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Identification of cell types underlying thousands of rare diseases and subtraits

Authors

Brian M. Schilder, Kitty B. Murphy, Bobby Gordon-Smith, Jai Chapman, Momoko Otani, Nathan G. Skene

Summary

Rare diseases (RDs) are an extremely heterogeneous and underserved category of medical conditions. While the majority of RDs are strongly genetic, it remains largely unknown via which physiological mechanisms genetics cause RD. Therefore, we sought to systematically characterise the cell type-specific mechanisms underlying all RD phenotypes with a known genetic cause by leveraging the Human Phenotype Ontology and transcriptomic single-cell atlases of the entire human body from embryonic, foetal, and adult samples.

This repository contains the data and code needed to replicate the analyses in our preprint (https://doi.org/10.1101/2023.02.13.23285820), as well as links to the R packages required (see below).

Manuscript

To reproduce this entire study, we have provided a quarto document which programmatically recreates all analyses and plots. To use it, follow these steps:

  • Clone this repository: git clone https://github.com/neurogenomics/rare_disease_celltyping.git

  • Install the quarto Command Line Tool, and the quarto R package.

  • Within the manuscript directory of the cloned repository, run quarto render index.qmd to generate the manuscript.

A pre-rendered PDF version of the manuscript is available here.

Datasets / Results

All of the datasets used in this study can be imported using functions within the HPOExplorer and MSTExplorer R packages. Additional resources, such as phenotype-cell type enrichment results, can be found on the Releases pages of HPOExplorer and MSTExplorer.

Packages

  • KGExplorer: Imports and analyses large-scale biomedical knowledge graphs and ontologies.

  • HPOExplorer: Contains extensive functions for easily importing, annotating, filtering, and visualising the Human Phenotype Ontology (HPO) at the disease, phenotype, and gene levels.

  • MSTExplorer: Systematically identifies, prioritises, and visualises cell-type-specific gene therapy targets across the phenome.