Genetic contributions to autism spectrum disorder

Abstract

Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

Keywords: Autism; common variation; epigenetics; genetics; heterogeneity; rare variation; transcriptomics.

Fig. 1.

Relative risk of autism by degree of relatedness with a person with autism. Relative risk for full and half siblings, and full cousins was provided in Hansen et al. (2019). Relative risk for half first cousins was estimated based on Xie et al. (2019). GS, genome shared.

Fig. 2.

Variance explained by different classes of genetic variants in autism. (a) Donut chart of the variance explained by different classes of variants. The narrow-sense heritability (82.7%, Nordic average, shades of green) has been estimated using familial recurrence data from Bai et al. (2019). The total common inherited heritability (12%) has been estimated using LDSC-based SNP-heritability (additive) from Grove et al. (2019) and the total rare inherited heritability (3%) has been obtained from Gaugler et al. (2014). The currently unexplained additive heritability is thus 67.7% (total narrow-sense heritability minus common and rare inherited heritabilities combined). This leaves a total of 17.3% of the variance to shared and unique environmental estimates (Bai et al., 2019). The term environmental refers to non-additive and non-inherited factors that contribute to variation in autism liability. Of this, de novo missense and protein-truncating variants (Satterstrom et al., 2020) and variation in non-genic regions (An et al., 2018) together explain 2.5% of the variance. Whilst de novo variation can be inherited in some cases (germline mutation in the parent) and thus shared between siblings, it is unlikely that this will be shared by other related individuals, and thus unlikely to be included in the narrow-sense heritability in Bai et al. (2019). This is likely to be a lower-bound of the estimate as we have not included the variance explained by de novo structural variants and tandem repeats. Additionally, non-additive variation accounts for ~4% of the total variance (Autism Sequencing Consortium et al., 2019). Thus, ~11% of the total variance is currently unaccounted for, though this is likely to be an upper bound. (b) The variance explained is likely to change in phenotypic subgroups. For instance, the risk ratio for de novo protein-truncating variants in highly constrained genes (pLI > 0.9) is higher in autistic individuals with ID compared to those without ID (point estimates and 95% confidence intervals provided; Kosmicki et al., 2017). (c) Similarly, the proportion of the additive variance explained by common genetic variants is higher in autistic individuals without ID compared to autistic individuals with ID (Grove et al., 2019). Point estimates and 95% confidence intervals provided.

Fig. 3.

Karyogram showing the 102 genes implicated by rare variant findings at a false discovery rate of 0.1 or less (Satterstrom et al., 2020) and the five index SNPs identified in GWAS (Grove et al., 2019) of autism.

Fig. 4.

Most commonly reported three pathways (Ayhan & Konopka, ; Gordon et al., ; Voineagu et al., 2011) associated with autism. (a) The synaptic connectivity and neurotransmitter pathway involves genes (yellow rectangular box) within presynaptic and postsynaptic neurons. Neurotransmitter transport through numerous receptors is an essential function of this pathway; (b) the chromatin remodeling pathway involves binding of remodeling complexes that initiate the repositioning (move, eject, or restructure) of nucleosomes that potentially can disrupt gene regulation; and (c) the neural projection pathway [adapted from Greig, Woodworth, Galazo, Padmanabhan, & Macklis (2013)] involves the projection of neural dendrite into distant regions and the migration of neuronal cells through ventricular (VZ) and subventricular zones (SVZ) into the different cortical layers (I-VI).