Dai Rujia, Chu Tianyao, Zhang Ming, Wang Xuan, Jourdon Alexandre, Wu Feinan, Mariani Jessica, Vaccarino Flora M, Lee Donghoon, Fullard John F, Hoffman Gabriel E, Roussos Panos, Wang Yue, Wang Xusheng, Pinto Dalila, Wang Sidney H, Zhang Chunling, Chen Chao, Liu Chunyu
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
bioRxiv. 2023 Mar 15:2023.03.13.532468. doi: 10.1101/2023.03.13.532468.
Sample-wise deconvolution methods have been developed to estimate cell-type proportions and gene expressions in bulk-tissue samples. However, the performance of these methods and their biological applications has not been evaluated, particularly on human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk-tissue RNAseq, single-cell/nuclei (sc/sn) RNAseq, and immunohistochemistry. A total of 1,130,767 nuclei/cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expression. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk-tissue or single-cell eQTLs alone. Differential gene expression associated with multiple phenotypes were also examined using the deconvoluted data. Our findings, which were replicated in bulk-tissue RNAseq and sc/snRNAseq data, provided new insights into the biological applications of deconvoluted data.
已开发出样本反卷积方法来估计大块组织样本中的细胞类型比例和基因表达。然而,这些方法的性能及其生物学应用尚未得到评估,特别是在人类大脑转录组数据方面。在这里,使用来自大块组织RNA测序、单细胞/细胞核(sc/sn)RNA测序和免疫组织化学的样本匹配数据对九种反卷积方法进行了评估。总共使用了来自149个成人死后大脑和72个类器官样本的1,130,767个细胞核/细胞。结果表明,dtangle在估计细胞比例方面表现最佳,而bMIND在估计样本特异性细胞类型基因表达方面表现最佳。对于八种脑细胞类型,通过反卷积表达(反卷积eQTL)鉴定了25,273个细胞类型eQTL。结果表明,与单独的大块组织或单细胞eQTL相比,反卷积eQTL解释了更多的精神分裂症全基因组关联研究(GWAS)遗传力。还使用反卷积数据检查了与多种表型相关的差异基因表达。我们的研究结果在大块组织RNA测序和sc/snRNA测序数据中得到了重复,为反卷积数据的生物学应用提供了新的见解。