6 November 2009. The bright diagnostic line between autism and schizophrenia, only about 30 years old, has again begun to blur, prompted by genomic studies of copy number variations (CNVs) that have implicated the same chromosomal regions in both disorders. Four recent CNV studies continue this trend, and further evidence for shared genetic causes of autism and schizophrenia comes from new behavioral and electrophysiological experiments with knockout mice lacking the presynaptic protein neurexin-1α, the gene for which has been implicated in both disorders.
Are schizophrenia and autism two sides of one coin?
Though now thought of as quite different disorders, historically autism and schizophrenia have been tightly intertwined. Bleuler (1911 [Bleuler, E. Dementia praecox oder Gruppe der Schizophrenien. Leipzig und Wien: F. Deuticke]) coined the term “autism” to describe social withdrawal as a negative symptom of schizophrenia. In his classic description of children with autism, Kanner (1943: Autistic disturbances of affective contact. Nerv Child 2: 217–50. Reprinted in Acta Paedopsychiatr, 1968) made a convincing case that a pervasive disposition to aloneness could occur in the absence of psychosis (see SRF related news story), but it wasn’t until Kolvin’s (1971) differentiation of autism and schizophrenia based on age of onset that this idea began to enter the psychiatric mainstream, capped in 1980 by the inclusion of autism as a diagnostic category distinct from schizophrenia in DSM-III.
Not surprisingly, many genes in the putative shared chromosomal regions reported in recent studies are involved in neural development and synaptogenesis (see SRF related news story; SRF news story), and researchers have begun to formulate genetic, epigenetic, and environmental hypotheses to explain how variations in a suite of shared chromosomal regions could lead to either an autistic or schizophrenic phenotype.
One of the most provocative ideas, proposed by Bernard Crespi of Simon Fraser University and Christopher Badcock of the London School of Economics, holds that autism and schizophrenia are diametrically opposed disorders of the “social brain,” and that genomic imprinting of the same set of mutated genes can cause schizophrenia or autism, respectively, depending on developmental biases toward the expression of maternally versus paternally imprinted genes (see, e.g., Crespi and Badcock, 2008). One of the new studies appears to provide some supporting data for this hypothesis in the broad sense of two mutually exclusive disorders.
16p11.2: a clear-cut case?
“Crespi and colleagues are right on for the most part,” says Jonathan Sebat of Cold Spring Harbor Laboratory, who led the latest CNV study (McCarthy et al., 2009). Sebat and colleagues report that, in a cohort of 1,906 cases of schizophrenia and 3,971 controls, both drawn from a variety of sources, microduplications in a ~500-kb region of 16p11.2 were strongly associated with schizophrenia, a finding that was replicated in an independent sample of 2,645 cases and 2,420 healthy controls.
However, because members of five families in their original sample had a range of psychiatric diagnoses other than schizophrenia, the team also performed a meta-analysis on a sample assembled from publicly available datasets that included 8,590 individuals with schizophrenia, 2,172 with autism, 4,822 with bipolar disorder, and 30,492 controls. In the meta-analysis, the duplication was strongly associated with schizophrenia (P = 4.8 x 10-7), autism (P = 1.9 x 10-7), and bipolar disorder (P = 0.017), but the reciprocal microdeletion was associated only with developmental delay or autism (P = 2.3 x 10-13). The microdeletion was also significantly associated with larger head circumference, a phenotype that has been associated with brain hypertrophy early in development in autism (see, e.g., Courchesne, 2007).
Sebat says the findings do not perfectly reflect the complex models, which involve imprinting, proposed by Crespi and Badcock. However, he adds, “Crespi has also proposed that reciprocal deletion and duplication syndromes would possibly create diametrically opposed disorders, including schizophrenia and autism.”
Though perhaps not as clear-cut as these 16p11.2 findings, a series of recent CNV studies have also reported genetic overlaps between schizophrenia and autism. In April, members of Michael O’Donovan’s group at Cardiff University reported a deletion at 22q11.2 in two cases of schizophrenia (Kirov et al., 2009); deletions in this region are associated with velo-cardio-facial syndrome and with autism (Ousley et al., 2007). Other large deletions, one disrupting exons in neurexin-1 (NRXN1) and the other affecting the neurexophilin (NXPH2) gene, which interacts with NRXN1, were found in cases of schizophrenia. Neither neurexin-related deletion achieved significance, but it is notable that deletions affecting neurexin-1 have previously been implicated in both autism and schizophrenia (see SRF related news story).
Recent work with neurexin-1α knockout mice by Thomas Südhof and colleagues (Etherton et al., 2009) revealed an electrophysiological phenotype related to a loss of presynaptic strength at excitatory synapses. Though these mice exhibited no notable deficits in social behaviors, they displayed marked changes in behaviors with face validity to autism (repetitive grooming) and to autism and schizophrenia (impaired prepulse inhibition).
The Cardiff team also found a large duplication on 16p13.1 that has been associated with autism and mental retardation (Ullmann et al., 2007; Behjati et al., 2008) in three schizophrenia cases, and a 5-Mb duplication in one case in the Prader-Willi/Angelman syndrome critical region on chromosome 15. A large international team (Ingason et al., 2009) also found that duplications in the 16p13.1 region containing NTAN1 and NDE1, neurodevelopmental genes previously associated with mental retardation, are three times more common in schizophrenia cases than in controls. A link between NDE1, a DISC1 binding partner, and schizophrenia in women has been previously reported (see SRF related news story).
In a clever paradigm, a French-Italian team (Guilmatre et al., 2009) combed the literature, identifying 28 candidate CNV loci that have been associated with schizophrenia, autism, or mental retardation in microarray studies. After assembling a sample of individuals representing each diagnosis roughly equally, the groups used several methods in a fine-grained analysis of the candidate loci. They found recurrent or overlapping CNVs at nearly 40 percent of these locations for all three diagnoses. A particularly strong association was found between a 350-kb deletion at 22q11 spanning the PRODH and DGCR6 genes. Deletions affecting this chromosome have been tied to schizoaffective disorder and autism (see SRF related news story). “This implies the existence of shared biologic pathways in these three neurodevelopmental conditions,” the authors write.
According to Sebat, both genomewide association and CNV studies are spurring interest in commonalities between psychiatric disorders. He says, “Clearly there is genetic overlap between psychiatric brain disorders—between schizophrenia and bipolar disorder, between schizophrenia and autism. Maybe a large set of brain genes can give rise to multiple disorders, and it’s how those genes are mutated that influences the phenotype. People have said that you can’t place autism and schizophrenia on a spectrum. Well, maybe you can.”—Pete Farley.
Etherton MR, Blaiss CA, Powell CM, Südhof TC. Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17998-8003. Abstract
Guilmatre A, Dubourg C, Mosca AL, Legallic S, Goldenberg A, Drouin-Garraud V, Layet V, Rosier A, Briault S, Bonnet-Brilhault F, Laumonnier F, Odent S, Le Vacon G, Joly-Helas G, David V, Bendavid C, Pinoit JM, Henry C, Impallomeni C, Germano E, Tortorella G, Di Rosa G, Barthelemy C, Andres C, Faivre L, Frébourg T, Saugier Veber P, Campion D. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry. 2009 Sep;66(9):947-56. Abstract
Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietiläinen OP, Buizer-Voskamp JE, Strengman E, Francks C, Muglia P, Gylfason A, Gustafsson O, Olason PI, Steinberg S, Hansen T, Jakobsen KD, Rasmussen HB, Giegling I, Möller HJ, Hartmann A, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Bramon E, Kiemeney LA, Franke B, Murray R, Vassos E, Toulopoulou T, Mühleisen TW, Tosato S, Ruggeri M, Djurovic S, Andreassen OA, Zhang Z, Werge T, Ophoff RA; GROUP Investigators, Rietschel M, Nöthen MM, Petursson H, Stefansson H, Peltonen L, Collier D, Stefansson K, Clair DM. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry. 2009 Sep 29. Abstract
Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P; International Schizophrenia Consortium; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet. 2009 Apr 15;18(8):1497-503. Abstract
McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009 Nov;41(11):1223-7. Abstract