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After centuries of genetic studies, one of the most fundamental questions, i.e. in what cell types do DNA mutations regulate a phenotype, remains unanswered for most complex phenotypes. The current availability of hundreds of genome-wide association studies (GWASs) and single-cell RNA sequencing (scRNA-seq) of millions of cells provides a unique opportunity to address the question. In the present study, we firstly constructed an association landscape between over 20,000 single cell clusters and 997 complex phenotypes by a cross annotation framework with scRNA-seq expression profiles and GWAS summary statistics. We then performed an extensive overview of cell-type specificity and pleiotropy in human phenotypes and found most phenotypes (>90%) were moderately selectively associated with a limited number of cell types while a small fraction cell types (<10%) had strong pleiotropy in multiple phenotypes (~100). Moreover, we identified three cell type-phenotype mutual pleiotropy blocks in the landscape. The application of the single cell type-phenotype cross annotation framework (named SPA) also explained the T cell biased lymphopenia and suggested important supporting genes in severe COVID-19 from human genetics angle. All the cell type-phenotype association results can be queried and visualized at http://pmglab.top/spa.
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10.1101/2020.11.18.388488
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document_parses/pdf_json/b73303687e52ddbb67d68244ba826f27d4cbae25.json
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A global overview of single-cell type selectivity and pleiotropy in complex diseases and traits
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