Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan dataset. We defined a fetal effect score (FES) to quantify the involvement of each gene in prenatal brain development. We further employed the specificity indexes (SIs) to evaluate cell-type expression specificity from single-cell expression data in cerebral cortices of humans and mice. Compared with SCZ-commonGenes, SCZ-neuroGenes and SCZ-moduleGenes were highly expressed in the prenatal stage, had higher FESs, and had higher SIs in fetal replicating cells and undifferentiated cell types. Our results suggested that gene expression patterns in specific cell types in early fetal stages might have impacts on the risk of SCZ during adulthood.

中文翻译：

---

从头突变比精神分裂症的常见变异更频繁地干扰早期大脑发育

研究突变的功能、时间和细胞类型表达特征对于理解复杂疾病很重要。在这里，我们收集并分析了精神分裂症 (SCZ) 中的常见变异和从头突变 (DNM)。我们在 3,477 名 SCZ 患者 (SCZ-DNM) 的 2,263 个基因中收集了 2,636 个错义和功能丧失 (LoF) DNM。我们整理了三个基因列表：(a) SCZ-neuroGenes（159 个基因），它们对 LoF 和错义 DNM 不耐受并且在神经学上很重要，(b) SCZ-moduleGenes（52 个基因），它们来自 SCZ- 的网络分析DNM 和 (c) 来自最近 GWAS 的 SCZ-commonGenes（120 个基因）作为参考。为了比较时间基因表达，我们使用了 BrainSpan 数据集。我们定义了胎儿效应评分 (FES) 来量化每个基因在产前大脑发育中的参与。我们进一步使用特异性指数 (SIs) 来评估人类和小鼠大脑皮层中单细胞表达数据的细胞类型表达特异性。与SCZ-commonGenes相比，SCZ-neuroGenes和SCZ-moduleGenes在产前阶段高表达，具有更高的FES，并且在胎儿复制细胞和未分化细胞类型中具有更高的SI。我们的结果表明，胎儿早期阶段特定细胞类型的基因表达模式可能会影响成年期 SCZ 的风险。并且在胎儿复制细胞和未分化细胞类型中具有更高的 SI。我们的结果表明，胎儿早期特定细胞类型的基因表达模式可能会影响成年期 SCZ 的风险。并且在胎儿复制细胞和未分化细胞类型中具有更高的 SI。我们的结果表明，胎儿早期阶段特定细胞类型的基因表达模式可能会影响成年期 SCZ 的风险。