TY - JOUR T1 - Single-cell deconvolution of 3,000 post-mortem brain samples for eQTL and GWAS dissection in mental disorders JF - bioRxiv DO - 10.1101/2021.01.21.426000 SP - 2021.01.21.426000 AU - Yongjin Park AU - Liang He AU - Jose Davila-Velderrain AU - Lei Hou AU - Shahin Mohammadi AU - Hansruedi Mathys AU - Zhuyu Peng AU - David Bennett AU - Li-Huei Tsai AU - Manolis Kellis Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/21/2021.01.21.426000.abstract N2 - Thousands of genetic variants acting in multiple cell types underlie complex disorders, yet most gene expression studies profile only bulk tissues, making it hard to resolve where genetic and non-genetic contributors act. This is particularly important for psychiatric and neurodegenerative disorders that impact multiple brain cell types with highly-distinct gene expression patterns and proportions. To address this challenge, we develop a new framework, SPLITR, that integrates single-nucleus and bulk RNA-seq data, enabling phenotype-aware deconvolution and correcting for systematic discrepancies between bulk and single-cell data. We deconvolved 3,387 post-mortem brain samples across 1,127 individuals and in multiple brain regions. We find that cell proportion varies across brain regions, individuals, disease status, and genotype, including genetic variants in TMEM106B that impact inhibitory neuron fraction and 4,757 cell-type-specific eQTLs. Our results demonstrate the power of jointly analyzing bulk and single-cell RNA-seq to provide insights into cell-type-specific mechanisms for complex brain disorders.Competing Interest StatementThe authors have declared no competing interest. ER -