NYAS 2011—Probing the Genome for Schizophrenia Drug Targets
22 March 2011. On 10-11 March 2011, over 200 researchers gathered at the New York Academy of Sciences for a meeting entitled Advancing Drug Discovery for Schizophrenia. With a lofty view of Manhattan from the fortieth floor, researchers sifted through clues—from dopaminergic and glutamatergic to genetic and epigenetic, not to mention stem cell, imaging, and postmortem—that could be leveraged into treatment strategies.
Since the 1950s, schizophrenia treatment has relied solely on antipsychotic drugs that block dopamine receptors, specifically the D2 subtype, to dampen the hallucinations and psychosis ("positive symptoms") of schizophrenia. Newer antipsychotics appear to have avoided the motor system side effects of the older drugs, while producing modest gains in antipsychotic efficacy. However, most carry their own side effect of significant metabolic syndrome. Worse still, no drug has been found to treat the anhedonia, blunted affect, and lack of motivation ("negative symptoms"), or cognitive deficits that are also debilitating. This state of affairs, coupled with the exit of major drug companies from research into psychiatric disorders, makes finding new approaches to treating schizophrenia especially urgent.
To expedite this, meeting organizers Stephen Marder of UCLA, Bita Moghaddam of the University of Pittsburgh, and Bryan Roth of the University of North Carolina assembled a line-up of speakers who brought diverse perspectives to the question. With a measure of optimism, and caution, three keynote speakers kicked off Day 1 of the meeting by outlining the current genetic landscape of schizophrenia, which has been propelled by mapping of the human genome, but which remains limited by animal models.
A route to rational drug discovery
Narrowing in on the genetic basis of schizophrenia should uncover core problems giving rise to the disorder, and suggest novel targets for treatment. Patrick Sullivan of the University of North Carolina argued that schizophrenia is a polygenic disorder, characterized by variation in multiple genes. He enumerated new schizophrenia-related variants discovered through genomewide association studies (GWAS), including the stretch along chromosome 6 that is home to major histocompatibility complex (MHC) genes (see SRF related news story), and miR137, a microRNA that targets other schizophrenia-associated genes, such as c10orf26, TCF4, and CACNA1C. GWAS are just reaching the critical size for producing hits, and even larger GWAS (on the order of 100,000 subjects) are needed to uncover more variants, he argued.
Edward Scolnick of the Broad Institute of Massachusetts Institute of Technology and Harvard University described how the bottom-up approach of using genetics to find targets for drugs has paid dividends in treating diseases like cardiovascular disease and breast cancer. Though psychiatry lags behind, he insisted that the genetic results just coming in—even those of small effect—are setting up the pathway to discovery. "Nothing, except money and time, stands in the way of really figuring this out," he said.
Though genetic findings can point to new understandings of basic brain biology, research has struggled to "close the loop" in turning these insights into something for the clinic, said Eric Nestler of Mount Sinai Medical Center. This is partly due to the unique challenges of modeling a psychiatric disorder in animal models (Nestler and Hyman, 2010). Although no one expects to come up with a mouse model that copies all aspects of schizophrenia, efforts to model components of the disorder are hampered by the fact that it is defined entirely in terms of behavior, rather than with measurable biomarkers. To help researchers evaluate their animal models, Nestler categorized them as those with: construct validity, where a mouse carries a genetic variant linked to a disorder; face validity, where a mouse behavior is equivalent to a human symptom; and predictive validity, where both are treated by the same interventions. Those with construct validity might be on firmer ground, but the complicated genetics of schizophrenia—with different patients potentially harboring different complements of disease variants—hinder more accurate construct validity. "We as a field should be more honest and self-reflective about what we are able to do in a rodent," Nestler said.
Despite these difficulties, Nestler has developed a mouse model of social defeat that has some features of depression (see SRF related news story). Interestingly, one-third of the mice subjected to the paradigm do not develop the symptoms of anhedonia and anxiety. Gene expression patterns distinguish resilient from susceptible mice, and suggest that the pathway to resilience is independent from that for susceptibility. This means that ways to promote resilience to stress, rather than dampening the effects of stress, could be a viable strategy.
Genetic approaches before GWAS
The next two speakers explored genetic clues that came to light independently from GWAS. Daniel Weinberger of the National Institute of Mental Health described his work on a brain-specific potassium channel called KCNH2 3.1 that is overexpressed in schizophrenia brains relative to controls, and which produces hyperexcitable cells (see SRF related news story). Antipsychotics bind to this channel, raising the question of whether subtle variations in the channel could predict antipsychotic response.
Weinberger presented new results from a placebo-controlled study of antipsychotic therapy in two patient groups. Those homozygous for single nucleotide polymorphisms (SNPs) in KCNH2 3.1 that are associated with elevated levels of KCNH2 3.1 had significant improvements in their positive symptoms scores, and were five times more likely to continue on the antipsychotic olanzapine than those who were not homozygous for these alleles. The next steps for the Weinberger group involve expressing the novel isoform in cell lines to screen compounds that could stem the hyperexcitability. A recent study suggests that simply adding back the missing intracellular piece of protein missing from this isoform may do the trick (Gustina et al., 2009).
Maria Karayiorgou of Columbia University made the case for using rare, highly penetrant variants to understand schizophrenia. She looks for copy number variations (CNVs)—the loss or gain of an extra segment of DNA—that occur in people with schizophrenia more often than in controls. Though rare, these discrete anomalies in the genome offer clear genes for follow-up and lend themselves to animal modeling. In collaboration with others, her group has recently linked a duplication containing the vasoactive intestinal peptide receptor gene (VIPR2) to schizophrenia (see SRF related news story); however, her talk focused on deletions at 22q11, which comprise the strongest known genetic risk factor for schizophrenia.
With 30 percent of people with these deletions developing schizophrenia, Karayiorgou and her team have been studying mice engineered to carry the equivalent deletion. They find working memory deficits, and disrupted signaling between the prefrontal cortex and hippocampus (see SRF related news story). A suspected risk-conferring gene in the deleted region is a microRNA-processing gene called Dgcr8 (see SRF related news story). This gene controls miRNA expression in the brain, and when deleted in mice, this produces some of the cognitive defects observed in the full deletion, and perturbs cortical circuitry (Fénelon et al., 2011).
The epigenome cometh
The last three talks of the day focused on epigenetic mechanisms involved in schizophrenia. Because the development of schizophrenia involves environmental factors, researchers have been interested in finding signatures of environmental hits, like stress, on the genome. For example, chemical add-ons to the DNA sequence of the genome, like methyl groups, can obstruct transcription, thus dictating which genes are turned on or off. These epigenetic marks do not distinguish cause from consequence, however; they may reflect environmental factors that tilt someone towards schizophrenia, or they may arise from disease progression or treatment. Still, many researchers mentioned that any epigenetic signature of schizophrenia may be a useful biomarker for the disorder.
Alessandro Guidotti of the University of Illinois at Chicago explored the idea that epigenetic marks that repress several different brain genes are involved in schizophrenia (see SRF hypothesis). Postmortem studies have found decreased levels of mRNA for the GABA-synthesizing enzyme GAD-67, the neural migration player called reelin (RELN), and other neurotransmitter receptors and transporters, and have suggested that epigenetic marks inhibit the expression of these proteins. Guidotti presented results showing that inhibiting histone deacetylase, which normally facilitates methylation of DNA, with valproate may be a way to rewrite the patterns of epigenetic marks on the genome. He finds that antipsychotic drugs like clozapine interact synergistically with valproate to promote demethylation—a state that is permissive for expression—at the promoter of RELN in the frontal cortex of mice. Other dibenzepine compounds, like olanzapine, share this ability, but haloperidol and risperidone do not.
Prompted by epidemiology that shows that advanced paternal age increases risk for schizophrenia in offspring (see SRF hypothesis), Jay Gingrich of Columbia University talked about epigenetic mechanisms behind this effect. With each round of sperm production, epigenetic marks are erased then reprogrammed—a process which may become degraded with advanced paternal age. To explore this, Gingrich and colleagues compared the offspring from older mouse fathers to those from young mouse fathers. Several behaviors differed between the two, including measures of an open field ambulatory test, startle responses, and paired pulse inhibition. These mice showed different methylation patterns on their genomes at 0.4 percent of methylation sites. At these sites, the offspring of older males were less methylated than those of the younger males in introns, exons, and promoters. This suggests that differences in promoter activity and in alternate splicing may drive some of the changes observed in the mice. Notably, hotspots of altered DNA methylation could be found in schizophrenia-related genes, though the researchers didn't select the mice for disease-related behaviors.
Schahram Akbarian of the University of Massachusetts rounded out the epigenetics discussion with a talk focused on an epigenetic mark—called histone H3-trimethyl-lysine 4 (H3K4me3)—placed on proteins rather than DNA. H3K4me3 marks are found on the histone protein spools around which DNA wraps, near transcriptional start sites, and are thought to make the nearby DNA open for transcription. Akbarian finds large-scale remodeling of chromatin that occurs over lifespan (Cheung et al., 2010), as well as subtle changes in H3K4me3 patterns in disease. Using postmortem tissue from prefrontal cortex taken from 15 control brains and 30 from people with autism and schizophrenia, neuron-specific chromatin can be isolated and screened for H3K4me3 marks by ChIP-Seq (Robertson et al., 2007). For example, a subset of autism cases had H3K4me3 marks that occurred at transcriptional start sites, but which were more variable, spreading abnormally away from the site rather than being concentrated in a tight peak. A similar kind of spreading was noted in three schizophrenia brains at the start sites for genes encoding GABA receptors, and one exhibited a loss of the marker at this site; neither type of change was observed in controls.
These subtle differences suggest that the precise pattern of these marks matter. If they turn out to be therapeutically relevant, procedures such as simply promoting or inhibiting methylation will be too coarse a manipulation to normalize these patterns. Furthermore, not much is known about the mechanisms that govern where these marks are put down in the first place. Though it is uncertain whether epigenetic marks hold clues to the origins of the disease or instead reflect things like subsequent drug treatment history, stress, or smoking, they might still form part of a molecular phenotype of schizophrenia. Several researchers mentioned the need to check whether these epigenetic patterns hold true in readily available peripheral tissues like blood cells, which could potentially make them a much-needed biomarker.—Michele Solis.
Comments on Related News
Related News: BDNF In the Nucleus Accumbens—Too Much of a Good Thing?Comment by: NN Kudryavtseva
Submitted 23 February 2006
Posted 23 February 2006
Berton and colleagues show very impressive data of molecular studies demonstrating numerous changes of gene expression in brain under repeated social defeats. However, the behavioral or pharmacological data that the authors use to support the development of depression in socially defeated mice may be interpreted otherwise.
The authors used decreases in the level of social communication (they called it avoidance-approach behavior) in defeated losers as parameters of depression. We repeatedly noted in our experiments on the social model of depression induced by social confrontations in mice of the C57BL/6J strain (Kudryavtseva et al., 1991) that even one or two social defeats lead to a decrease of communication in mice. Thus, avoidance behavior cannot be used as a specific parameter of depression; rather, it may represent anxiety. However, our experiments demonstrated that longer experience of defeats over 20-30 days (but not 10 days, as used by Berton et al.) in male mice produces development of a depression-like state (anxious depression): similarities of symptoms, etiological factors (social unavoidable emotional stress, permanent anxiety), sensitivity to chronic antidepressants and anxiolytics (imipramine, tianeptine, citalopram, fluoxetine, buspirone, etc.), as well as brain neurochemistry changes (serotonergic and dopaminergic systems) (Kudryavtseva et al., 1991; for reviews see Kudryavtseva, Avgustinovich, 1998; Avgustinovich et al., 2004).
In our molecular studies, we also demonstrated changes of gene expression in the brains of male mice after daily agonistic interactions. Three experimental groups were compared: the losers with repeated experience of social defeats; winners with repeated aggression accompanied by social victories; and controls (very important—the same strain). In has been shown that MAOA and SERT mRNA levels in the raphe nuclei of the losers were higher than in the controls and winners. TH and DAT gene expression in the ventral tegmental area was higher and κ opioid receptor gene expression was lower in the winners in comparison with the losers and controls (see Filipenko et al., 2001; 2002; Goloshchapov et al., 2005; reviewed in Kudryavtseva et al., 2004). Thus, there are different specific changes in gene expression in different brain areas in male mice with opposite social behaviors—winners and losers.
As for BDNF, there is an emerging body of data suggesting that different mood disorders are associated with changed BDNF. I think that changes of BDNF gene expression in the losers may be nonspecific for depression state. Expression of the BDNF gene in the winners should be investigated to confirm or reject this idea.
Again, Berton et al. (2006) have demonstrated very impressive data. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model) may be used for the study of association between agonistic behavior and gene expression. We called this scientific direction “From behavior to gene” (reviewed in Kudryavtseva et al., 2004), as an addition to the traditional “From gene to behavior.”
Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain.
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Kudryavtseva NN, Avgustinovich DF. (1998) Behavioral and physiological markers of experimental depression induced by social conflicts (DISC). Aggress Behav. 24:271-286.
Filipenko ML, Alekseyenko OV, Beilina AG, Kamynina TP, Kudryavtseva NN. Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience.
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Filipenko ML, Beilina AG, Alekseyenko OV, Dolgov VV, Kudryavtseva NN. Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice.
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View all comments by NN Kudryavtseva
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.
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: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model
Comment by: Anthony-Samuel LaMantia
Submitted 5 April 2010
Posted 5 April 2010
In a recent report, Sigurdsson et al. provide data that synchrony between hippocampal and cortical activity is subtly altered during a specific spatial motor memory task in a mouse model of the 22q11 Deletion syndrome (also known as DiGeorge syndrome). There have been several studies of other mouse models of 22q11 Deletion syndrome, the first of which were published in the late 1990s and early 2000s (Lindsey et al., 1999; Merscher et al., 2001). All of the data indicate that the development and function of the cerebral cortex is compromised by diminished dosage of the approximately 30 genes whose deletion is obligate in the disease. The reason for the intense interest in 22q11 Deletion syndrome is the high (but not invariant) incidence of schizophrenia in patients with this genetic disorder.
The likely disruption of hippocampal/cortical circuitry, based on subtly altered synchrony (but not, apparently, synaptic connectivity) makes sense if one assumes that diminished dosage of 22q11 genes compromises local circuit organization without wholesale changes in basic mechanisms of synaptic communication. Such results can be compared—cautiously—to hypotheses of regional/circuit malfunction in schizophrenic patients. The synchrony argument is intriguing, especially given the currency of models of cognition that invoke oscillatory behavior of forebrain circuits to explain coherence between diverse, related representations that are thought necessary for cognition and complex behaviors. Nevertheless, it is not clear that current experimental methods in humans can identify the subtle task-dependent dysregulation of synchrony that goes awry in the mouse. Thus, the report by Sigurdsson et al., while intriguing, provides a novel starting point for further investigation. Several questions arise in the mouse model: is cortical or hippocampal circuitry compromised in some way that goes beyond detectable changes in synaptic transmission? If so, how? Is some additional neuronal population that receives information from or provides input to both regions compromised by 22q11 deletion? Finally, how do such abnormalities arise? Are they the result of altered development, or disruptions in mature neuronal function?
While these observations raise exciting possibilities for further research in the relationship between 22q11 Deletion syndrome and schizophrenia pathology, some issues should be considered when comparing the mouse work and human disease. It remains difficult to confirm whether the sort of spatial memory tasks used by Sigurdsson et al. are really examples of mouse “executive function,” “working memory,” or the sorts of cognitive domains thought to be selectively compromised in schizophrenic patients. Moreover, it is generally agreed by comparative neuro-anatomists that the mouse does not have "prefrontal cortex" that is comparable to that seen in non-human and human primates—especially the dorsolateral prefrontal cortex. In humans, the performance of working memory tasks relies upon the integrity of this region, and its connections with a number of other cortical and subcortical areas. These circuits remain the focus of investigation in human schizophrenia pathology. Thus, while dysregulation of hippocampal activity and motor association cortical activity in the frontal aspect of the mouse brain (which is not actually prefrontal cortex) is likely occurring in 22q11 Deletion syndrome model mice, additional work must be done to determine how this relates to human behavioral disruptions in schizophrenia.
Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM, Bradley A, Baldini A. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature . 1999 Sep 23 ; 401(6751):379-83. Abstract
Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell . 2001 Feb 23 ; 104(4):619-29. Abstract
View all comments by Anthony-Samuel LaMantia
Related News: Working Memory, Cortical Circuitry Disrupted in 22q11DS Mouse Model
Comment by: Wendy Kates
Submitted 7 April 2010
Posted 8 April 2010
The links between genetic variants, neural circuitry, and cognitive dysfunction in schizophrenia are not well understood, due in part to the diagnostic and etiological heterogeneity of schizophrenia, which creates enormous challenges to understanding its pathophysiology. Several research groups are responding to this challenge by investigating the etiologically homogeneous microdeletion disorder, 22q11.2 deletion syndrome (22q11.2 DS), which poses the highest known genetic risk for schizophrenia, second only to having two parents with the disorder. Accordingly, 22q11.2 DS is a compelling model for understanding the pathophysiology of cognitive dysfunction in schizophrenia. Gogos, Karayiorgou, Sigurdsson, and colleagues are investigating this issue with a mouse model of 22q11.2 DS, and their latest, high-impact study of functional connectivity in the context of a working memory paradigm has brought us palpably closer to understanding these elusive links. They elegantly demonstrate that the 22q11.2 microdeletion disrupts prefrontal-hippocampal synchrony, which, in turn, likely contributes to impairments in working memory performance.
Although the specific genes within the microdeletion that are linked to neurocognitive deficits still need to be identified, this study begins to disentangle the complex associations among genetic variants, neural connectivity, and cognition in 22q11.2 DS. The elegance of a mouse model is that it can utilize methods that provide exquisite temporal and spatial resolution that is very difficult to obtain in human studies. Thus, this study identifies, at the neuronal level, disruptions in timing and connectivity that may underlie the white matter deficits that have been observed in neuroimaging studies (Barnea-Goraly et al., 2003; Kates et al., 2001; Simon et al., 2005) of patients with this genetic syndrome, and that putatively account for some of the syndrome’s prominent neurocognitive deficits. These findings provide support for future, more focused studies of neural connectivity, using EEG and diffusion tensor imaging, in patients with this mutation as well as the larger population of patients with schizophrenia.
Barnea-Goraly N, Menon V, Krasnow B, Ko A, Reiss A, Eliez S. (2003) Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study. Am J Psychiatry, 160 (10): 1863-9. Abstract
Kates WR, Burnette CP, Jabs EW, Rutberg J, Murphy AM, Grados M, Geraghty M, Kaufmann WE, Pearlson GD. (2001) Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis. Biol Psychiatry, 49 (8): 677-84. Abstract
Simon TJ, Ding L, Bish JP, McDonald-McGinn DM, Zackai EH, Gee J. (2005) Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study.Neuroimage. 25 (1): 169-80. Abstract
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