Common genetic variants, acting additively, are a major source of risk for autism

Weill Cornell Medical College, New York, New York, United States
Molecular Autism (Impact Factor: 5.41). 10/2012; 3(1):9. DOI: 10.1186/2040-2392-3-9
Source: PubMed


Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals.

By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status.

By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating.

Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

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    • "Idiopathic ASD is used to describe cases where ASD is the primary diagnosis and syndromic ASD consists of cases where ASD is a secondary diagnosis, which can be linked to common genetic variants such as Rett syndrome or fragile X syndrome (Carter and Scherer, 2013). As such, ASD is considered a polygenic disorder, which can arise from multiple different genetic variants, in addition to unidentified environmental factors (Carter and Scherer, 2013; Klei et al., 2012). Fragile X syndrome (FXS) is a developmental disorder and one of the most common inherited forms of ID, characterized by moderate to severe ID and mild facial deformities. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a group of heritable disorders with complex and unclear etiology. Classic ASD symptoms include social interaction and communication deficits as well as restricted, repetitive behaviors. In addition, ASD is often comorbid with intellectual disability. Fragile X syndrome (FXS) is the leading genetic cause of ASD, and is the most commonly inherited form of intellectual disability. Several mouse models of ASD and FXS exist, however the intellectual disability observed in ASD patients is not well modeled in mice. Using the Fmr1 knockout mouse, and the eIF4E transgenic mouse, two previously characterized mouse models of fragile X syndrome and ASD respectively, we generated the eIF4E/Fmr1 double mutant mouse. Our study shows that the eIF4E/Fmr1 double mutant mice display classic ASD behaviors, as well as cognitive dysfunction. Importantly, the learning impairments displayed by the double mutant mice spanned multiple cognitive tasks. Moreover, the eIF4E/Fmr1 double mutant mice display increased levels of basal protein synthesis. The results of our study suggest that the eIF4E/Fmr1 double mutant mouse may be a reliable model to study cognitive dysfunction in the context of ASD. Copyright © 2015. Published by Elsevier Inc.
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    • "Family studies indicate a significant genetic basis for ASD susceptibility, but the underlying genetic architecture is highly complex and heterogeneous. Recent genome-wide studies have documented that common variants exert only small individual main effects on risk, although when common variation (CV) across the genome is considered in aggregate, CV is found to contribute measurably to ASD risk [Klei et al., 2012]. In addition, rare inherited and de novo copy number variants (CNVs) and single nucleotide variants (SNVs) of large effect size have a major role in the etiology of ASD, contributing in as many as 5–10% of idiopathic cases examined [Devlin and Scherer, 2012]. "
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    ABSTRACT: Chromosome 15q13.3 recurrent microdeletions are causally associated with a wide range of phenotypes, including autism spectrum disorder (ASD), seizures, intellectual disability, and other psychiatric conditions. Whether the reciprocal microduplication is pathogenic is less certain. CHRNA7, encoding for the alpha7 subunit of the neuronal nicotinic acetylcholine receptor, is considered the likely culprit gene in mediating neurological phenotypes in 15q13.3 deletion cases. To assess if CHRNA7 rare variants confer risk to ASD, we performed copy number variant analysis and Sanger sequencing of the CHRNA7 coding sequence in a sample of 135 ASD cases. Sequence variation in this gene remains largely unexplored, given the existence of a fusion gene, CHRFAM7A, which includes a nearly identical partial duplication of CHRNA7. Hence, attempts to sequence coding exons must distinguish between CHRNA7 and CHRFAM7A, making next-generation sequencing approaches unreliable for this purpose. A CHRNA7 microduplication was detected in a patient with autism and moderate cognitive impairment; while no rare damaging variants were identified in the coding region, we detected rare variants in the promoter region, previously described to functionally reduce transcription. This study represents the first sequence variant analysis of CHRNA7 in a sample of idiopathic autism. © 2015 Wiley Periodicals, Inc.
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    • "While few studies have looked at the role of common variants in autism, an earlier study that involved Dr. Roeder also examined the role of additive genetic effects in autism. That paper, published in 2012, showed that myriad common variants, each with very small effect, impact risk for autism [Klei et al., 2012]. "

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