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The Paradox of Copy Number Variants in ASD and Schizophrenia: False Facts or False Hypotheses?

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Abstract

A series of recent papers has demonstrated “mirror extreme” variation in measures of brain size, between individuals with deletions compared to duplications, for copy number variation loci. For most loci, ASD-associated CNVs involve larger brain sizes, and schizophrenia-associated CNVs involve smaller brain sizes, the same patterns also found for idiopathic cases of ASD and schizophrenia. However, some CNVs have been linked with both disorders. Taken together, these findings appear paradoxical and require explanation. One possibility is that the paradoxical CNV data represents, to some degree, false positive diagnoses. A second possibility is that the paradox is based on false premises. I review current evidence salient to the two hypotheses, and suggest future studies to test them in a definitive way.

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References

  • Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008). Neuroanatomy of autism. Trends in Neurosciences, 31(3), 137–145.

    Article  PubMed  Google Scholar 

  • Anagnostou, E., & Taylor, M. J. (2011). Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here. Molecular Autism, 2(1), 4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Angkustsiri, K., Goodlin-Jones, B., Deprey, L., Brahmbhatt, K., Harris, S., & Simon, T. J. (2014). Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype? Journal of Autism and Developmental Disorders, 44(4), 739–746.

    Article  PubMed  PubMed Central  Google Scholar 

  • Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium. (2017). Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Molecular Autism, 8, 1–17.

    Article  Google Scholar 

  • Baribeau, D. A., & Anagnostou, E. (2013). A comparison of neuroimaging findings in childhood onset schizophrenia and autism spectrum disorder: a review of the literature. Frontiers in Psychiatry, 4, 175.

    Article  PubMed  PubMed Central  Google Scholar 

  • Barlati, S., Deste, G., Ariu, C., & Vita, A. (2016). Autism spectrum disorder and schizophrenia: do they overlap? International Journal of Emergency Mental Health, 18, 760–763.

    Article  Google Scholar 

  • Bernier, R., et al. (2016). Clinical phenotype of the recurrent 1q21.1 copy-number variant. Genetics in Medicine, 18(4), 341–349.

    Article  PubMed  Google Scholar 

  • Brunetti-Pierri, et al. (2008). Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics, 40(12), 1466–1471.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bucci, P., et al. (2016). Characterization of premorbid functioning during childhood in patients with deficit vs. non-deficit schizophrenia and in their healthy siblings. Schizophrenia Research, 174(1), 172–176.

    Article  PubMed  Google Scholar 

  • Byars, S. G., Stearns, S. C., & Boomsma, J. J. (2014). Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects. Proceedings of the Royal Society of London. Series B: Biological Sciences, 281, 20140604.

    Article  PubMed  Google Scholar 

  • Chang, Y. S., et al. (2016). Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications. Human Brain Mapping, 37(8), 2833–2848.

    Article  PubMed  Google Scholar 

  • Chaste, P., et al. (2014). Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2. Autism Research, 7(3), 355–362.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chisholm, K., Lin, A., Abu-Akel, A., & Wood, S. J. (2015). The association between autism and schizophrenia spectrum disorders: a review of eight alternate models of co-occurrence. Neuroscience & Biobehavioral Reviews, 55, 173–183.

    Article  Google Scholar 

  • Clarke, D. J., Littlejohns, C. S., Corbett, J. A., & Joseph, S. (1989). Pervasive developmental disorders and psychoses in adult life. British Journal of Psychiatry, 155(5), 692–699.

    Article  PubMed  Google Scholar 

  • Cools, R., & D'Esposito, M. (2011). Inverted-U–shaped dopamine actions on human working memory and cognitive control. Biological Psychiatry, 69(12), e113–e125.

    Article  PubMed  PubMed Central  Google Scholar 

  • Costas, J., et al. (2011). Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. Journal of Psychiatric Research, 45(1), 7–14.

    Article  PubMed  Google Scholar 

  • Crespi, B. J. (2011). One hundred years of insanity: genomic, psychological, and evolutionary models of autism in relation to schizophrenia. In M. S. Ritsner (Ed.), Handbook of schizophrenia spectrum disorders, volume I (pp. 163–185). Dordrecht: Springer.

    Chapter  Google Scholar 

  • Crespi, B. (2013). Diametric gene-dosage effects as windows into neurogenetic architecture. Current Opinion in Neurobiology, 23(1), 143–151.

    Article  PubMed  Google Scholar 

  • Crespi, B. J. (2016). The evolutionary etiologies of autism spectrum and psychotic affective spectrum disorders. In A. Alvergne, C. Jenkinson, & C. Faurie (Eds.), Evolutionary thinking in medicine: from research to policy and practice (pp. 299–327). London: Springer.

    Chapter  Google Scholar 

  • Crespi, B. J., & Crofts, H. J. (2012). Association testing of copy number variants in schizophrenia and autism spectrum disorders. Journal of Neurodevelopmental Disorders, 4(1), 15.

    Article  PubMed  PubMed Central  Google Scholar 

  • Crespi, B. J., & Go, M. C. (2015). Diametrical diseases reflect evolutionary-genetic tradeoffs: evidence from psychiatry, neurology, rheumatology, oncology and immunology. Evolution, Medicine, and Public Health, 2015(1), 216–253. https://doi.org/10.1093/emph/eov021.

    Article  PubMed  PubMed Central  Google Scholar 

  • Crespi, B., Stead, P., & Elliot, M. (2010). Comparative genomics of autism and schizophrenia. Proceedings of the National Academy of Sciences, 107(suppl 1), 1736–1741.

    Article  Google Scholar 

  • D’Angelo, D., et al. (2016). Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry, 73(1), 20–30.

    Article  PubMed  PubMed Central  Google Scholar 

  • Darwin, C. (1871). The descent of man, and selection in relation to sex. London: John Murray.

    Book  Google Scholar 

  • Dossetor, D. R. (2007). ‘All that glitters is not Gold’: misdiagnosis of psychosis in pervasive developmental disorders—a case series. Clinical Child Psychology and Psychiatry, 12(4), 537–548.

    Article  PubMed  Google Scholar 

  • Eliez, S. (2007). Autism in children with 22q11.2 deletion syndrome. Journal of the American Academy of Child & Adolescent Psychiatry, 46(4), 433–434.

    Article  Google Scholar 

  • Eliez, S., Schmitt, J. E., White, C. D., & Reiss, A. L. (2000). Children and adolescents with velocardiofacial syndrome: a volumetric MRI study. American Journal of Psychiatry, 157(3), 409–415.

    Article  PubMed  Google Scholar 

  • Fiksinski, A. M., Breetvelt, E. J., Duijff, S. N., Bassett, A. S., Kahn, R. S., & Vorstman, J. A. S. (2017). Autism spectrum and psychosis risk in the 22q11.2 deletion syndrome. Findings from a prospective longitudinal study. Schizophrenia Research, 188(1), 59–62.

  • Fitzgerald, M. (2013). Overlap between autism and schizophrenia: history and current status. Advances in Mental Health and Intellectual Disabilities, 8(1), 15–23.

    Article  Google Scholar 

  • Foss-Feig, J. H., McPartland, J. C., Anticevic, A., & Wolf, J. (2016). Re-conceptualizing ASD within a dimensional framework: positive, negative, and cognitive feature clusters. Journal of Autism and Developmental Disorders, 46(1), 342–351.

    Article  PubMed  PubMed Central  Google Scholar 

  • Golzio, C., & Katsanis, N. (2013). Genetic architecture of reciprocal CNVs. Current Opinion in Genetics & Development, 23(3), 240–248.

    Article  Google Scholar 

  • Gur, R. E., Keshavan, M. S., & Lawrie, S. M. (2007). Deconstructing psychosis with human brain imaging. Schizophrenia Bulletin, 33(4), 921–931.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hazlett, H. C., et al. (2017). Early brain development in infants at high risk for autism spectrum disorder. Nature, 542(7641), 348–351.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jacquemont, S., et al. (2011). Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 478(7367), 97–102.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jones, R. B., Thapar, A., Lewis, G., & Zammit, S. (2012). The association between early autistic traits and psychotic experiences in adolescence. Schizophrenia Research, 135(1), 164–169.

    Article  Google Scholar 

  • Jones, H. P., Testa, R. R., Ross, N., Seal, M. L., Pantelis, C., & Tonge, B. (2015). The Melbourne assessment of Schizotypy in kids: a useful measure of childhood schizotypal personality disorder. BioMed Research International, 2015, 635732.

  • Kaneda, Y., Kawamura, I., Fujii, A., & Ohmori, T. (2003). Repetitive behaviors in chronic schizophrenia: using the Japanese version of the Elgin behavior rating scale (JEBRS). International Journal of Neuroscience, 113(6), 879–890.

    Article  PubMed  Google Scholar 

  • Lainhart, J. E., et al. (1997). Macrocephaly in children and adults with autism. Journal of the American Academy of Child & Adolescent Psychiatry, 36(2), 282–290.

    Article  Google Scholar 

  • LeBlanc, J. J., & Nelson, C. A. (2016). Deletion and duplication of 16p11.2 are associated with opposing effects on visual evoked potential amplitude. Molecular Autism, 7(1), 30.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin, A., et al. (2017). Mapping 22q11.2 gene dosage effects on brain morphometry. Journal of Neuroscience, 37(26), 6183–6199.

  • Maddox, B. B., et al. (2017). The accuracy of the ADOS-2 in identifying autism among adults with complex psychiatric conditions. Journal of Autism and Developmental Disorders, 47(9), 2703–2709.

    Article  PubMed  PubMed Central  Google Scholar 

  • Maillard, A. M., et al. (2015). The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 20(1), 140–147.

    Article  PubMed  Google Scholar 

  • Malhotra, D., & Sebat, J. (2012). CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell, 148(6), 1223–1241.

    Article  PubMed  PubMed Central  Google Scholar 

  • Matheson, S. L., Vijayan, H., Dickson, H., Shepherd, A. M., Carr, V. J., & Laurens, K. R. (2013). Systematic meta-analysis of childhood social withdrawal in schizophrenia, and comparison with data from at-risk children aged 9–14 years. Journal of Psychiatric Research, 47(8), 1061–1068.

    Article  PubMed  Google Scholar 

  • McCarthy, S. E., et al. (2009). Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics, 41(11), 1223–1227.

    Article  PubMed  PubMed Central  Google Scholar 

  • McIntosh, A. M., et al. (2006). Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141(1), 76–83.

    Article  Google Scholar 

  • Mekori-Domachevsky, E., et al. (2016). Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: a two-site study. Schizophrenia Research. https://doi.org/10.1016/j.schres.2016.12.023.

  • Mulle, J. G., et al. (2014). Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biological Psychiatry, 75(5), 371–377.

    Article  PubMed  Google Scholar 

  • Ousley, O., et al. (2017). Examining the overlap between autism spectrum disorder and 22q11.2 deletion syndrome. International Journal of Molecular Sciences, 18(5), 1071.

    Article  PubMed Central  Google Scholar 

  • Qureshi, A. Y., et al. (2014). Opposing brain differences in 16p11.2 deletion and duplication carriers. Journal of Neuroscience, 34(34), 11199–11211.

    Article  PubMed  Google Scholar 

  • Rapoport, J., Chavez, A., Greenstein, D., Addington, A., & Gogtay, N. (2009). Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. Journal of the American Academy of Child & Adolescent Psychiatry, 48(1), 10–18.

    Article  Google Scholar 

  • Reaven, J. A., Hepburn, S. L., & Ross, R. G. (2008). Use of the ADOS and ADI-R in children with psychosis: importance of clinical judgment. Clinical Child Psychology and Psychiatry, 13(1), 81–94.

    Article  PubMed  PubMed Central  Google Scholar 

  • Redcay, E., & Courchesne, E. (2005). When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biological Psychiatry, 58(1), 1–9.

    Article  PubMed  Google Scholar 

  • Rees, E., et al. (2014). Evidence that duplications of 22q11.2 protect against schizophrenia. Molecular Psychiatry, 19(1), 37–40.

    Article  PubMed  Google Scholar 

  • Rimol, L. M., et al. (2012). Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder. Biological Psychiatry, 71(6), 552–560.

    Article  PubMed  Google Scholar 

  • Sahoo, T., et al. (2011). Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genetics in Medicine, 13(10), 868–880.

    Article  PubMed  Google Scholar 

  • Sanders, S. J., et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron, 70(5), 863–885.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sass, L. A., & Parnas, J. (2003). Schizophrenia, consciousness, and the self. Schizophrenia Bulletin, 29, 427–444.

    Article  PubMed  Google Scholar 

  • Schmitt, J. E., et al. (2015). Aberrant cortical morphometry in the 22q11.2 deletion syndrome. Biological Psychiatry, 78(2), 135–143.

    Article  PubMed  Google Scholar 

  • Schneider, M., et al. (2012). Preliminary structure and predictive value of attenuated negative symptoms in 22q11.2 deletion syndrome. Psychiatry Research, 196(2), 277–284.

    Article  PubMed  Google Scholar 

  • Sheitman, B. B., et al. (2004). Are the negative symptoms of schizophrenia consistent with an autistic spectrum illness? Schizophrenia Research, 69, 119–120.

    Article  PubMed  Google Scholar 

  • Shinawi, M., et al. (2010). Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 47(5), 332–341.

    Article  PubMed  Google Scholar 

  • Snyder, L. G., et al. (2016). Autism spectrum disorder, developmental and psychiatric features in 16p11.2 duplication. Journal of Autism and Developmental Disorders, 46(8), 2734–2748.

    Article  Google Scholar 

  • Solomon, M., Ozonoff, S., Carter, C., & Caplan, R. (2008). Formal thought disorder and the autism spectrum: relationship with symptoms, executive control, and anxiety. Journal of Autism and Developmental Disorders, 38(8), 1474–1484.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sporn, A. L., et al. (2004). Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness? Biological Psychiatry, 55(10), 989–994.

    Article  PubMed  Google Scholar 

  • Sprong, M., et al. (2008). Pathways to psychosis: a comparison of the pervasive developmental disorder subtype multiple complex developmental disorder and the “at risk mental state”. Schizophrenia Research, 99(1), 38–47.

    Article  PubMed  Google Scholar 

  • Steen, R. G., Mull, C., Mcclure, R., Hamer, R. M., & Lieberman, J. A. (2006). Brain volume in first-episode schizophrenia. The British Journal of Psychiatry, 188(6), 510–518.

    Article  PubMed  Google Scholar 

  • Stefansson, H., et al. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature, 505(7483), 361–366.

    Article  PubMed  Google Scholar 

  • Steinman, K. J., et al. (2016). 16p11.2 deletion and duplication: characterizing neurologic phenotypes in a large clinically ascertained cohort. American Journal of Medical Genetics Part A, 170(11), 2943–2955.

    Article  PubMed  Google Scholar 

  • Stigler, K. A., McDonald, B. C., Anand, A., Saykin, A. J., & McDougle, C. J. (2011). Structural and functional magnetic resonance imaging of autism spectrum disorders. Brain Research, 1380, 146–161.

    Article  PubMed  Google Scholar 

  • Sugihara, G., Tsuchiya, K. J., & Takei, N. (2008). Distinguishing broad autism phenotype from schizophrenia-spectrum disorders. Journal of Autism and Developmental Disorders, 38(10), 1998–1999.

    Article  PubMed  Google Scholar 

  • Tamminga, C. A., & Holcomb, H. H. (2005). Phenotype of schizophrenia: a review and formulation. Molecular Psychiatry, 10, 27–39.

    Article  PubMed  Google Scholar 

  • Tandon, R., Nasrallah, H. A., & Keshavan, M. S. (2009). Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophrenia Research, 110, 1), 1–1),23.

    Article  PubMed  Google Scholar 

  • Ulfarsson, M. O., et al. (2017). 15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia. Translational Psychiatry, 7(4), e1109.

    Article  PubMed  PubMed Central  Google Scholar 

  • van Amelsvoort, T., et al. (2004). Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia: preliminary results of a structural magnetic resonance imaging study. Archives of General Psychiatry, 61(11), 1085–1096.

    Article  PubMed  Google Scholar 

  • Van Schalkwyk, G. I., Peluso, F., Qayyum, Z., McPartland, J. C., & Volkmar, F. R. (2015). Varieties of misdiagnosis in ASD: an illustrative case series. Journal of Autism and Developmental Disorders, 45(4), 911–918.

    Article  PubMed  Google Scholar 

  • Weisman, O., et al. (2017). Subthreshold psychosis in 22q11.2 deletion syndrome: multisite naturalistic study. Schizophrenia Bulletin in press.

  • Wenger, T. L., et al. (2016). 22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening. Molecular Autism, 7(1), 27.

    Article  PubMed  PubMed Central  Google Scholar 

  • White, S., O’Reilly, H., & Frith, U. (2009). Big heads, small details and autism. Neuropsychologia, 47(5), 1274–1281.

    Article  PubMed  Google Scholar 

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  1. Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada

    Bernard J. Crespi

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Crespi, B.J. The Paradox of Copy Number Variants in ASD and Schizophrenia: False Facts or False Hypotheses?. Rev J Autism Dev Disord 5, 199–207 (2018). https://doi.org/10.1007/s40489-018-0132-x

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