What is known about autism: genes, brain, and behavior

Psychiatric & Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
American Journal of PharmacoGenomics 02/2005; 5(2):71-92.
Source: PubMed


Autism is a neurodevelopmental disorder of genetic origins, with a heritability of about 90%. Autistic disorder is classed within the broad domain of pervasive developmental disorders (PDD) that also includes Rett syndrome, childhood disintegrative disorder, Asperger syndrome, and PDD not otherwise specified (PDD-NOS). Prevalence estimates suggest a rate of 0.1-0.2% for autism and 0.6% for the range of PDD disorders. There is considerable phenotypic heterogeneity within this class of disorders as well as continued debate regarding their clinical boundaries. Autism is the prototypical PDD, and is characterized by impairments in three core domains: social interaction, language development, and patterns of behavior (restricted and stereotyped). Clinical pattern and severity of impairment vary along these dimensions, and the level of cognitive functioning of individuals with autism spans the entire range, from profound mental retardation to superior intellect. There is no single biological or clinical marker for autism, nor is it expected that a single gene is responsible for its expression; as many as 15+ genes may be involved. However, environmental influences are also important, as concordance in monozygotic twins is less than 100% and the phenotypic expression of the disorder varies widely, even within monozygotic twins. Multiple susceptibility factors are being explored using varied methodologies, including genome-wide linkage studies, and family- and case-control candidate gene association studies. This paper reviews what is currently known about the genetic and environmental risk factors, neuropathology, and psychopharmacology of autism. Discussion of genetic factors focuses on the findings from linkage and association studies, the results of which have implicated the involvement of nearly every chromosome in the human genome. However, the most consistently replicated linkage findings have been on chromosome 7q, 2q, and 15q. The positive associations from candidate gene studies are largely unreplicated, with the possible exceptions of the GABRB3 and serotonin transporter genes. No single region of the brain or pathophysiological mechanism has yet been identified as being associated with autism. Postmortem findings, animal models, and neuroimaging studies have focused on the cerebellum, frontal cortex, hippocampus, and especially the amygdala. The cerebello-thalamo-cortical circuit may also be influential in autism. There is evidence that overall brain size is increased in some individuals with autism. Presently there are no drugs that produce major improvements in the core social or pragmatic language deficits in autism, although several have limited effects on associated behavioral features. The application of new techniques in autism research is being proposed, including the investigation of abnormal regulation of gene expression, proteomics, and the use of MRI and postmortem analysis of the brain.

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    • "Gene mutations have been found to play a large role in the onset of ASD (Abrahams and Geschwind, 2008). Yet while the heritability of ASD is high (nearly 90% by some estimates; Santangelo and Tsatsanis, 2005), genetic mutations known to result in the appearance of the ASD phenotype have been identified in only 30% of all ASD cases (Sakai et al., 2011). While several potential causes of ASD have been suggested (Chugani, 2004; Geschwind and Levitt, 2007; Pizzarelli and Cherubini, 2011; Zou et al., 2011; Choudhury et al., 2012), the exact etiology of ASD has yet to be elucidated (Persico and Bourgeron, 2006; Abrahams and Geschwind, 2008). "
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    ABSTRACT: Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including “axon guidance” and “regulation of actin cytoskeleton.” In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.
    Full-text · Article · Nov 2015 · Frontiers in Physiology
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    • "Evidence indicates that ASD has complex inheritance patterns [Bailey et al., 1995; Fombonne, 2005; Lauritsen et al., 2005; Freitag, 2007]. Yet despite the high heritability estimate of over 90% [Bailey et al., 1995], genetic variants that have been reported to be associated with ASD have either failed to be replicated or accounted for only a small proportion of cases [Santangelo and Tsatsanis, 2005]. Furthermore, the wide range of clinical manifestations of ASD suggests that it may in fact comprise multiple disorders that have separate etiologies but share behavioral commonalities. "
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    ABSTRACT: Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p = 3.8 × 10(-8) ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 3.3 × 10(-5) to 5.3 × 10(-7) ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2013 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "population (Bailey et al., 1995; Rutter, 2000; Szatmari, 1999), the underlying etiology of ASDs is still unknown. Many different theories researching the biological basis of ASDs have been suggested, including multiple genetic mutation, chromosomal abnormalities, epiphenomena (pre-and peri-natal complications interact with genetic factors), and immune hypotheses (Ashwood & Van de Water, 2004; Brimacombe, Ming, & Lamendola, 2007; Kolevzon, Gross, & Reichenberg, 2007; Newschaffer, Fallin, & Lee, 2002; Santangelo & Tsatsanis, 2005; Zwaigenbaum et al., 2002). Similar to the substantially increased prevalence of ASDs worldwide over the last few decades, the prevalence rates of asthma, allergic rhinitis (AR), and atopic dermatitis (AD) have risen gradually and simultaneously. "
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    ABSTRACT: Previous clinical and genetic studies have suggested autism spectrum disorders (ASDs) is associated with immunological abnormalities involving cytokines, immunoglobulins, inflammation, and cellular immunity, but epidemiological reports are still limited. Patients with ASDs were identified in the National Health Insurance Database from 1996 to 2010, and compared with age and gender-matched controls (1:4) in an investigation of the association between ASDs and allergic/autoimmune diseases. A total of 1596 patients with ASDs were identified, and were found to have a significantly higher prevalence of allergic and autoimmune diseases than the control group. Patients with ASDs had increased risks of asthma (OR = 1.74, 95%CI = 1.51–1.99), allergic rhinitis (OR = 1.70, 95%CI = 1.51–1.91), atopic dermatitis (OR = 1.52, 95%CI = 1.30–1.78), urticaria (OR = 1.38, 95%CI = 1.12–1.69) and type 1 diabetes (OR = 4.00, 95%CI = 1.00–16.00), and a trend toward increasing comorbidity with Crohn's disease (OR = 1.46, 95%CI = 0.90–2.35). Our results support the association between ASDs and allergic diseases, and autoimmune comorbidities (type 1 diabetes and Crohn's disease). Further basic study is required to elucidate the possible underlying mechanisms and roles of allergy immunity and autoimmunity in the etiology of ASDs.
    Full-text · Article · Feb 2013 · Research in Autism Spectrum Disorders
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