Genome-wide association studies (GWAS) of schizophrenia (SCZ) have revealed over 100 risk loci. We investigated whether these SCZ-associated variants regulate gene expression by cell type. Using a fully unsupervised deconvolution method, we calculated gene expression by clusters of estimated cell types (cell-groups, CGs). Five CGs emerged in the dorsolateral prefrontal cortices (DLPFC) of 341 donors with and without SCZ. By mapping expression quantitative trait loci (eQTL) per CG, we partitioned the heritability of SCZ risk in GWAS by CGs. CG-specific expressions and eQTLs were replicated in both a deconvoluted bulk tissue data set with a different method and also in sorted-cell expression data. Further, we characterized CG-specific gene differential expression and cell proportion changes in SCZ brains. We found upper-layer neurons in the DLPFC to be associated with SCZ based on enrichment of SCZ heritability in eQTLs, disease-related transcriptional signatures, and decreased cell proportion. Our study suggests that neurons and related anomalous circuits in the upper layers of the DLPFC may have a major contribution to SCZ risk.

中文翻译：

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细胞群分析揭示了与精神分裂症相关的上层神经元的变化

精神分裂症（SCZ）的全基因组关联研究（GWAS）已揭示了100多个风险基因座。我们调查了这些与SCZ相关的变体是否通过细胞类型调节基因表达。使用完全无监督的反卷积方法，我们通过估计的细胞类型（细胞群，CG）的簇来计算基因表达。在有和没有SCZ的341个供体的背外侧前额叶皮质（DLPFC）中出现了五种CG。通过映射每个CG的表达数量性状基因座（eQTL），我们按CG划分了GWAS中SCZ风险的遗传力。CG特异的表达和eQTL在采用不同方法解卷积的大块组织数据集中以及在分选的细胞表达数据中均得到了复制。此外，我们表征了CG特异性基因差异表达和SCZ脑中细胞比例的变化。我们发现，基于eQTL中SCZ遗传力的丰富，疾病相关的转录特征以及细胞比例的降低，DLPFC中的上层神经元与SCZ相关。我们的研究表明，DLPFC上层的神经元和相关异常电路可能对SCZ风险有重要贡献。