Rare inherited variation in autism: beginning to see the forest and a few trees

Abstract

In this issue of Neuron, two papers (Lim et al., 2013; Yu et al., 2013) use whole-exome sequencing (WES) to elucidate the contribution of inherited variation to the risk for autism by leveraging the increased penetrance of homozygous and compound heterozygous rare variants in autosomes and hemizygous rare variants in the X chromosome of males. Together, they expand our knowledge about the genetic architecture of ASD, verify previously identified genes, and identify novel mutations that will guide the discovery of the critical biological processes disrupted in autism.

Figure 1. Risk imparted by different kinds of rare genetic variants

The enrichment of each form of rare mutation in ASD versus controls studied to date at a population-level(SNV estimates from Sanders et al., 2012 but also see Neale et al., 2012; O’Roak et al., 2012; Iossifov et al., 2012; CNV estimates from Sanders et al., 2011; 2-hit transmitted SNV estimates from Lim et al., 2013). These risk estimates do not include confidence intervals or all of the studies, but attempt to convey the relative effect sizes. Below the bar graph are diagrams illustrating the method of inheritance and type of mutation.

Figure 2. The percentage of variance explained by various forms of genetic risk factors for ASD

Common variants capture a large percentage of population risk for ASD (Klei et al., 2012), whereas current studies show that rare exonic variants explain a smaller amount of variance. Percent variance explained for rare variants, based on cited references in Figure 1, is estimated via the squared correlation of outcome with predicted probabilities from logistic regression (Hosmer and Lemeshow, 2012). Note that though common variants explain a large proportion of the variance, each locus is expected to be of small effect; whereas, though rare variants explain a small proportion of the variance, each locus is expected to be of larger effect. As yet unexplored rare variation (in the 98% of the genome not studied by WES), interactions among genes, and the influence of the environment are potential culprits to explain the remaining risk. Additionally, because syndromic forms of autism are typically excluded from most population-level studies from which these genetic estimates have been derived, they are not included here. Clinical ascertainment suggests that their prevalence is on the order of 5% within the entire population of autism.