Most genetic risk for autism resides with common variation

Abstract

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

Figure 1

Results for PAGES (Population-based Autism Genetics and Environment Study), the Swedish study of the heritability of autism. (a) Heritability estimate (95% confidence interval) compared across study designs and analytical methods. Horizontal reference is the PAGES estimate of heritability from SNP genotypes. Twin studies: 1 California twins for strict autism (95% confidence interval: 8–84%), the largest twin study to date using diagnosis only; 2, Swedish twins 9–12 years old (95% confidence interval: 29–91%); 3, Swedish twins 9–12 years old characterized for a quantitative measure of autism (most extreme cutoff; 95% confidence interval: 44–74%). SNP-based estimates of heritability: 4, Swedish family study (95% confidence interval: 44–64%); 5, simplex cases versus population controls (95% confidence interval: 26–73%); 6, multiplex autism cases versus population controls (95% confidence interval: 38–93%). SNP-based estimates from the PAGES study, assuming prevalence K=0.3%; 7, heritability due to common variants using autism cases versus population controls (95% confidence interval: 31–69%); 8, total narrow-sense heritability due to both common and rare variation using smoothed estimates of relatedness (95% confidence interval: 35–71%). (b) Heritability per chromosome versus length in cM. (c) Prevalence by county for all 21 counties in Sweden tallied by birth year cohort. Each boxplot has a lower tail that extends from the minimum county-level prevalence to the 25^th percentile; a central box that begins at the 25^th percentile and ends at the 75^th percentile, with a line demarcating the median prevalence; and an upper tail that extends from the 75^th percentile to either (1) the maximum county-level prevalence (in the absence of any outliers) or (2) to a value of the 75^th percentile + 1.5 times the vertical distance covered by the box – in this case, any outliers that exceed this end of the tail are noted by circular points on the plot. (d) PAGES heritability versus population prevalence of autism for two estimators of heritability: case-control contrast using SNP genotypes (green); total heritability from smoothed relationships amongst subjects, based on SNP genotypes (blue). Beyond the analysis of the PAGES study we applied meta-analysis of selected h² estimates (Methods) to obtain h² = 51.4% (SE = 5.2), which corresponds to a 95% confidence interval of (41.0, 61.8). Contrasting this with the comprehensive estimate of h² obtained from the Swedish family study (h² = 54%, SE = 5) produces an estimate of h² due to rare variants: h² = 2.6% (SE = 7.2, 95% confidence interval: 0–17%). Hence we conclude that common variants explain the bulk of the heritability for autism, at least 41% of the variability, and rare variants explain at most 17%, based on the upper and lower bounds of the respective 95% confidence intervals.

Figure 2

Results regarding the genetic architecture of autism spectrum disorder. The variance of autism liability is determined by genetic and environmental factors. The genetic factors include: ‘A’ additive effects, ‘D’ non-additive effects (dominant, recessive, epistatic), and ‘N’ de novo mutations. The environmental factors are split between ‘C’ common or shared environment and ‘E’ stochastic or unique environment. (a) Early autism twin studies estimate ‘A’ from the contrast of monozygotic (MZ) and dizygotic (DZ) correlations while assuming that ‘D’ and ‘N’ are zero. These are common assumptions for ‘ACE’ heritability models, but are unlikely to be appropriate for autism. (b) Applying the ACE model to the largest autism twin study to date yields a lower estimate of additive heritability. (c) Heritability results using a more extensive set of family relationships and based on much of the population of Sweden. (d) Results from the PAGES study (see Fig. 1). (e) Contribution of the various factors to the variance of autism liability according to family relationship. De novo variation should not be shared in dizygotic twins, and when it appears to be, it is almost surely inherited variation from a parent with gonadal mosaicism because the chance of the same mutation appearing de novo in the dizygotic twins is negligible. Most twin studies assume ‘C’ is the same for monozygotic and dizygotic twins, although that approximation has been debated. Of note, the excess covariance of monozygotic twins relative to dizygotic twins is 1/2 A+ 3/4 D + N as opposed to the 1/2 A assumed in the ACE model. (f) Synthesis of results for the genetic architecture of autism.