Autism and Schizophrenia: Two Pieces of the genomic Puzzle
The term “Autism” referred as neural developmental disorder, which affect normal development of social brain. Psychopathological features of autism become apparent during infancy or childhood and pursue a stable course without diminution and comprise impaired social interaction and communication, and restricted and repetitive behaviours. These symptoms commonly begun following the age of six months, which become established by age of two to three years and persist throughout the life. On the other hand, schizophrenia typically refer to insufficiency of distinctive emotional responses and impairment with thought processes, which is accompanied by major social or occupational dysfunction. A combination of diverse factors, such as genetic, environment, neurobiology, along with psychological and social processes appears to be contributing in disease manifestation. Schizophrenia usually begins in early youth or young adulthood (i.e. teens and twenties) and categorized by a combination of positive (i.e. thought disorders such as racing thoughts, visual and/or auditory hallucinations, and delusions), negative (i.e. withdrawal or loss of social functioning, apathy, anhedonia, alogia, and behavioural perseveration) and cognitive (i.e. Instability in decision-making functions, memory dilemma or impairment, and failure to sustain attention) psychotic symptoms.
Historical perspective: The missing link
Over the past several decades, a great deal of scientific and medical research has been conducted on childhood and adult neuropsychiatric disorders, specially autism and schizophrenia. At a first glance, the autism and schizophrenia both seems to be the case of mental illness and phenol-typically connect with each other. In this context, autism is assumed as an early manifestation of schizophrenia and therefore referred as “schizophrenic syndrome of childhood” or “childhood psychosis”. The term Schizophrenia and Autism was firstly coined by famous Swiss psychiatrist “Eugen Bleuler” as the splitting of psychic functions in Kraepelin’s dementia praecox and withdrawal from reality in people with schizophrenia. Meanwhile, in 1943, Leo kanner suggested autism as an early, distinct subtype of schizophrenia” and conceive an association between the two. However, Leo kanner later on gave up his theory and put them as distinct and unrelated conditions. Subsequently, several theories or models have been put forth to explain the inter relationship between autism and schizophrenia. It was in the year 1971, when the concept was changed and an obvious delineation of symptomatic variations between the infantile autism and adult schizophrenia were marked. The major criteria for such delineation include, age of onset of diseases, differential treatment responses and family histories etc.
Evidences for genetic connections between schizophrenia and autism
Autistic and psychotic spectrum conditions (i.e. schizophrenia, bipolar disorder) signify two major groups of disorders of human perception and behaviour with impaired social brain. Historically, autism and schizophrenia are renowned as intimately linked in some form or another, although subsequent studies and diagnosis established a clear difference between the two. However, recent genetic studies suggest that several genes present in the chromosomal regions are caught up in Autistic and psychotic spectrum conditions. These studies were further supported by genetic, epigenetic, social and environmental studies and make clear that how genetic variations or mutations in chromosomal area could decide the fate, as either an autistic or schizophrenic phenotype.
One of such studies conducted at Department of Biosciences, Simon Fraser University, Burnaby, and Department of Sociology, London School of Economics, London, revealed that autism and schizophrenia exhibits diametrically opposite phenotypic traits linked to social development of brain. These phenotypic traits are interrelated and follow a general pattern of constrained overgrowth (in autism) and undergrowth (in schizophrenia). These studies advocate that the development of autism and schizophrenia is associated by variation of genetic imprinting. Furthermore, it is observed that etiologies of these diseases biases towards increased relative effects from imprinted genes with maternal and paternal expression.
Existance of genetic link in autism and schizophrenia were further strengthened by Jonathan Sebat and collageous of Cold Spring Harbor Laboratory, who identified the role for rare mutations and genetic heterogeneity in childhood-onset developmental disorders. They observed a strong alliance of microduplication in genomic region of chromosome 16p11.2 with extensive risk to schizophrenia. Furthermore, meta-analysis of individuals with multiple psychiatric disorders revealed the link of this microduplication with schizophrenia, bipolar disorder and autism. Taken together, these studies suggest that microduplication of 16p11.2 deliberate strong affiliation with schizophrenia and bipolar disorder, while the reciprocal microdeletion is barely associated with autism and developmental disorder.
Besides this, a number of studies using genetic linkage and chromosomal rearrangements in ASDs and schizophrenia patients report the existence of copy-number variations in the neurexin-1 gene. These studies suggest a strong association between autism, schizophrenia and de novo copy number mutations/ variants of neurexin-1 gene. According to these studies deletion / disruption or even subtle changes in neurexin-1 gene contribute to susceptibility to autism and schizophrenia. Furthermore, studies conducted on neurexin-1α deficient mice revealed that these mice were defective in excitatory synaptic transmission and exhibit marked behavioural neural phenotypes, which can correlate with impairment in autistic and schizophrenic human patients. Comparative genomic hybridization approaches identified the role of recurrent/overlapping copy number variations (CNVs) at several loci in clinical manifestation of schizophrenia, mental retardation and autism spectrum disorders. These studies suggested the existence of shared biological pathways and persistent rearrangement of neurodevelopmental and synaptic genes in autism, schizophrenia and mental retardation. Kirov and collageous at Department of Psychological Medicine, Cardiff University, Uk , also provided evidences in support of connection between large copy number variants and pathogenesis of schizophrenia. Another, recent studies published in journal of Molecular Psychiatry in 2011, suggest that reciprocal duplication and deletion of the chromosomal region 16p13.1 is firmly connected with autism schizophrenia and mental retardation. They have also identified NTAN1 and NDE1 as candidate genes present in this region. To determine the impact of family history of schizophrenia or bipolar disorder on ASD prevalence, a research study was performed, in 3 population inventory in Sweden, Stockholm County and Israel. The research work was published in Archives of General Psychiatry in 2012. According to this study, schizophrenia in parents or in sibling was firmly associated with an increased risk for ASD. These findings revealed the existence of common etiological factors among ASD, schizophrenia, and bipolar disorder.
Summary
The clinical and pathogenesis relationship between autism spectrum disorders (ASDs) and schizophrenia is still poorly understood. However, when link was properly traced, it reveals that schizophrenia and autism shared several common features including social and cognitive dysfunction, and genetic connection. It makes valid sense to historically renowned association between the two. Autism and schizophrenia both represents neuro-developmental disorders of complex etiology, characterized by participation of genetic factors. A large number of studies accounted that people with schizophrenia and those with autism share an irregularity in the same genes. Advances in human genetic in association with human genome sequence have led to the identification of multiple genes and copy number variations (CNV) in etiology of autism, schizophrenia, and many other psychiatric disorders. Genome wide association and CNV studies reported genetic overlaps between schizophrenia and autism patients and find out share genes and genetic mutations among autistic and schizophrenic patients. The Copy number variants (CNV) are emerging as an important genomic cause of autism and schizophrenia and may account for increased susceptibility to more than one psychiatric phenotype. In conclusion, autism and schizophrenia share certain clusters of genes as well as similar DNA fingerprints. These finding speculate that there may be a large number of genes in brain that are dedicated for these disorders. Thus, understanding the biology of these genes and their role in the pathogenesis of ASDs and schizophrenia has important implications for researchers and clinicians, and those affected by the disorders.
Suggested literature
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Kim, H. G., S. Kishikawa, et al. (2008). “Disruption of neurexin 1 associated with autism spectrum disorder.” Am J Hum Genet 82(1): 199-207.Abstract
McCarthy, S. E., V. Makarov, et al. (2009). “Microduplications of 16p11.2 are associated with schizophrenia.” Nat Genet 41(11): 1223-1227. Abstract.
Etherton, M. R., C. A. Blaiss, et al. (2009). “Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.” Proc Natl Acad Sci U S A 106(42): 17998-18003.Abstract.
Rujescu, D., A. Ingason, et al. (2009). “Disruption of the neurexin 1 gene is associated with schizophrenia.” Hum Mol Genet 18(5): 988-996. Abstract.
Parnas, J., P. Bovet, et al. (2002). “Schizophrenic autism: clinical phenomenology and pathogenetic implications.” World Psychiatry 1(3): 131-136.Abstract.
Guilmatre, A., C. Dubourg, et al. (2009). “Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.” Arch Gen Psychiatry 66(9): 947-956. Abstract
Kirov, G., D. Grozeva, et al. (2009). “Support for the involvement of large copy number variants in the pathogenesis of schizophrenia.” Hum Mol Genet 18(8): 1497-1503.Abstract
Ingason, A., D. Rujescu, et al. (2011). “Copy number variations of chromosome 16p13.1 region associated with schizophrenia.” Mol Psychiatry 16(1): 17-25.Abstract
McCarthy, S. E., V. Makarov, et al. (2009). “Microduplications of 16p11.2 are associated with schizophrenia.” Nat Genet 41(11): 1223-1227. Abstract
Sullivan, P. F., C. Magnusson, et al. (2012). “Family history of schizophrenia and bipolar disorder as risk factors for autism.” Arch Gen Psychiatry 69(11): 1099-1103.Abstract