Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment

Abstract

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.

Figure 1

ASD risk factors converge onto shared biological pathways and cell-types during early brain development. (A) Rare inherited, de novo and common inherited variants contribute to ASD liability, in addition to environmental risk factors. (B) Genetic (and likely environmental) factors converge onto biological pathways as schematized in this PPI network made using the STRING database (62) derived from risk genes in (36,41). Genes implicated in synaptic transmission (blue), transcriptional and epigenetic regulation (red), protein ubiquitination (purple), axon outgrowth (black) and the cellular cytoskeleton (green) are highlighted. Risk genes that do not fall into those categories are shown in gray and include those related to Wnt signaling, such as CTNNB1, and the cell cycle, such as PTEN. (C) The expression of risk genes peaks during prenatal development but is not exclusive to this period. Adapted from (63). (D) Expression of risk genes is concentrated in developing glutamatergic neurons. RG—radial glia; MP—migrating progenitor; IP—intermediate progenitor; EN—excitatory neuron; IN—inhibitory neuron; O—oligodendrocyte precursor cell; E—endothelial cell; P—pericyte; M—microglia. Adapted from (64). (E) Impacted biological pathways and phenotypes will vary across individuals and in their convergence and divergence on clinical manifestation.