Figure 1.

The impact of CNV burden and PRS-IQ on ASD risk and cognitive ability. The estimate and 95% confidence interval (CI) of genetic factors related to cognition in conferring risk for ASD and impact on cognitive ability. (A) A greater burden of CNV deletions and duplications increase the risk for ASD and decrease cognitive ability (divergent effects). Conversely, PRS-IQ increases the risk for ASD and increases cognitive ability (convergent effects). (B) Adjusting for cognitive ability does not change the risk for ASD conferred by CNVs and PRS-IQ. The risk for ASD is evaluated only in a subgroup of cases with ASD (n=8,426) and extrafamilial controls (n=169,804) for which cognitive ability data were available. CNVs and PRS-IQ increase the risk for ASD, independently from their effects on cognitive ability. (C) The impact of deletions and duplications on ASD risk is significant – albeit, lower – when comparing subjects with ASD to their unaffected family members versus extrafamilial controls. Although they do not have a diagnosis of ASD, intrafamilial controls have an excess burden of deletions and duplications in comparison to the general population. A similar PRS-IQ between intrafamilial and extrafamilial controls suggests that the differences in PRS-IQ in (A, B) are not driven by batch effects between ASD and general population cohorts. Filled-in points represent statistically significant terms (P value ≤ 0.05 following FDR adjustment for multiple corrections). Error bars represent the 95% CIs. For detailed model results, see Supplementary Table S2 .