Fig. 2: A model of rare large-effect de novo mutations acting in combination with common risk alleles.

a An idealized distribution of common polygenic risks that are normally distributed in the general population. The red vertical dotted line represents an arbitrary cutoff for the diagnosis of ASD. For a highly heritable disorder such as ASD, those at the low end of the distribution of risk (left) will be less likely to meet diagnostic criteria than those on the far right end of the distribution. The superimposition of the upper panel and the lower panel (b), representing the distribution of ASD symptoms in the population, models the observation that the vast majority of common allele population risk is present in individuals without a clinical diagnosis. The lower panel (b) shows the same red dotted vertical line reflecting an arbitrary cutoff for the categorical diagnosis of ASD. The abbreviations in parenthesis (epi epilepsy, ADHD attention deficit hyperactivity disorder, SCZ schizophrenia, SLI specific language impairment) reflects the observation that highly penetrant ASD risks may also carry risks for diagnoses apart from ASD. The arrows on the bottom of the diagram represent large-effect rare de novo mutations. The purple arrow is showing how a large risk de novo mutation can move an individual with intermediate risk and the likelihood of no symptoms across the diagnostic threshold. The gray arrow reflects the observation that these risks while large are not Mendelian and that sometimes rare large-effect mutations do not show a phenotype at all, which may reflect that they are acting in the context of very low polygenic risk. The purple box on the right side of (b), reflects the finding that while de novo mutations carry a very small proportion of population risk, they represent a substantial fraction of individuals who exceed clinical thresholds.