Fig. 1. Study design for analysis of genic and allelic pleiotropy.

a Study design for analysis of genic pleiotropy. Genes enriched for protein-truncating variants or missense variants in neurodevelopmental disorders with a P value <2.5 × 10⁻⁶ were identified from the Deciphering Developmental Disorders study¹⁴. For each NDD gene set, the observed and expected number of de novo variants in 3444 schizophrenia trios was compared using a two-sided two-sample Poisson rate ratio test. See Methods for further details. b Study design for analysis of allelic pleiotropy. Neurodevelopmental disorder variants were defined as de novo mutations reported in the largest sequencing studies of developmental disorders¹⁴ and autism spectrum disorders³². Neurodevelopmental disorder variants were stratified into a NDD primary variant set, defined as those alleles annotated as protein-truncating variants affecting loss-of-function intolerant genes or missense variants with an MPC score ≥2. The remaining neurodevelopmental disorder variants (protein-truncating variants not affecting loss-of-function intolerant genes, missense variants with an MPC score ≤2 and synonymous variants) were grouped into a NDD comparator variant set. The observed and expected number of schizophrenia de novo variants overlapping alleles within each NDD variant set was compared using a two-tailed Poisson exact test. See Methods for further details. NDD, neurodevelopmental disorder; SZ, schizophrenia; DD, developmental disorder; ASD, autism spectrum disorder; PTV, protein-truncating variant; MPC, “Missense badness, Polyphen-2, Constraint” pathogenicity score²⁹.