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Research Roundup: 22q11.2 Is Hotspot for Schizophrenia Research

December 18, 2013. Over 20 years ago, several genetics groups simultaneously linked a region of chromosome 22, containing about 45 genes, to schizophrenia. This evidence was bolstered by the fact that people with deletions of the region, who often have a developmental disorder called velocardiofacial syndrome (VCFS), are more likely to develop schizophrenia (Pulver et al., 1994), and the finding that several patients with schizophrenia had 22q11.2 deletions (Karayiorgou et al., 1995).

Since then, researchers have been working out how this rare deletion elevates risk for schizophrenia. “Even as we find other deletions or duplications elsewhere in the genome associated with schizophrenia, 22q11.2 deletions remain the standard bearer,” Anne Bassett of the University of Toronto, Canada, told SRF. “It’s the only proven molecular genetic subtype of schizophrenia.”

In this research roundup, Schizophrenia Research Forum reviews some of the latest findings in 22q11.2 deletion syndrome research, including insights from across the lifespan in people with the deletion, as well as from the affected brain circuits in mouse models.

A big clue
People missing all or much of a 3 Mb stretch on one strand of DNA in the region of 22q11.2 develop a variable syndrome, including heart defects, facial abnormalities, and cognitive impairments, which sometimes convene to create the classic VCFS. But up to one-quarter also go on to develop schizophrenia, perhaps accounting for up to 1 percent of all schizophrenia cases.

Bassett has followed patients with the deletion for over 20 years, with an interest in understanding how the full spectrum of phenotypes develops. As a rule, people with 22q11.2 deletion syndrome (22q11.2DS) vary in terms of which features they have, and their severity. But the schizophrenia observed in some of these patients is the real thing, Bassett says: “They have negative symptoms, they have positive symptoms, they have disorganized thought—the whole DSM symptom list is in these people.”

Their intelligence quotients (IQs) are lower on average than those measured for people with schizophrenia, however, but most people with 22q11.2DS do not meet the criterion for intellectual disability. This means they constitute a naturally occurring human model for common variety schizophrenia, Bassett argues. More recently, a connection to schizophrenia has been bolstered by the report that duplications of the 22q11.2 region protect from schizophrenia (see SRF related news story).

“It is so gratifying that people have finally recognized how much the rare can inform the common,” Bassett says.

Still, sifting through the different genes in the region to find the key instigators of schizophrenia remains a formidable task. Among the early, obvious candidates were the genes for catechol-O-methyltransferase (COMT), involved in dopamine metabolism, and proline dehydrogenase (PRODH), which helps regulate glutamate levels (see SRF related news story). More recently, mouse models carrying a similar deletion have highlighted a possible role for microRNAs, which regulate gene expression. Within the 22q11.2 region lies the gene DGCR8, which prepares microRNAs for action. The loss of DGCR8 (see SRF related news story), and more recently, of a specific microRNA-185 in the region (see SRF related news story), have been linked to schizophrenia-like signs in mice.

These microRNAs might normally help the brain compensate for mutations elsewhere in the genome, either in the intact 22q11.2 region on the counterpart chromosome or beyond. When microRNA buffering capacity is reduced through a 22q11.2 deletion, then, this might unmask the effects of these other mutations and explain the variable effects of 22q11.2 deletions (Brzustowicz and Bassett, 2012). An international consortium has just been funded by the National Institute of Mental Health to sequence the entire genomes of people with 22q11.2 deletions to find genetic factors that influence whether someone develops schizophrenia, Bassett said.

Across the lifespan
Most 22q11.2 deletions begin as mistakes during meiosis, when chromosomes misalign prior to exchanging bits of DNA. This means egg or sperm cells carry the deletion, whereas the parents themselves do not. A majority of 22q11.2 deletions stem from mothers, according to a study published in the American Journal of Human Genetics in March. Bernice Morrow of Albert Einstein College of Medicine, Bronx, New York, teamed up with other researchers around the world to survey a large enough sample of people with 22q11.2 deletions and their parents. First author Maria Delio and colleagues reported that 57 percent of subjects with 22q11.2 deletions acquired them from their mother’s egg, whereas 43 percent were from sperm, which suggests that the 22q11.2 region is more vulnerable to meiotic mishaps in females than in males.

Psychiatric problems emerge early in many children with 22q11.2 deletions, but these do not result from their cognitive impairments, according to a study published in the British Journal of Psychiatry from Marianne van den Bree of Cardiff University, Wales, United Kingdom, and colleagues. Assessing 80 children with 22q11.2 deletions, first author Maria Niarchou reported that 54 percent qualified for a psychiatric disorder, including anxiety disorders and attention-deficit hyperactivity disorder, compared to only 10 percent of their siblings. Though 22q11.2DS subjects also had lower IQ scores than their siblings, their IQ did not explain the risk for these psychiatric disorders. This bolsters the idea that childhood psychiatric disorders are directly related to the deletion, rather than being non-specific fallout of cognitive impairments.

As if the risk for psychiatric disorders in childhood and early adulthood wasn’t enough, a study published in JAMA Neurology in November from Bassett and colleagues reported an increased risk for Parkinson's disease (PD) later in life. First author Nancy Butcher and colleagues found that adults with 22q11.2 deletions more frequently developed PD than expected, with 70 times the number seen in the general population. Furthermore, they developed PD before 50 years of age, which points to a new, rare form of early-onset PD. Postmortem brain samples confirmed that this was true PD, with loss of dopamine-containing substantia nigra neurons and other signs of neurodegeneration. Why 22q11.2 deletions would increase risk for a disorder associated with too much dopamine (schizophrenia) and one associated with too little dopamine (PD) is “a sweet mystery,” Bassett says, and suggests that the conception of schizophrenia as primarily a disorder of dopamine is incomplete.

Early signs of psychosis
Following the development of children with 22q11.2 deletions could divulge early predictors of psychosis, and three studies report comparisons of features in the same people across two time points. One study from Stephan Eliez and colleagues at the University of Geneva School of Medicine, Switzerland, points to anxiety: As reported in the Journal of the American Academy of Child and Adolescent Psychiatry, first author Doron Gothelf and colleagues found that, of 10 people with 22q11.2DS who developed psychosis, nine had an anxiety disorder as children. Another study from the same group, published in European Child and Adolescent Psychiatry, found that low-grade psychotic symptoms preceded the onset of full-blown psychosis in people with 22q11.2 deletions, similar to the prodrome described for schizophrenia in general. First author Maude Schneider and colleagues did not find concomitant changes in cognition: Though those who developed psychosis had lower IQs to begin with, the slope of the change in IQ over time did not differ from those who did not develop psychosis. They suggest low IQ as a marker for increased risk for psychosis.

A third study, published in Research in Developmental Disabilities, also found that adolescents with 22q11.2 deletions displayed evidence of the schizophrenia prodrome—mild psychotic symptoms not reaching a diagnostic level. Led by Vandana Shashi at Duke University, Durham, North Carolina, the study found that these subjects did not show the expected gains in attention and general function as they matured. First author Stephen Hooper and colleagues also noted that lower IQ at baseline was associated with the development of schizophrenia 3.5 years later.

As for genetic factors that might tilt a person with a 22q11.2 deletion toward psychosis, the COMT gene has been a go-to candidate. Lying within the 22q11.2 region, COMT encodes an enzyme that degrades dopamine and other monoamines. In people with a 22q11.2 deletion, any consequences of any variant in the remaining, intact COMT may be unmasked. Though the well-known Val158Met variant has not been consistently linked to schizophrenia in subjects with 22q11.2DS, a study in Biological Psychiatry suggests other COMT variants may influence COMT function and the development of psychosis. Led by Daniel Weinberger of the Lieber Institute in Baltimore, Maryland, the study analyzed blood cells from 53 people with 22q11.2 deletions. First authors Doron Gothelf and Amanda Law reported that combinations of single nucleotide polymorphisms (SNPs) could modulate the effect of Val158Met on COMT expression and activity. Moreover, one SNP in an untranslated region of COMT was associated on its own with low COMT activity and occurred more frequently in those who developed psychosis than in those who did not.

In the brain
As a group, people with 22q11.2 deletions display deficits in sensorimotor gating and mismatch negativity (MMN), both neurophysiological signs associated with schizophrenia. According to a study in the Journal of Psychiatric Research led by Doron Gothelf at Tel Aviv University, Israel, these measures are modulated by the Val158Met variant in COMT, as well as by SNPs in PRODH, a modulator of glutamatergic and dopaminergic neural transmission. First author Omer Zarchi also found that the degree of the deficit in MMN correlated with schizophrenia-like symptoms and measures of executive function; however, these measures did not differ between psychotic and non-psychotic people with 22q11.2 deletions, suggesting that MMN deficits flag general risk for psychosis.

Two neuroimaging studies led by Stephan Eliez of the University of Geneva, Switzerland, also revealed schizophrenia-like patterns of connectivity in people with 22q11.2 deletions. As reported in PLoS One, diffusion tensor imaging (DTI) used to characterize the trajectories of white matter bundles throughout the brain found sparser connections in 30 people with 22q11.2 deletions compared to 30 controls. First author Marie-Christine Ottet and colleagues reported that this reduction was pronounced in connections linking the frontal and temporal cortices, as well as those within and between limbic areas, and suggests that the state of frontotemporal connections may serve as a biomarker for vulnerability to psychosis. The second study, also from Ottet, Eliez, and colleagues, explored the network of brain connections in 46 people with 22q11.2 deletions who also had hallucinations, and so may be at even higher risk of developing schizophrenia than 22q11.2DS subjects without hallucinations. In general, connections in the brain are organized like airplane flight routes, with many connections stopping through key hub regions, and in schizophrenia, the brain has been reported to contain fewer hubs with fewer connections (see SRF related news story). Writing in Frontiers of Human Neuroscience, first author Ottet reports a similarly disrupted network in the 22q11.2DS population, with fewer connections between hubs, suggesting that this fragmented network reflects a predisposition for schizophrenia.

Mouse models
Researchers have modeled the 22q11.2 deletion in mice by knocking out the equivalent region, which resides on mouse chromosome 16. Several models exist that show a variety of schizophrenia-related phenotypes ranging from disruptions of brain development to deficits in sensory gating. The advent of small animal brain imaging will supplement the comparisons between mice and humans (see SRF related news story). In a study published in Molecular Psychiatry, Joseph Gogos and Maria Karayiorgou teamed up with researchers in Toronto to scan their mouse model of 22q11.2 deletion syndrome, called Df(16)A+/-, which lacks 27 genes. Using a 7 Tesla scanner, first authors Jacob Ellegood and Sander Markx report 13 different regions that had significantly smaller or larger volumes than wild-type mice, and several of these overlapped with changes observed in humans with 22q11.2 deletions, including the frontal lobe, the striatum, the third ventricle, and the cerebellum.

Another study of this mouse model suggests that the brain’s ability to change may be compromised by multiple factors within 22q11.2 deletions. Published in the Journal of Neuroscience in September, the study, led again by Gogos and Karayiorgou, evaluated synapses in the medial prefrontal cortex (mPFC), a region key for cognition. First author Karine Fénelon and colleagues found impaired short- and long-term plasticity in mPFC synapses, meaning that the synapses did not adequately scale their responses up or down according to input. The impaired short-term plasticity, as well as working memory, could be blamed on the loss of DGCR8, as similar deficits are seen in mice lacking that single gene; however, the long-term plasticity deficits and accompanying changes to dendritic spine shapes suggests other genetic culprits in the region, which may involve miRNA processing.

Finally, however, a study led by Jennifer Linden at University College London, United Kingdom, sounds a note of caution in evaluating mouse models of 22q11.2 deletions or other large genetic hits. Published in PLoS One, the study reports that the Df1/+ mouse model, which lacks 18 genes in the human 22q11.2 region, showed hearing loss arising from chronic ear infections. First author Jennifer Fuchs and colleagues found that the hearing loss often occurred in one—not both—ears and mimics a susceptibility to ear infections found in humans with 22q11.2 deletions. The results, however, suggest that previous reports of impaired sensorimotor gating in 22q11.2 deletion mouse models may stem from deficits in hearing rather than problems with the interface between sensory processing and motor responses.—Michele Solis.

References:
Delio M, Guo T, McDonald-McGinn DM, Zackai E, Herman S, Kaminetzky M, Higgins AM, Coleman K, Chow C, Jalbrzikowski M, Bearden CE, Bailey A, Vangkilde A, Olsen L, Olesen C, Skovby F, Werge TM, Templin L, Busa T, Philip N, Swillen A, Vermeesch JR, Devriendt K, Schneider M, Dahoun S, Eliez S, Schoch K, Hooper SR, Shashi V, Samanich J, Marion R, van Amelsvoort T, Boot E, Klaassen P, Duijff SN, Vorstman J, Yuen T, Silversides C, Chow E, Bassett A, Frisch A, Weizman A, Gothelf D, Niarchou M, van den Bree M, Owen MJ, Suñer DH, Andreo JR, Armando M, Vicari S, Digilio MC, Auton A, Kates WR, Wang T, Shprintzen RJ, Emanuel BS, Morrow BE. Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am J Hum Genet. 2013 Mar 7;92(3):439-47. Abstract

Niarchou M, Zammit S, van Goozen SH, Thapar A, Tierling HM, Owen MJ, van den Bree MB. Psychopathology and cognition in children with 22q11.2 deletion syndrome. Br J Psychiatry. 2013 Oct 10. Abstract

Butcher NJ, Kiehl TR, Hazrati LN, Chow EW, Rogaeva E, Lang AE, Bassett AS. Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. JAMA Neurol. 2013 Nov 1;70(11):1359-66. Abstract

Gothelf D, Schneider M, Green T, Debbané M, Frisch A, Glaser B, Zilkha H, Schaer M, Weizman A, Eliez S. Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. J Am Acad Child Adolesc Psychiatry. 2013 Nov;52(11):1192-1203. Abstract

Schneider M, Schaer M, Mutlu AK, Menghetti S, Glaser B, Debbané M, Eliez S. Clinical and cognitive risk factors for psychotic symptoms in 22q11.2 deletion syndrome: a transversal and longitudinal approach. Eur Child Adolesc Psychiatry. 2013 Sep 3. Abstract

Hooper SR, Curtiss K, Schoch K, Keshavan MS, Allen A, Shashi V. A longitudinal examination of the psychoeducational, neurocognitive, and psychiatric functioning in children with 22q11.2 deletion syndrome. Res Dev Disabil. 2013 May;34(5):1758-69. 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

Zarchi O, Carmel M, Avni C, Attias J, Frisch A, Michaelovsky E, Patya M, Green T, Weinberger R, Weizman A, Gothelf D. Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes. J Psychiatr Res. 2013 Nov;47(11):1623-9. Abstract

Ottet MC, Schaer M, Cammoun L, Schneider M, Debbané M, Thiran JP, Eliez S. Reduced fronto-temporal and limbic connectivity in the 22q11.2 deletion syndrome: vulnerability markers for developing schizophrenia? PLoS One. 2013;8(3):e58429. Abstract

Ottet MC, Schaer M, Debbané M, Cammoun L, Thiran JP, Eliez S. Graph theory reveals dysconnected hubs in 22q11DS and altered nodal efficiency in patients with hallucinations. Front Hum Neurosci. 2013 Sep 5;7:402. Abstract

Ellegood J, Markx S, Lerch JP, Steadman PE, Genç C, Provenzano F, Kushner SA, Henkelman RM, Karayiorgou M, Gogos JA. Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion. Mol Psychiatry. 2013 Sep 3. Abstract

Fuchs JC, Zinnamon FA, Taylor RR, Ivins S, Scambler PJ, Forge A, Tucker AS, Linden JF. Hearing loss in a mouse model of 22q11.2 deletion syndrome. PLoS One. 2013 Nov 14;8(11):e80104. Abstract

Comments on Related News


Related News: Chromosome 22 Link to Schizophrenia Strengthened

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

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

View all comments by Anthony Grace

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Caterina Merendino
Submitted 5 November 2005
Posted 5 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment by:  Leboyer Marion
Submitted 6 November 2005
Posted 6 November 2005
  I recommend the Primary Papers

Related News: Chromosome 22 Link to Schizophrenia Strengthened

Comment 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

Related News: News Brief: Schizophrenia-linked AKT1 Variant Affects Brain Parameters

Comment by:  Takeo YoshikawaAkihiko Takashima
Submitted 17 June 2008
Posted 17 June 2008

Some researchers in the field of psychiatric genetics have become somewhat pessimistic about the ability to detect robust genotype-phenotype correlations using the diagnostic criteria defined by DSM-IV. If we analyze tens of thousands of samples, the ensuing results may be statistically robust, but still the effect of common variant(s) of each gene will be modest. Recently, Tan et al. (2008) reported that the AKT1 gene SNP rs1130233 and its encompassing haplotypes are significantly associated with IQ/processing speed, activities that may reflect frontal cortex function. They also showed that performance in their psychological test battery is influenced not only by AKT1 genetic variants but also the well-known COMT gene non-synonymous polymorphism (SNP rs4680, Val158Met). By undertaking fMRI analysis, they intertwined the IQ/processing speed-frontal cortex-AKT1 signal-DA system, i.e., the. integration of multidimensional disciplines. In citing references (Meyer-Lindenberg and Weinberger, 2006; Weinberger et al., 2001), they state that “there is a growing body of data showing that genes weakly associated with complex constellations of behavioral symptoms are much more strongly associated with in vivo brain measures.” Indeed, they have succeeded in explaining a possible role for AKT1 in brain execution capability, but have not provided convincing evidence for genetic associations between AKT1 and schizophrenia.

Their current results are elegantly derived from “a complex set of experiments addressing association of multiple variants in a gene with many phenotypic measures.” However, from a genetic perspective, we may still ask the following questions, irrelevant of the current study:

1. What is the genetic component (or heritability) of each psychological and imaging trait? Can variations in some of the psychological/cognitive/intellectual performances be fully captured by a single gene in an experimental set that examines, at the most, a hundred samples? We have learned the hard way from genetic association studies done in the 1990s, which examined a small number of samples, that we simply cannot trust those results. With regard to this point, the heritability calculations of so-called “endophenotypes” as reported by Greenwood et al. (2007) can give helpful information [also see Watanabe et al., 2007, supplementary Table S2]. There is the possibility that the genetic architecture of neurocognitive functions and imaging measures may not be simpler than the current disease category (entity).

2. Given the rapid advances in genotyping technology, we may be able to generate genome-wide genetic test results for every neuropsychiatric trait in the near future.

3. Because of the functional significance of AKT1 and the divergence in the signaling cascade downstream of AKT1, it would be wise to confine analysis to this gene. However, it is frustrating that we still do not know the functionally important SNP(s) of AKT1 in spite of numerous association studies.

4. Nackley et al. (2006) have convincingly demonstrated that the haplotype of the COMT gene constructed by synonymous SNPs has much more functional impact than the Val158Met polymorphism. Therefore, we would like to see the association studies examining this haplotype in future neuropsychiatric studies.

From a biochemical perspective, the following issues would be interesting and future targets for clarification:

1. The authors suggest that the coding synonymous variation of AKT1 affects protein expression, leading to the alteration of frontostriatal function and gray matter volume. The activity of AKT1 is regulated by its phosphorylation status. Therefore, readers would want to know whether the reduction of AKT1 expression levels actually affect the AKT signaling pathway. Behavioral analysis and an MRI study of Akt1 heterozygote knockout mice may provide relevant information.

2. Impairment of the AKT signal is known to result in tau hyperphosphorylation through activation of GSK3 as seen in Alzheimer disease brains. According to this idea, a reduction of AKT levels caused by SNP(s) should elicit hyperphosphorylation of tau and ultimately form neurofibrillary tangles (NFTs). In contrast, there are some reports suggesting the absence of NFTs and neuroinjury in elderly patients with schizophrenia (Arnold et al., 1998; Purohit et al., 1998). It is also reported that GSK3 is reduced in schizophrenia (Beasley et al., 2001). It would be interesting to know whether the genetic variation(s) of AKT1 that induce decreased protein expression affect tau accumulation.

3. Lithium inhibits the arrestin-Akt signal (Beaulieu et al., 2008). If so, it would be interesting to know whether lithium treatment can restore some of the effects of reduced AKT1 expression levels caused by the SNP(s) of interest.

References:

Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998 55:225-232. Abstract

Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 2001 302:117-120. Abstract

Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG.. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 2008 132:125-36. Abstract

Greenwood TA, Braff DL, Light GA, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RE, Gur RC, Mintz J, Nuechterlein KH, Olincy A, Radant AD, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Swerdlow NR, Tsuang DW, Tsuang MT, Turetsky BI, Schork NJ. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 2007 64:1242-1250. Abstract

Meyer-Lindenberg AS, Weinberger DR: Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006 7:818-827. Abstract

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L: Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006 314:1930-1933. Abstract

Purohit DP, Perl DP, Haroutunian V, Powchik P, Davidson M, Davis KL: Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 1998 55:205-211. Abstract

Tan HY, Nicodemus KK, Chen Q, Li Z, Brooke JK, Honea R, Kolachana BS, Straub RE, Meyer-Lindenberg A, Sei Y, Mattay VS, Callicott JH, Weinberger DR: Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. J Clin Invest 2008 118:2200-2208. Abstract

Watanabe A, Toyota T, Owada Y, Hayashi T, Iwayama Y, Matsumata M, Ishitsuka Y, Nakaya A, Maekawa M, Ohnishi T, Arai R, Sakurai K, Yamada K, Kondo H, Hashimoto K, Osumi N, Yoshikawa T: Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 2007 5:e297. Abstract

Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE: Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001 50:825-844. Abstract

View all comments by Takeo Yoshikawa
View all comments by Akihiko Takashima

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.

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View all comments by Bernard Crespi

Related News: Children With Early Psychotic Symptoms Lag in Cognition

Comment by:  Philip Harvey
Submitted 25 February 2014
Posted 25 February 2014

The Gurs have done it again. First, they developed the first truly remotely deliverable cognitive assessment with any validity data that would stand the test of peer review. Now they have passed another hurdle: general population screening. For years, those of us interested in this topic have said: "Sure. Those kids look different, but can you go into the community, screen the whole group, and find the outliers who may be impaired?" So these studies are really important because they constitute a true, largely epidemiologically interesting sample of the population. Then the researchers relate psychosis and cognition and find a link. As Ruben said, it may happen that someday we can have high-throughput cognitive (or functional capacity, to give our work a plug) testing that can be administered at a routine clinical visit to a doctor. Any findings could lead to a referral. This could lead to targeted early interventions. The only weak link is the family who never goes to the doctor at all. Are they the ones really at risk? This study does not have to answer that question. The results stand on their own.

View all comments by Philip Harvey

Related News: Children With Early Psychotic Symptoms Lag in Cognition

Comment by:  Michael F. Green, SRF Advisor
Submitted 26 February 2014
Posted 26 February 2014

The very impressive article by Gur et al. on neurocognitive growth charting was already summarized by Michele Solis, so I will just make a couple of additional comments.

As mentioned in the summary, one of the remarkable contributions of this paper is to extend the link between cognitive impairment and psychosis down to the age of eight. This is uncharted territory, and, despite some variations, the lags in complex cognition and social cognition are relatively consistent from age eight to 20. Some of us would have expected a gradually increasing gap with increasing age, but that did not happen. That is encouraging in itself.

The authors were forward thinking and included a social cognitive domain in the battery. Sometimes people assume that social cognitive tests must be more inherently complex than mundane, non-social cognitive tests (after all, they are social), but that is not always the case. Indeed, the social cognitive tests in this battery can be considered low-level tests that place minimal demands on social inference. That means they are tapping only a subset of social cognitive processes, but they are useful here because they are fully appropriate for children.

What does a 1.5-year delay in social cognition mean for the kids? At these ages—it probably means a lot. The kids with psychosis spectrum are over a year behind in identifying the emotional expressions of their classmates, siblings, and teachers. It is not hard to imagine the social and functional consequences that might accompany the delay. Fortunately, such skills can be trained. Based on this study, we may need to develop training programs for younger participants.

View all comments by Michael F. Green

Related News: 22q11DS Model Suggests Substrate for Auditory Hallucinations

Comment by:  Jeremy Hall, SRF Advisor
Submitted 10 June 2014
Posted 10 June 2014

The paper by Chun et al. provides some very interesting and provocative new insights into the pathogenesis of psychosis in 22q11 deletion syndrome. They provide evidence for disrupted projections from the thalamus to auditory cortex which appears to be, at least in part, related to altered thalamic DRD2 receptor density. Furthermore the dopaminergic lesion appears to be mediated in part though a specific gene in the deletion region - Dgcr8. The study raises a number of interesting questions. Firstly, individuals with 22q11DS suffer from a broad range of psychotic symptoms, not just in the auditory domain. Are DRD2 abnormalities seen in other regions of the brain which may sub-serve (for example) delusional beliefs? Also, how generalizable are these findings to other genetic causes of psychosis? Perhaps most intriguingly, can similar pathway abnormalities be demonstrated in human 22q11DS sufferers with methods such as EEG/MEG and PET? This interesting study is bound to provoke more research in these areas, which can only help advance our understanding of this rare but highly penetrant genetic risk factor for schizophrenia.

View all comments by Jeremy Hall