Trends in Genetics
Volume 23, Issue 8, August 2007, Pages 387-395
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Rethinking the nature of genetic vulnerability to autistic spectrum disorders

https://doi.org/10.1016/j.tig.2007.06.003Get rights and content

Autism is a common and genetically heterogeneous disorder, with an estimated heritability of >90%. Its specific underlying causes are largely unknown. Here, I propose that low levels of autistic vulnerability, reflected in social-cognitive processing differences, do not necessarily manifest in a behavioural phenotype but are usually compensated for during development. They are more likely to lead to a recognizable syndrome among individuals of low intelligence, who are male or have independent neurodevelopmental vulnerability owing to a wide range of gene mutations, chromosomal anomalies or environmental insults. Consequently, the apparent association between mental retardation and autistic syndromes is not because they usually have common causes, but rather because the presence of both features greatly increases the probability of clinical ascertainment.

Section snippets

Autism: identification and proposed causes

Autism is generally regarded as a severe and distinct disorder, with neurodevelopmental origins in early childhood. It affects the ability to engage in the normal to-and-fro of social interaction and is associated with restricted or abnormal use of language; by definition, these symptoms are accompanied by a range of ritualistic behaviours, restricted interests and motor stereotypies (Box 1). The ultimate cause of the condition is, in most cases, thought to be genetic susceptibility but,

Confounding between autism and mental retardation in twin studies

Evidence that autism is strongly influenced by genetic susceptibility comes largely from twin studies 18, 19, 20, 21, 22, which have shown substantially greater concordance for autistic symptoms in identical [monozygotic (MZ)] twins than dizygotic (DZ) twins (Table 1). However, the same twin studies have also shown that autistic symptoms are most prominent if there is associated mental retardation. The greater the degree of retardation, the more severe the autistic phenotype. A close

Revisiting estimates of heritability

Heritability estimates make certain assumptions. An often-quoted estimate of autism heritability is ∼90% [13]. In deriving this estimate, it was necessary to consider the findings of contemporaneous prevalence surveys of autism in the general population. Assuming a base rate of 0.0175% (derived from UK national statistics of the proportion of autistic children in educational facilities at the time the estimate was made), heritability was estimated to be 93%; however, this was reduced to 91% if

What is inherited?

These observations raise important questions about what is being inherited. If autism, as conventionally defined, is so heritable, why do so few siblings (who share half of the genetic risk) display the full (as distinct from a partial) phenotype? One possibility is that the risk of displaying the full phenotype is greatly increased if another independent risk factor is present (which could be genetic, epigenetic, stochastic or environmental in origin). There are potentially many factors that

Categorical versus dimensional aspects of the phenotype

Evidence has emerged during the past decade to indicate that clinically defined autism is not a qualitatively distinct syndrome, but it is variable in severity, independent of general intelligence, both within and between families. Several different methods of measuring autistic traits have been developed to capture the full spectrum of severity, which were extended into the general population. The first such study [30] used a questionnaire later known as the ‘Social and Communication Disorders

Genetic heterogeneity of autism

An outstanding question, for those engaged in research to find the genetic basis of autistic disorders, is whether we should expect the same set of genes to influence the risk of developing the following characteristics:

  • (i)

    Conventional autism, strictly clinically defined.

  • (ii)

    Autistic spectrum disorders, defined according to conventional criteria but with less strict degrees of severity.

  • (iii)

    Autistic traits, defined according to one or more dimensions that are continuous between clinical cases and general

Concluding remarks

Autism is a set of heritable traits, as indicated by twin and family studies, but it is probably not as heritable as previously claimed. Recent research calls into question the assumption that genes predisposing to autism also predispose to low IQ and neuropathological processes resulting in phenotypes such as epilepsy. Revised estimates of heritability, derived from conventional diagnoses in twin or family studies, would yield approximately the same values as those found by screening

Acknowledgements

I thank Tony Charman and Dorothy Bishop for their helpful and incisive comments on various drafts of the manuscript and Rebecca Chilvers whose clinical insights have contributed to the development of many of the ideas expressed herein. Particular thanks are due to the families of autistic children who have contributed to our research during the past decade, work that is supported by the Wellcome Trust, Nancy Lurie Marks Family Foundation, National Alliance for Autism Research and Simons

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