Trends in Cognitive Sciences
Volume 15, Issue 9, September 2011, Pages 409-416
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Review
Special Issue: The Genetics of Cognition
Genetics of autism spectrum disorders

https://doi.org/10.1016/j.tics.2011.07.003Get rights and content

Characterized by a combination of abnormalities in language, social cognition and mental flexibility, autism is not a single disorder but a neurodevelopmental syndrome commonly referred to as autism spectrum disorder (ASD). Several dozen ASD susceptibility genes have been identified in the past decade, collectively accounting for 10–20% of ASD cases. These findings, although demonstrating that ASD is etiologically heterogeneous, provide important clues about its pathophysiology. Diverse genetic and genomic approaches provide evidence converging on disruption of key biological pathways, many of which are also implicated in other allied neurodevelopmental disorders. Knowing the genes involved in ASD provides us with a crucial tool to probe both the specificity of ASD and the shared neurobiological and cognitive features across what are considered clinically distinct disorders, with the goal of linking gene to brain circuits to cognitive function.

Section snippets

Autism genetics: a decade of progress

In many ways, autism is a mysterious disorder because it involves core abnormalities in social cognition and language, both of which are central to what makes us human. Because of this, understanding autism will have a significant impact on our basic knowledge of these fundamental cognitive processes, in addition to the obvious crucial role that such mechanistic understanding has on therapeutic development. Until the past decade, virtually nothing was known about the neurobiological basis of

Definition and evolution of ASD

Autism is a developmental neuropsychiatric syndrome with onset before the age of three. The fundamental conceptualization of the disorder is based on the initial observation of Kanner in 1943 [1], where he described 11 children with autism, mostly boys with a combination of severe social and variable language dysfunction and the presence of repetitive restrictive behaviors. Kanner made numerous interesting observations based on these case studies, including the identification of large head size

Autism is a complex genetic disorder

Perhaps the biggest advance in understanding autism pathophysiology has been the appreciation of a significant genetic contribution to the etiology of ASD. Three main areas of evidence support a genetic etiology in ASD: twin studies, comparing monozygotic twins (MZ) and dizogotic twins (DZ), family studies comparing the rate of autism in first degree relatives of affected probands (see Glossary) versus the population, and studies of rare genetic syndromes with a comorbid autism diagnosis.

The role of rare mutations versus common polymorphisms (CPs) in ASD

A series of important findings over the past four years clearly challenges the notion that autism is mainly caused by combinations of common variants by identifying a large number of rare, recurrent and nonrecurrent mutations that lead to ASD. At the same time, whole genome association studies with common variants, although identifying a few loci with very small effect sizes, have not yielded independently replicated results 28, 29. These rare mutations, mostly in the form of submicroscopic

The molecular diversity of ASD

Several recent reviews summarize the growing list of dozens of common and rare genetic variants that have been associated with ASD at varying levels of statistical evidence 27, 41, 45, 46, 47, so I refer the reader to these reviews for comprehensive gene lists. Here, instead, I will try to synthesize what these findings might be telling us about ASD pathophysiology at what is still an early juncture in the search for ASD susceptibility genes.

The most obvious general conclusion from all of the

Converging circuits and common pathways

Convergence of pathways could be assessed at many levels, ranging from molecular mechanisms to brain circuitry. The earliest synthetic molecular model was based on the notion that the primary area of convergence in ASD was the postnatal, experience-dependent development of the synapse [48]. This was a highly productive model based on several forms of Mendelian mutations in ASD, which has led to successful exploration of synaptic scaffolding molecules and other synaptic genes as ASD

Endophenotypes, common variants and domain specificity in ASD

The relations between specific genetic variants and specific cognitive processes, such as language, highlight the notion that the broad syndrome of ASD can be broken down into many component or intermediate phenotypes, referred to as endophenotypes. The familial segregation of endophenotypes provides a genetic basis for the broader phenotype described earlier. A logical extension of this concept is that these endophenotypes represent one end of the continuum of the normal spectrum of behavior

Evidence for converging molecular pathways

Several recent studies have suggested that in addition to convergent brain pathways, there could as well be convergence at the level of molecular mechanisms in ASD. One class of such studies has asked whether putative ASD susceptibility genes are enriched in members for specific molecular or biological processes more than expected by chance. The value of this approach depends on the level of experimental support for the specific genes tested and the degree to which current pathway annotations

Concluding remarks

Many genes have been identified for ASD and some biologically coherent functional pathways that link these genes are emerging. Few of the genes, whether contributing by common or rare variation, are specific to ASD but instead variably contribute to genetic risk for ASD, ID, SZ, SLI, epilepsy and even attention deficit hyperactivity disorder (ADHD). Therefore, understanding the specificity of individual variants to ASD is a crucial challenge that requires several advances to be made (Box 1).

Acknowledgments

I thank Lauren Kawaguchi for her editorial assistance and Brett Abrahams for permission to use a previously published figure. Our laboratory's work in autism and the molecular basis of human higher cognition is supported by two Autism Center of Excellence grants from NIMH: ACE Network 5R01MH081754-03 to D.H.G and ACE Center 5P50HD055784-03 (S. Bookheimer PI, D.H.G. co-PI), a Merit award from NIMH to D.H.G., 4R37MH060233-10, as well as funding from Autism Speaks and The Simons Foundation.

Glossary

Complex genetics
a term used in contrast to Mendelian patterns of inheritance, whereby instead of being dominantly or recessively inherited a phenotype is caused by multiple genes that could interact with each other and/or the environment.
Concordance
the rate at which a second individual has the same phenotype as the first, for example in the second sibling of a pair, or the second twin.
Copy number variation
a greater than one Kb change in chromosomal complement so that a particular region or

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