The Genetics of Autism Spectrum Disorders
TLDR
Three approaches to identifying genetic factors that contribute to the pathogenesis of ASDs are reviewed: common variants and genome-wide association studies (GWAS); 2) rare variants and copy number variation (CNV) studies, and 3) familial forms of autism and the role of next-generation sequencing (NGS) methods.Abstract:
Autism is a neurodevelopmental disorder of complex etiology and is amongst the most heritable of neuropsychiatric disorders while sharing genetic liability with other neurodevelopmental disorders such as intellectual disability (ID). Autism spectrum disorders (ASDs) are defined more broadly and include autism, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. Under the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised (DSM-IVTR), these disorders are grouped together with Rett syndrome (“Rett’s disorder”) as pervasive developmental disorders. However, Rett syndrome has a reportedly distinct pathophysiology, clinical course, and diagnostic strategy (Levy & Schultz, 2009) and will likely be removed in the impending publication of DSM-V (APA, 2010). The new diagnostic manual will formally adopt the single diagnostic category “ASDs”, which is used here. Reported prevalence rates for ASDs range from 20 (Newschaffer et al. 2007) to 116 (Baird et al., 2006) per 10,000 children, and vary in accordance with diagnostic, sampling, and screening criteria. The Centers for Disease Control and Prevention (CDC) suggest that in the United States, the prevalence of ASDs is 1 in 110 (1/70 in boys and 1/315 in girls) (ADDM, 2009). The three primary characteristics of ASDs are communication impairments, social impairments, and repetitive/stereotyped behaviors. The DSM-IVTR, ICD-10, and many other diagnostic instruments require impairment in each of these domains for a diagnosis of autistic disorder. Within the last decade, a number of major technological developments have transformed our understanding of the genetic causes of autism, and the field continues to evolve rapidly. In this chapter, we will review three approaches to identifying genetic factors that contribute to the pathogenesis of ASDs: 1) common variants and genome-wide association studies (GWAS); 2) rare variants and copy number variation (CNV) studies, and 3) familial forms of autism and the role of next-generation sequencing (NGS) methods. Data from all three approaches underscores the conclusion that autism is a highly complex and heterogeneous disorder, involving a multifactorial etiology. Moreover, it is becoming increasingly apparent that autism is not a unitary disorder, and that the spectrum may consist of any number of different autisms that share similar symptoms or phenotypes. This conclusion has important implications for evaluation and treatment, which are discussed in the conclusion.read more
Citations
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Autworks: a cross-disease network biology application for Autism and related disorders
Tristan Nelson,Tristan Nelson,Jae-Yoon Jung,Todd DeLuca,Byron Kent Hinebaugh,Kristian Che St. Gabriel,Dennis P. Wall,Dennis P. Wall +7 more
TL;DR: Autworks is a web application that provides an easy-to-use resource for researchers of varied backgrounds to analyze the autism gene network structure within and between disorders.
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Spontaneous belief attribution in younger siblings of children on the autism spectrum
TL;DR: It is concluded that difficulties with using mental state understanding for action prediction may be an endophenotype of autism spectrum disorders.
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Dopaminergic variants in siblings at high risk for autism: Associations with initiating joint attention.
TL;DR: This paper found that younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) exhibit lower levels of initiating joint attention (IJA), sharing an object or experience with a social partner through gaze and/or gesture.
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Addressing the issue of fractionation in autism spectrum disorder: A commentary on Brunsdon and Happé, Frazier et al., Hobson and Mandy et al.:
TL;DR: It is argued that autism is a multifactorial disorder in which the particular mix of causal influences will vary from child to child, and that training studies may also be helpful in delineating causal pathways by showing the direction of different effects.
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Protein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noise
TL;DR: Analysis of the intersection between the networks obtained from the two ASD GWAS and six unrelated disease datasets identified fourteen genes exclusively present in the ASD networks, highlighting novel susceptibility genes previously hidden within GWAS statistical “noise” that warrant further analysis for causal variants.
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TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.