The conundrums of understanding genetic risks for autism spectrum disorders

Abstract

Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. At the same time, the emerging data challenge long-standing diagnostic conventions and the notion of phenotypic specificity. This review addresses the particular issues that attend gene discovery in neuropsychiatric and neurodevelopmental disorders and ASDs in particular, summarizes recent findings in human genetics broadly that are driving the reevaluation of the conventional wisdom regarding the allelic architecture of common psychiatric conditions, reviews selected discoveries in ASDs and their relevance to models of pathology, highlights the conceptual and practical issues raised by the observation of a convergence of ASD genetic risks with distinct psychiatric disorders, and considers the important interplay of studies of neurobiology and genetics in clarifying and extending our understanding of social disability syndromes.

Figure 1. Allele frequency and effect size in ASD

The graph illustrates the relationship of allele frequency to effect size for ASD-related variants. Rare mutations, as expected, have been found to carry larger effects than common variations. Consistent with the broad medical literature, the scale of effects for common alleles implicated in ASD has been quite modest. The linkage (blue) and association (green) sections illustrate the historically divergent approaches to demonstrating the role of rare versus common variation in disease; rare alleles have been expected to show an approximately 1:1 relationship with a given phenotype, often demonstrated via linkage, while common polymorphisms have been expected to show more probabilistic outcomes, typically demonstrated by some type of case-control association design. The shaded area illustrates that the range of effect sizes for rare alleles identified in ASD to date have been broader than those expected for strictly Mendelian disorders, and that association approaches have been necessary to confirm the relationship of genotype to phenotype.

Figure 2. Convergent rare risks and common modulators leading to divergent neuropsychiatric disorders

The figure illustrates one explanatory model for the combination of specific rare variations, carrying large effects for ASD, with common functional variants modulating the risk for clinically distinct phenomenon. The ideogram on the left represents the human genome and the black bars, the high degree of locus heterogeneity underlying ASD; the dotted lines link divergent loci to rare mutations that disrupt protein function and/or structure and sub-serve coherent molecular pathways. Here this is illustrated as multiple mutations in synaptic molecules, though as noted in the text, it is likely that a variety of distinct neural-developmental processes are altered by ASD-related mutations. In this model, alterations to basic cellular and molecular processes are expressed through increasingly complex layers of organization, represented in the figure by the diffusion tensor imaging data showing long-range neural pathways. Moreover, the manifestations of these altered molecular and cellular processes play out across development and are influenced by a variety of factors, including, importantly, common functional genetic variation (most likely regulatory in nature), as well as stochastic effects, environmental inputs and epigenetic phenomenon (shown in the text box at the bottom of the figure). The graph on the far right further illustrates that particular genetic variations may launch and simultaneously influence diverse developmental trajectories (lines of similar colors reflect rare mutations in the same CNV or gene) that may ultimately correspond to a range of distinct clinical phenomenon (in this example ASD and schizophrenia (Scz)) or to typical development.