Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.

Figure 1

ASD probands over inherit polygenic risk for ASD, schizophrenia, and greater educational attainment. Transmission disequilibrium is shown in terms of standard deviations on the mid-parent distribution ± 1.96 standard error (95% confidence intervals). P-values denote the probability that the mean of the pTDT deviation distribution is 0 (two-sided, one-sample t-test). (a) ASD probands over inherit ASD associated polygenic risk in the Simon Simplex Collection (SSC, n = 2,584), Psychiatric Genomics Consortium Autism Group (PGC ASD, n = 3,870), and combined cohorts (n = 6,454). Unaffected siblings in SSC (n = 2,091) do not over inherit ASD associated polygenic risk. (b) Both male (n = 5,490) and female (n = 962) probands over inherit ASD associated polygenic risk in the SSC+PGC ASD combined cohort. (c) ASD probands with (n = 1,341) and without (n = 2,743) intellectual disability (full-scale IQ < 70) over inherit ASD associated polygenic risk in the SSC+PGC ASD combined cohort.

Figure 2

Contributing de novo mutations are associated with adverse neurological and developmental outcomes and act additively with polygenic burden to influence ASD risk. (a) Simons Simplex Collection (SSC) probands are grouped by their count of the following: delayed walking (≥ 19 months); presence of seizures; intellectual disability (full-scale IQ < 70) (n = 1,476 with no outcomes; n = 719 with 1 outcome; n = 134 with 2 outcomes; n = 16 with 3 outcomes). Contributing de novo variant (CDNV) rate is calculated by dividing the count of CDNVs by the count of individuals. The odds ratio (OR) was calculated via Poisson regression predicting CDNV count from case/control status for all controls (n = 1,736) and cases in the outcome category, controlling for maternal and paternal age at birth of the child. P-values above each diamond are from the Poisson regression and indicate the probability that the CDNV rate in cases is not different from the CDNV rate in controls. P-values between the diamonds are calculated from Poisson exact test and indicate the probability that there is no difference in CDNV rate between the two noted groups. Error bars are ± 1 standard error. (b) pTDT analysis for SSC CDNV proband carriers (n = 221). Transmission disequilibrium is shown in terms of standard deviations on mid-parent distribution ± 1.96 standard error (95% confidence intervals). P-values denote the probability that the mean of the pTDT deviation distribution is 0 (two-sided, one-sample t-test).

Figure 3

(a) Additivity among orthogonal risk factors can yield high cumulative risk. (b) Polygenic risk scores (PRS) for ASDs, schizophrenia (SCZ), and educational attainment (EA) are not strongly associated at either the mid-parent level (above diagonal) or the pTDT deviation level (below diagonal). The table contains Pearson correlation coefficients and associated p-values indicating the probability with which the true correlation is 0. Mid-parent correlations are controlled for first 10 principal components of parental ancestry. PRS are from European ancestry SSC families (n = 1,851). (c) Polygenic risk factors for ASD exhibit independent, distinct effects on IQ in European ancestry SSC probands (n = 1,674). P-values, which estimate the probability of no association between each PRS and IQ, are calculated from linear regression. We predicted full-scale IQ from each PRS, z-normalized following residualization for the other two PRS, CDNV presence/absence, proband sex, and the first 10 principal components of proband ancestry. Each panel displays the linear association between full-scale proband IQ and the normalized PRS.