Autism genetics: searching for specificity and convergence

Abstract

Advances in genetics and genomics have improved our understanding of autism spectrum disorders. As many genes have been implicated, we look to points of convergence among these genes across biological systems to better understand and treat these disorders.

Figure 1

Genetic models of ASD risk. Schematic representations of Mendelian and polygenic models of ASD risk are depicted, with evidence for and against each model listed below. In the diagram at the top, the rows represent the type of individual: those with ASD, and those with some risk factors but not sufficient to manifest the clinical syndrome, such as unaffected relatives. The columns represent the basic categories of genetic models under consideration. The size of the variant represents effect size, with a larger symbol indicating increased effect size. For simplicity, these models are presented as distinct categories, whereas in reality ASD risk is likely to be represented by a more continuous distribution of risk architecture. A single asterisk indicates that there is evidence to suggest that de novo CNVs in unaffected controls are smaller [21,51,52] and less gene-rich [20,21] than in people with ASD. A double asterisk indicates that there is conflicting evidence for increased oligogenic heterozygosity [25,156].

Figure 2

Emerging biological themes in ASD. (a,b) Predominant areas of neuroanatomical convergence in ASD. (a) Aberrant brain growth trajectories, with the size of ASD brains outlined in red against a background of normal brains [144-146] (images adapted from [157]); (b) abnormal cortical columns [151]. (c,d) Systems-level convergence in ASD. (c) White matter tract and functional connectivity abnormalities [126,147-150,152,153] (images reproduced with permission from Mark Bastin, University of Edinburgh, UK); (d) excitation/inhibition network imbalances [93,132,136-141], (e-g) Genetic convergence at the cellular and molecular levels. ASD-associated genes implicated in (e) activity-dependent protein synthesis [17,21,23,79,109,113-123], (f) neuronal activity [21,22,25,70,105-112], and (g) neuronal cell adhesion [20-22,34-37,49-52,68,75,79,93,109,126-129,131-137].