Schizophrenia Research Forum - A Catalyst for Creative Thinking

Rees E, Kirov G, Sanders A, Walters JT, Chambert KD, Shi J, Szatkiewicz J, O'Dushlaine C, Richards AL, Green EK, Jones I, Davies G, Legge SE, Moran JL, Pato C, Pato M, Genovese G, Levinson D, Duan J, Moy W, Göring HH, Morris D, Cormican P, Kendler KS, O'Neill FA, Riley B, Gill M, Corvin A, , Craddock N, Sklar P, Hultman C, Sullivan PF, Gejman PV, McCarroll SA, O'Donovan MC, Owen MJ. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol Psychiatry. 2014 Jan ; 19(1):37-40. Pubmed Abstract

Comments on News and Primary Papers
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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