Advancing the understanding of autism disease mechanisms through genetics

Abstract

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

Figure 1

Genetic architecture of autism spectrum disorders. (a) The inheritance patterns of syndromes with known genetic etiology and high incidence of autism, as well as that of genes recently identified to be associated with autism. The red stars indicate a causal allele and the red pie charts indicate a small proportion of risk. Most dominant disorders show de novo inheritance. Autosomal recessive, autosomal dominant and X-linked inheritance patterns best fit a major gene model, whereas a polygenic model is best represented by additive risk. (b) The types of genetic variation (left and middle) and the developmental disorders (right) associated with autism. Genes that have been associated with ASD are also indicated. (c) The penetrance of known syndromic mutations summarized from multiple studies. 95% binomial proportion confidence intervals, based on Wilson’s score interval, are shown. (d) The percentage of individuals with ASD harboring known mutations, as well as the percentage of liability from different classes of mutations (taken from ref. 57). The percentage variance in liability measures the contribution of a particular variant or class of variants relative to the population variance in a theoretical variable called liability. Liability is a continuous and normally distributed latent variable that represents each individual’s risk (both genetic and environmental) for developing a disease. Notably, percentage variance in liability is directly dependent on the frequency of the variant and the effect size of the variant, and it is inversely dependent on the frequency of the disease in the population. References for this figure are found in Supplementary Table 1.

Figure 2

Convergent neurobiological mechanisms in ASD. Normal brain development requires the generation and positioning of the correct number and type of cells, the growth and targeting of neuronal processes, and the formation of the precise number and type of synapses. (a) These events are regulated by molecular pathways in development. Genes within these pathways for which there is genetic evidence for a link to ASD (Fig. 1), including from our meta-analysis of SNVs and CNVs (compiled from refs. 43,44,73,74), are colored in gold. Chemical compounds that reverse behavioral or cellular ASD phenotypes in model systems are indicated in green font near their predicted site of action. (b) The cellular events leading to changes in the higher-order organization of the brain, including disruption of fetal cortical development and synaptic function. The cortical laminae are depicted from early fetal to neonatal stages (not to scale). The numbers indicate the molecular pathways important at each stage of development. (c) The widespread pathology and functional phenotypes observed in ASD, including altered brain growth trajectories, altered cortical cytoarchitecture (red triangles indicate excitatory upper layer neurons; green triangles are excitatory deep-layer neurons; blue triangles are interneurons; numbers indicate cortical layers; WM, white matter) and connectivity, may arise from combined deficits in neurogenesis, cell fate, neuronal migration and morphogenesis during fetal development and dysregulated synaptic function, possibly in combination with reactive microglia infiltration and astrocytosis. RG, radial glia; oRG, outer radial glia; IP, intermediate progenitor; MN, migrating neuron; EN, excitatory neuron; IN, interneuron; A, astrocyte; E/I, excitatory or inhibitory neuron; U/D, upper-layer or deep-layer neuron. MPEP, 2-methyl-6-(phenylethynyl)-pyridine; CDPPB, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; DCS, D-cycloserine; IGF1, insulin-like growth factor 1. VZ, ventricular zone; ISVZ, inner subventricular zone; OSVZ, outer subventricular zone; IZ, intermediate zone; SP, subplate; CPi, inner cortical plate; CPo, outer cortical plate; MZ, marginal zone.