Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1–10 genes; permuted P = 3 × 10⁻⁵). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.

蛋白质编码从头突变 (DNM) 是许多神经发育障碍的重要危险因素，而迄今为止，与 DNM 相关的精神分裂症 (SCZ) 风险并不大。我们分析了 1,695 个受 SCZ 影响的三重奏和 1,077 个已发表的受 SCZ 影响的三重奏的 DNM，以更好地了解对 SCZ 风险的贡献。在 2,772 名 SCZ 先证者中，全外显子组 DNM 负担仍然不大。基因集分析表明，SCZ DNM 显着集中在大脑中高度表达的基因中，这些基因受到强烈的进化限制和/或与其他神经发育障碍中发现的基因重叠。没有任何一个基因具有超过外显子组范围的显着性；然而，有 16 个基因反复被蛋白质截断 DNM 击中，对应的比率比突变模型预期高 3.15 倍（排列 95% 置信区间：1-10 个基因；排列P = 3 × 10 ^{− 5} ）。总体而言，DNM 解释了一小部分 SCZ 风险，并且需要更大的样本来识别单个风险基因，因为许多基因的编码变异会导致人群中出现 SCZ 风险。