Clinical and Translational Implications of an Emerging Developmental Substructure for Autism

Abstract

A vast share of the population-attributable risk for autism relates to inherited polygenic risk. A growing number of studies in the past five years have indicated that inherited susceptibility may operate through a finite number of early developmental liabilities that, in various permutations and combinations, jointly predict familial recurrence of the convergent syndrome of social communication disability that defines the condition. Here, we synthesize this body of research to derive evidence for a novel developmental substructure for autism, which has profound implications for ongoing discovery efforts to elucidate its neurobiological causes, and to inform future clinical and biomarker studies, early interventions, and personalized approaches to therapy.

Keywords: canalization; causation; development; endophenotype; infancy; inheritance.

Figure 1.

Competing models for the causal sub structure of autism. In the traditional model (Panel A), inherited liabilities corresponding to the three characterizing symptom manifestations of autism (the so-called “autism triad”) contribute to genetic susceptibility for autism (See Frazier et al., 2014) In a reconceptualization informed by recent developmental research (Panel B), permutations and combinations of independent inherited liabilities (A through X, none specific to a particular autism symptom domain nor to autism itself) contribute to allostatic load for a singular latent quantitative trait (“autism”) which secondarily gives rise to the array of characterizing traits and features of the autistic syndrome. Notable implications of reconceptualization B include: (i) a unitary factor structure for the manifest symptoms of autism (i.e. that they arise from a singular underlying biological deficit), and (ii) genotype-phenotype associations will be more pronounced for the relationship between each inherited liability (A-X) and a sub structural neurobehavioral trait (a-x) than for genotypic association with “autism”, especially if autism can arise from numerous combinatorial aggregations of a-x, the effects of which might be accentuated by de novo mutations, perinatal complications, or stochastic influences on brain development.

Figure 2

shows four possible models of the developmental emergence of behavioural symptoms of ASD and ADHD. For simplicity, bidirectional interactions between genetic and environmental risk factors, intermediate phenotypes and behavior over developmental time are not shown. A: ASD and ADHD are associated with condition-specific liabilities; in addition, there are some inherited liabilities that specifically lead to comorbid ASD and ADHD. B: Here, ASD and ADHD are caused by a combination of transdiagnostic inherited liabilities, and condition-specific liabilities. C: Here, common inherited liabilities and adaptive processes are activated at condition-specific points in development. Comorbidity is created by a longer period of activation. Condition-specific genetic and environmental factors affect the timing of expression of common inherited liabilities. D: Inherited liabilities for ASD and ADHD are condition-specific, but require the absence of condition-general protective factors to be expressed. Here, comorbidity simply results from the true statistical overlap of the presence of inherited liabilities for ASD and ADHD. Reproduced with permission from Johnson et al., 2015. Key: RM = Risk Marker; PF = Protective Factor; A = ASD; D = ADHD; AD = Adaptive response. GE = genetic and/or environmental risk factors.