial periods without effective medication, many studies (including our own) may partially overcome this limitation. Still, assessment of the relation between genetic variation and dimensions of psychosis in study groups not undergoing treatment with pharmacological agents would be a compelling source of confirmation for these preliminary findings.

Perhaps most importantly, the data reported by Tomppo et al. suggest that previously identified risk genes should not be marginalized but rather, should be studied in non-clinical samples to identity phenotypic variation that may be related to the signs and symptoms of psychiatric illness.

References:

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport. 2005; 16(12):1399-402. Abstract

Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM, Kucherlapati R, Malhotra AK. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet. 2006; 15(10):1563-8. Abstract

DeRosse P, Hodgkinson CA, Lencz T, Burdick KE, Kane JM, Goldman D, Malhotra AK. Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry. 2007; 61(10):1208-10. Abstract

DeRosse P, Funke B, Burdick KE, Lencz T, Ekholm JM, Kane JM, Kucherlapati R, Malhotra AK. Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry. 2006; 163(3):532-4. Abstract

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

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 25 February 2009
Posted 25 February 2009

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 L. Kennedy

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Kevin J. Mitchell
Submitted 2 March 2009
Posted 2 March 2009

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; Hemminki et al., 2008; Bodmer and Bonilla, 2008). It has been suggested that epistatic interactions may generate discontinuous risk from a continuous distribution of common alleles; however, while comparisons of risk in monozygotic and dizygotic twins are consistent with some contribution from epistasis, they are not consistent with the massive levels that would be required to rescue a purely polygenic mechanism, whether through a multiplicative or (biologically unrealistic) threshold model.

Thus, it seems most parsimonious to conclude that most cases of schizophrenia will involve a variant of large effect. As such variants are likely to be rapidly selected against, they are also likely to be quite rare. The findings of specific, gene-disrupting CNVs or mutations in individual genes in schizophrenia cases by Need et al. and numerous other groups support this idea. Excitingly, they also have highlighted specific molecules and biological pathways that provide molecular entry points to elucidate pathogenic mechanisms. The possible convergence on genes interacting with DISC1, including PCM1 and NDE1 in the current study, provides further support for the importance of this pathway, though, clearly, there may be many other ways to disrupt neural development or function that could lead to schizophrenia. (Conversely, it is becoming clearer that many of the putative causative mutations identified so far predispose to multiple psychiatric or neurological conditions.)

Despite the likely involvement of rare variants in most cases of schizophrenia, it remains possible that common alleles could have a modifying influence on risk—indeed, one early paper commonly cited as supporting a polygenic model for schizophrenia actually provided strong support for a model of a single gene of large effect and two to three modifiers (Risch, 1990). A rare variants/common modifiers model would be consistent with the body of literature on modifying genes in model organisms, where effects of genetic background on the phenotypic expression of particular mutations are quite common and can sometimes be large (Nadeau, 2001). Whether such genetic background effects would be mediated by common or rare variants is another question—there is certainly good reason to think that rare or even private mutations may make a larger contribution to phenotypic variance than previously suspected (Ng et al., 2008; Ji et al., 2008).

Nevertheless, common variants are also likely to be involved, and these effects might be detectable in large association studies, though they would be expected to be diluted across genotypes. This might explain inconsistent findings of association of common variants with disease state for various genes, including COMT, BDNF, and DISC1, for example. This issue has led some to look for association of variants in these genes with endophenotypes of schizophrenia in the general population—psychological or physiological traits that are heritable and affected by the symptoms of the disease, such as working memory, executive function, or, in the study by Tomppo et al., social interaction.

These approaches have tended to lead to statistically stronger and more consistent associations and are undoubtedly revealing genes and mechanisms contributing to normal variation in many psychological traits. How this relates to their potential involvement in disease etiology is far from clear, however. The implication of the endophenotype model is that the disorder itself emerges due to the combination of minor effects on multiple symptom parameters (Gottesman and Gould, 2003; Meyer-Lindenberg and Weinberger, 2006). An alternative interpretation is that these common variants may modify the phenotypic expression of some other rare variant, either due to their demonstrated effect on the psychological trait in question or through a more fundamental biochemical interaction, but that in the absence of such a variant of large effect, no combination of common alleles would lead to disease.

References:

Hemminki K, Försti A, Bermejo JL. The 'common disease-common variant' hypothesis and familial risks. PLoS ONE. 2008 Jun 18;3(6):e2504. Abstract

Hemminki K, Bermejo JL. Constraints for genetic association studies imposed by attributable fraction and familial risk. Carcinogenesis. 2007 Mar;28(3):648-56. Abstract

Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. Abstract

Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222-8. Abstract

Nadeau JH. Modifier genes in mice and humans. Nat Rev Genet. 2001 Mar;2(3):165-74. Abstract

Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC. Genetic variation in an individual human exome. PLoS Genet. 2008 Aug 15;4(8):e1000160. Abstract

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-9. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Abstract

Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006 Oct;7(10):818-27. Abstract

View all comments by Kevin J. Mitchell

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Katie Rodriguez
Submitted 7 November 2009
Posted 7 November 2009

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

Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Bernard Crespi
Submitted 12 November 2009
Posted 12 November 2009

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 Bluelerian incarnation (e.g., Carroll and Owen, 2009). An outstanding new paper by McCarthy et al. (2009), demonstrating that duplications of the CNV locus 16p11.2 are strongly associated with increased risk of schizophrenia, has brought this question to the forefront of psychiatric inquiry, because deletions of this same CNV are one of the most striking recently-characterized risk factors for autism. Additional CNVs, such as those at 1q21.1 and 22q11.21 have also been associated with autism and schizophrenia in one or more studies (e.g., Mefford et al., 2008; Crespi et al., 2009; Glessner et al., 2009), which has led some authors to infer that since an overlapping set of loci mediates risk of both conditions, autism and schizophrenia must be more similar than previously conceived (e.g., Carroll and Owen, 2009; Guilmatre et al., 2009). Similar considerations apply to several genes, such as CNTNAP2 and NRXN1, various disruptions of which have likewise been linked with both conditions (Iossifov et al., 2008; Kirov et al., 2008; Burbach and van der Zwaag, 2009).

So does this plethora of new molecular-genetic data imply that Blueler was indeed correct, if not prescient, that autism and schizophrenia are manifestations of similar disease processes? The answer may appear tantalizingly close, but will likely remain inaccessible without explicit consideration of alternative hypotheses and targeted tests of their differentiating predictions. This approach is simply Platt’s (1964) classic method of strong inference, which has propelled molecular biology so far and fast but left psychiatry largely by the wayside (Cannon, 2009). The alternative hypotheses in this case are clear: with regard to causation from specific genetic and genomic risk factors, autism and schizophrenia are either: 1) independent and discrete, 2) partially yet broadly overlapping, 3) subsumed with autism as a subset of schizophrenia, or 4) diametrically opposite, with normality in the centre. CNVs are especially useful for testing among such alternative hypotheses, because they naturally involve highly-penetrant perturbations in two opposite directions, due to deletions vs duplications of more or less the same genomic regions. Hypotheses 2), 3) and 4) thus predict that autism and schizophrenia should share CNV risk loci, but 2) and 3) predict specific rearrangements (deletions, duplications, or both) shared across both conditions; by contrast, hypothesis (4) predicts that, as highlighted by McCarthy et al. (2009), reciprocal CNVs at the same locus should mediate risk of autism versus schizophrenia. This general approach was pioneered by Craddock et al. (2005, 2009), in their discussion of explicit alternative hypotheses for the relationship between schizophrenia and bipolar disorder, which are now known to share a notable suite of risk alleles.

A key assumption that underlies tests of hypotheses for the relationship between autism and schizophrenia is accuracy of diagnoses. For schizophrenia, this is seldom at issue. However, diagnoses of autism, or autism spectrum disorders such as PDD-NOS, are normally made at an age well before the first manifestations of schizophrenia in adolescence or early adulthood, which generates a risk for false-positive diagnoses of premorbidity to schizophrenia as autism or autism spectrum (e.g., Eliez, 2007). The tendencies for males to exhibit worse premorbidity to schizophrenia than females (Sobin et al., 2001; Tandon et al., 2009), for CNVs to exert severe effects on diverse aspects of early neurodevelopment (Shinawi et al., 2009), and for schizophrenia of earlier onset to exhibit a higher male sex-ratio bias and a stronger tendency to be associated with CNVs rather than other causes (Remschmidt et al., 1994; Rapoport et al., 2009), all suggest a high risk for false-positive diagnoses of autistic spectrum conditions in individuals with these genomic risk factors (Feinstein and Singh, 2007; Reaven et al., 2008; Sugihara et al., 2008; Starling and Dossetor, 2009). Possible evidence of such risk comes from diagnoses of autism spectrum conditions in children with deletions at 15q11.2, 15q13.3, and 22q11.21, and duplications of 16p11.2, CNVs for which schizophrenia risk has been well established from studies of adults (Antshel et al., 2007; Stefansson et al., 2008; Weiss et al., 2008; Ben-Shachar et al., 2009; Doornbos et al., 2009; McCarthy et al., 2009). By contrast, autism-associated CNVs, such as deletions at 16p11.2 (Kumar et al., 2008), or duplications at 22q11.21 (Glessner et al., 2009; Crespi et al., 2009) have seldom also been reported in individuals diagnosed with schizophrenia, which suggests that false-positive diagnoses of schizophrenia as autism are uncommon.

Differentiating between a hypothesis of false-positive diagnoses of premorbidity to schizophrenia as autism, compared to a hypothesis of specific deletions or duplications shared between autism and schizophrenia, requires some combination of longitudinal studies, judicious use of endophenotypes, and adoption of relatively new diagnostic categories such as multiple complex developmental disorder (Sprong et al., 2008). Moreover, to the degree that such false positives are not uncommon, and autism and schizophrenia are underlain by diametric genetically based risk factors, inclusion of children premorbid for schizophrenia in studies on the genetic bases of autism will substantially dilute the probability of detecting significant results.

Ultimately, robust evaluation of alternative hypotheses for the relationship of autism with schizophrenia will require evidence from studies of common and rare SNP variants as well as CNVs, in-depth analyses of the neurodevelopmental and neuronal-function effects of different alterations to genes such as NRXN1, CNTNAP2, and SHANK3, and integrative data from diverse disciplines other than genetics, especially the neurosciences and psychology. Unless such interdisciplinary studies are deployed—in hypothesis-testing frameworks that use strong inference—we should expect to remain, as penned by García Márquez, in “permanent alternation between excitement and disappointment, doubt and revelation, to such an extreme that no one knows for certain where the limits of reality lay”—for yet another 100 years.

References
Antshel KM, Aneja A, Strunge L, Peebles J, Fremont WP, Stallone K, Abdulsabur N, Higgins AM, Shprintzen RJ, Kates WR. Autistic spectrum disorders in velo-cardio facial syndrome (22q11.2 deletion). J Autism Dev Disord. 2007 Oct;37(9):1776-86. Abstract

Ben-Shachar S, Lanpher B, German JR, Qasaymeh M, Potocki L, Nagamani SC, Franco LM, Malphrus A, Bottenfield GW, Spence JE, Amato S, Rousseau JA, Moghaddam B, Skinner C, Skinner SA, Bernes S, Armstrong N, Shinawi M, Stankiewicz P, Patel A, Cheung SW, Lupski JR, Beaudet AL, Sahoo T. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet. 2009 Jun;46(6):382-8. Abstract

Bleuler E. 1950. Dementia praecox or the group of schizophrenias. (Internat Univ Press, New York). (Translation from 1911 German original).

Burbach JP, van der Zwaag B. Contact in the genetics of autism and schizophrenia. Trends Neurosci. 2009 Feb;32(2):69-72. Abstract

Cannon TD. What is the role of theories in the study of schizophrenia? Schizophr Bull. 2009 May;35(3):563-7. Abstract

Carroll LS, Owen MJ. Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med. 2009 Oct 30;1(10):102. Abstract

Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005 May;186:364-6. Abstract

Craddock N, O'Donovan MC, Owen MJ. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses. Schizophr Bull. 2009 May;35(3):482-90. Abstract

Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci. 2008 Jun;31(3):241-61; discussion 261-320.

Crespi B, Stead P, Elliot M. Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci U S A. 2009 (in press).

Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC, Hilhorst-Hofstee Y, Hordijk R, Verbruggen KT, Kerstjens-Frederikse WS, van Essen T, Kok K, van Silfhout AT, Breuning M, van Ravenswaaij-Arts CM. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009 Mar-Jun;52(2-3):108-15. Abstract

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Related News: Genomic Studies Draw Autism and Schizophrenia Back Toward Each Other

Comment by:  Suzanna Russell-SmithDonna BaylissMurray Maybery
Submitted 9 February 2010
Posted 10 February 2010

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 from a genetic standpoint, we present the findings from our recent study (Russell-Smith et al., 2010), which provided the first test of Crespi and Badcock’s claim that autism and psychosis are at opposite ends of the cognitive spectrum.

In placing autism and psychosis at opposite ends of the cognitive spectrum, Crespi and Badcock (2008) propose that autistic and positive schizophrenia traits contrastingly affect preference for local versus global processing, with individuals with autism displaying a preference for local processing and individuals with positive schizophrenia displaying a preference for global processing. That is, these authors claim that while individuals with autism show a tendency to focus on detail or process features in their isolation, individuals with positive schizophrenia show a tendency to look at the bigger picture or process features as an integrated whole. Importantly, since Crespi and Badcock argue for a continuum stretching all the way from autism to psychosis, the same diametric pattern of cognition should be seen in individuals who display only mild variants of autistic and positive schizophrenia traits. This includes typical individuals who score highly on measures such as the Autism Spectrum Quotient (AQ; Baron-Cohen et al., 2001) and the Unusual Experiences subscale of the Oxford-Liverpool Inventory of Experiences (O-LIFE:UE; Mason et al., 2005). These are both reliable and commonly used measures which have been specifically designed to assess the levels of “autistic-like” traits and positive schizotypy traits in typical individuals. Since Crespi and Badcock actually argue their theory is best evaluated with reference to individuals with milder traits of autism and positive schizophrenia, it is with these populations that we investigated their claims.

A task often used to determine whether an individual has a preference for local over global processing is the Embedded Figures Test (EFT; Witkin et al., 1971), which requires individuals to detect hidden shapes within complex figures. As the test requires one to resist experiencing an integrated visual stimulus or gestalt in favor of seeing single elements, it is argued that a local processing style aids successful (i.e., faster) completion of this task (Bolte et al., 2007). Accordingly, from Crespi and Badcock’s (2008) theory, one would expect that relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should perform better on the EFT, while individuals with positive schizotypy traits should perform worse. To test this claim, our study obtained the AQ and O-LIFE:UE scores for 318 students completing psychology as part of a broader degree (e.g., a BSc or BA). Two pairs of groups (i.e., four groups in total), each consisting of 20 students, were then formed. One of these pairs consisted of High and Low AQ groups, which were selected such that they were separated substantially in their AQ scores but matched as closely as possible on their O-LIFE:UE scores. The other pair of groups, the High and Low O-LIFE:UE groups, were selected such that they were separated in their O-LIFE:UE scores, but matched as closely as possible on their AQ scores. The gender ratio was matched closely across the four groups.

To test the prediction that higher levels of autistic-like traits are associated with more skilled EFT performance, the High and Low AQ groups were compared in terms of their mean response time to accurately locate each of the embedded figures. Individuals in the High AQ group did display more skilled EFT performance than individuals in the Low AQ group, consistent with a greater preference for local over global processing in relation to higher levels of autistic-like traits (see also Almeida et al., 2010; Bolte and Poustka, 2007; Grinter et al., 2009; Grinter et al., 2009). We then compared EFT performance for the O-LIFE:UE groups to test the prediction that higher levels of positive schizotypy traits are associated with less skilled performance on this task. Consistent with a preference for global over local processing in relation to higher levels of positive schizotypy traits, individuals in the High O-LIFE:UE group displayed less skilled EFT performance than individuals in the Low O-LIFE:UE group. Therefore, results from both pairs of groups together provide support for Crespi and Badcock’s (2008) claim that autistic and positive schizophrenia traits are diametrically opposed with regard to their effect on local versus global processing.

However, the support our study offers for Crespi and Badcock’s (2008) theory was tempered slightly by our failure to find the expected contrasting patterns of non-verbal relative to verbal ability for our two pairs of groups. To display the expected patterns, relative to individuals with low levels of these traits, individuals with high levels of autistic-like traits should have displayed higher non-verbal ability relative to verbal ability, whereas individuals with high levels of positive schizotypy traits should have displayed lower non-verbal relative to verbal ability. While visual inspection of mean verbal and non-verbal scores for the O-LIFE:UE groups revealed a trend consistent with what would be expected based on Crespi and Badcock’s theory, none of the group differences was statistically significant. However, as we pointed out in our article, a study which offers a more complete assessment of this aspect of the theory is warranted. In particular, since the use of a student sample in our study no doubt led to a restriction in the range of IQ scores (especially with reference to verbal IQ), a test of community-based samples would be useful.

Therefore, while Crespi and Badcock’s (2008) theory has passed its first major test at the level of cognition, with our results indicating a contrasting effect of autistic-like and positive schizotypy traits with regard to preference for local versus global processing, further investigation of these authors’ theory at both the cognitive and genetic levels is required.

References:

Almeida, R., Dickinson, J., Maybery, M., Badcock, J., Badcock, D. A new step toward understanding Embedded Figures Test performance in the autism spectrum: The radial frequency search task. Neuropsychologia. 2010 Jan;48(2):374-81. Abstract

Badcock, C. (2010). Diametric cognition passes its first lab test. Psychology Today. Retrieved February 8, from http://www.psychologytoday.com/blog/the-imprinted-brain/201002/diametric-cognition-passes-its-first-lab-test.

Baron-Cohen, S., Wheelwright, S., Skinner, R., Martin, J., Clubley, E. (2001). The Autism-Spectrum Quotient (AQ): Evidence from Asperger Syndrome/High-Functioning Autism, males and females, scientists and mathematicians. Journal of Autism and Developmental Disorders, 31, 5-17. Abstract

Bolte, S., Holtmann, M., Poustka, F., Scheurich, A., Schmidt, L. (2007). Gestalt perception and local-global processing in High-Functioning Autism. Journal of Autism and Developmental Disorders, 37, 1493-1504. Abstract

Bolte, S., Poustka, F. (2006). The broader cognitive phenotype of autism in parents: How specific is the tendency for local processing and executive function. Journal of Child Psychology and Psychiatry, 47, 639-645. Abstract

Crespi, B., Badcock, C. (2008). Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences, 31, 241-261. Abstract

Grinter, E., Maybery, M., Van Beek, P., Pellicano, E., Badcock, J., Badcock, D. (2009). Global visual processing and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 1278-1290. Abstract

Grinter, E., Van Beek, P., Maybery, M., Badcock, D. (2009). Brief Report: Visuospatial analysis and self-rated autistic-like traits. Journal of Autism and Developmental Disorders, 39, 670–677. Abstract

Mason, O., Linney, Y., Claridge, G. (2005). Short scales for measuring schizotypy. Schizophrenia Research, 78, 293-296. Abstract

Russell-Smith, S., Maybery, M., Bayliss, D. Are the autism and positive schizotypy spectra diametrically opposed in local versus global processing? Journal of Autism and Developmental Disorders. 2010 Jan 28. Abstract

Witkin, H., Oltman, P., Raskin, E., Karp, S. (1971). A manual for the Embedded Figures Test. Palo Alto, CA: Consulting Psychologists Press.

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Related News: Protection From Schizophrenia—Too Much 22q11.2 Is a Good Thing

Comment by:  Bernard Crespi
Submitted 27 November 2013
Posted 27 November 2013
  I recommend the Primary Papers

Reciprocal CNVs at 22q11.2: New Insights Into Protection Versus Risk for Neurodevelopmental Disorders

The discovery of factors that protect against schizophrenia has immediate and important implications for prevention and treatment of this condition, as well as providing useful insights into the relationship of schizophrenia with other disorders. The recent finding that duplications of the 22q11.2 chromosome region protect against schizophrenia (Rees et al., 2013) provides an outstanding case in point, because the reciprocal deletion of this region represents one of the most highly penetrant and well-documented causes of schizophrenia uncovered to date. Of particular interest with regard to deletions and duplications of 22q11.2 is that, whereas deletions are strongly associated with schizophrenia risk, duplications of 22q11.2 not only protect against schizophrenia, but also increase risk for autism (Crespi et al., 2010; Sanders et al., 2011; Crespi and Crofts, 2012; Rees et al., 2013).

Comparable findings have been reported for 16p11.2: Whereas a 0.6 Mb deletion in this chromosomal region is strongly associated with risk of autism (Sanders et al., 2011), the reciprocal duplication is strongly associated with risk of schizophrenia (McCarthy et al., 2009). For both of these loci, the schizophrenia-associated CNV has also been linked with ASD, but these findings remain controversial because relatively severe premorbidity to schizophrenia may present as ASD in childhood, such that these autism spectrum diagnoses could represent false positives (Eliez, 2007; Crespi et al., 2010; Crespi and Crofts, 2012; Angkustsiri et al., 2013; Karayiorgou, 2013).

Why, then, should reciprocal CNVs predispose to autism on one hand, but schizophrenia on the other? Why should an autism risk factor protect against schizophrenia? And most importantly, how can these findings help to guide future research on these conditions?

The simplest explanation for why autism and schizophrenia may be mediated by reciprocal CNVs is that they represent, in some sense, "reciprocal" or "diametric" disorders (Crespi and Badcock, 2008). The idea of diametric disorders is novel to psychiatry, but it represents a straightforward application of the concept that biological systems may generally be perturbed in two opposite directions, towards, for example, lower versus higher levels of some gene product, lower versus higher activation of some pathway, or smaller versus larger size for a given structure. Here, the "system" is neurological and social-behavioral development. In this context, autism involves, in part, underdeveloped social cognition and behavior (Lai et al., 2013). By contrast, schizophrenia, and related psychotic-affective conditions, involve, in part, "hyper-developed" social cognition and behavior, expressed in such exaggerated social phenotypes as paranoia, auditory hallucinations, mania, megalomania, high levels of guilt and shame, and dysregulated, chaotic speech and language (Frith, 2004; Crespi and Badcock, 2008).

This diametric model will remain overly simplistic, and contentious, until its neurodevelopmental basis has been better elucidated and evaluated. However, it provides a straightforward hypothesis that, on face value, provides the clearest account to date for the observed psychiatric effects of these reciprocal CNVs. Directly comparable reciprocal risk and protective factors have also been reported for X chromosome dosage effects: Klinefelter syndrome (usually XXY) involves increased risk of schizophrenia and schizotypy (DeLisi et al., 2005; van Rijn et al., 2006), but Turner syndrome (XO) involves increased risk of autism but decreased risk of schizophrenia and bipolar disorder (Mors et al., 2001; Knickmeyer and Davenport, 2011).

The primary usefulness of the diametric model for autism spectrum and psychotic-affective conditions is that it makes novel, specific, and testable predictions regarding causes, protective factors, and potential therapies for both autism and schizophrenia. Such predictions are valuable because they allow for reciprocal illumination of the causes, correlates, and treatments of both sets of disorders, whose study has proceeded virtually independently for many decades.

Consider as examples:

1. Prenatal valproate represents a well-validated model for autism (Rinaldi et al., 2007), but in adulthood valproate serves as a therapeutic treatment for some psychotic-affective conditions (Haddad et al., 2009).

2. One of the best validated factors protecting against schizophrenia is congenital blindness (Landgraf and Osterheider, 2013; Silverstein et al., 2012); by contrast, congenital blindness represents a well-studied risk factor for autism (Hobson and Bishop, 2003).

3. mGluR5 antagonists represent one of the most promising new treatments for the autistic syndrome fragile X (Gürkan and Hagerman, 2012; Pop et al., 2013); by contrast, quite independently, mGluR5 agonists are under development and trials as treatment for schizophrenia (Lindsley and Stauffer, 2013).

4. Agonists of nicotinic acetylcholine receptors, the receptors that individuals with schizophrenia self-stimulate via their extraordinarily high rates of cigarette smoking (Mobascher and Winterer, 2008), are being developed and tested for schizophrenia (Deutsch et al., 2013). Again quite independently, antagonists of the same receptor have been proposed as therapeutic agents for autism, based on a variety of evidence including low rates of smoking in autism (Lippiello, 2006).

5. Deletions of the SHANK3 gene represent a strong risk factor for autism (Betancur and Buxbaum, 2013), but duplications of this gene are associated with schizophrenia (Crespi et al., 2010), and SHANK3 overexpression causes mania-like behavior in mice (Han et al., 2013).

With regard to CNVs at 22q11.2, and protection from schizophrenia in individuals with duplications, it is of notable interest that 1) selective prefrontal overexpression of COMT, a key 22q11.2-region gene, rescues schizophrenia-like symptoms in a mouse model of deletion of 22q11.2 (Kimoto et al., 2012), and 2) an allele linked to low COMT expression is associated with psychosis among individuals with 22q11.2 deletions (Gothelf et al., 2013). If higher COMT expression protects against schizophrenia, might it also represent a risk factor for autism? In turn, might therapies that reduce COMT expression or effects help to alleviate symptoms of autism?

Testing the diametric model, in comparison to models that posit overlap between schizophrenia and autism, requires strong inference tests of alternative predictions. Such tests must also carefully take into account possible confounding of autism spectrum disorder with childhood premorbidity to schizophrenia (especially for relatively penetrant risk factors) and confounding of autistic social deficits with negative symptoms of schizophrenia that are superficially but not causally similar.

Most importantly, joint, integrated study of autism and schizophrenia should generate new insights into both sets of conditions, including factors that increase risk as well as the remarkable ones that protect.

References

Angkustsiri K, Goodlin-Jones B, Deprey L, Brahmbhatt K, Harris S, Simon TJ. Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype? J Autism Dev Disord. 2013 Sep 18. Abstract

Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013 Jun 11;4(1):17. Abstract

Crespi B, Badcock C. Psychosis and autism as diametrical disorders of the social brain. Behav Brain Sci. 2008 Jun;31(3):241-61; discussion 261-320. Abstract

Crespi BJ, Crofts HJ. Association testing of copy number variants in schizophrenia and autism spectrum disorders. J Neurodev Disord. 2012 May 30;4(1):15. Abstract

Crespi B, Stead P, Elliot M. Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1736-41. Abstract

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Deutsch SI, Schwartz BL, Schooler NR, Brown CH, Rosse RB, Rosse SM. Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy. Schizophr Res. 2013 Aug;148(1-3):138-44. Abstract

Eliez S. Autism in children with 22q11.2 deletion syndrome. J Am Acad Child Adolesc Psychiatry. 2007 Apr;46(4):433-4. Abstract

Frith CD. Schizophrenia and theory of mind. Psychol Med. 2004 Apr;34(3):385-9. Abstract

Gothelf D, Law AJ, Frisch A, Chen J, Zarchi O, Michaelovsky E, Ren-Patterson R, Lipska BK, Carmel M, Kolachana B, Weizman A, Weinberger DR. Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome. Biol Psychiatry. 2013 Aug 27. Abstract

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Haddad PM, Das A, Ashfaq M, Wieck A. A review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol. 2009 May;5(5):539-51. Abstract

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Hobson RP, Bishop M. The pathogenesis of autism: insights from congenital blindness. Philos Trans R Soc Lond B Biol Sci. 2003 Feb 28;358(1430):335-44. Abstract

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Kimoto S, Muraki K, Toritsuka M, Mugikura S, Kajiwara K, Kishimoto T, Illingworth E, Tanigaki K. Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome. Transl Psychiatry. 2012 Aug 7;2:e146. Abstract

Knickmeyer RC, Davenport M. Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders. J Neurodev Disord. 2011 Dec;3(4):293-306. Abstract

Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2013 Sep 25. Abstract

Landgraf S, Osterheider M. "To see or not to see: that is the question." The "Protection-Against-Schizophrenia" (PaSZ) model: evidence from congenital blindness and visuo-cognitive aberrations. Front Psychol. 2013 Jul 1;4:352. Abstract

Lindsley CW, Stauffer SR. Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012). Pharm Pat Anal. 2013 Jan;2(1):93-108. Abstract

Lippiello PM. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med Hypotheses. 2006;66(5):985-90. Abstract

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