Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports 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, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.

精神分裂症是一种高度多基因疾病，常见和罕见的风险等位基因都有重要贡献。我们分析了 613 个精神分裂症三重奏的新样本中的从头变异 (DNV) 的外显子组测序数据，并将其与已发表的数据相结合，得出总共 3,444 个三重奏。在这些新数据中，功能丧失 (LoF) DNV 在 3,471 个 LoF 不耐受基因中显着富集，这支持了之前的发现。在完整数据集中，LoF DNV 中与神经发育障碍相关的基因 ( n = 159) 显着富集。在这些神经发育障碍基因中，编码 γ-氨基丁酸转运蛋白的SLC6A1与错义破坏性 DNV 相关。在可获得全基因组常见变异数据的 1,122 个三人组中，精神分裂症和双相情感障碍的多基因风险显着过度传递给先证者。在 LoF 不耐受或神经发育障碍基因中携带 LoF 或缺失 DNV 的先证者，其精神分裂症多基因过度传播的风险显着低于非携带者，这提供了第二个强有力的证据，表明这些 DNV 增加了精神分裂症的易感性。