Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analysed exome-sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. In our new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF intolerant genes, supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n=159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which we had genome-wide common variant data, schizophrenia and bipolar disorder polygenic risk were significantly over-transmitted to probands. Probands carrying LoF or deletion DNVs in LoF intolerant or neurodevelopmental disorder genes had significantly less over-transmission of schizophrenia polygenic risk than non-carriers, providing robust support for these DNVs increasing liability to schizophrenia.