β7 Gives Tregs a Gut Area Code

Liu, Cambrian Y.

doi:10.1016/j.jcmgh.2019.11.010

Cited by 2 publications

(1 citation statement)

References 5 publications

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“…We determined that attained a more accurate prioritization of disease-relevant genes compared to the top 1,000 MAGMA genes (median ratio of (excess overlap − 1) was 2.02, median ratio of − log 10 p-value was 2.76; see Methods), likely by capturing disease-relevant genes with weak GWAS signal 46 . For example, ITGB7 was prioritized by for association with IBD (rank 9) but was missed by MAGMA (rank 10565, MAGMA P =0.54); ITGB7 impacts IBD via controlling lymphocyte homing to the gut and is a drug target for IBD (using vedolizumab) 61, 62 . In addition, JAK1 was prioritized by for association with RA (rank 386) but was missed by MAGMA (rank 5228, MAGMA P =0.26); JAK1 plays a role in regulating immune cell activation and is a drug target for RA (using tofacitinib, baricitinib, or upadacitinib) 63, 64 .…”

Section: Resultsmentioning

confidence: 99%

Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data

Zhang

Hou

Dey

et al. 2021

Preprint

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Gene expression at the individual cell-level resolution, as quantified by single-cell RNA-sequencing (scRNA-seq), can provide unique insights into the pathology and cellular origin of diseases and complex traits. Here, we introduce single-cell Disease Relevance Score (scDRS), an approach that links scRNA-seq with polygenic risk of disease at individual cell resolution; scDRS identifies individual cells that show excess expression levels for genes in a disease-specific gene set constructed from GWAS data. We determined via simulations that scDRS is well-calibrated and powerful in identifying individual cells associated to disease. We applied scDRS to GWAS data from 74 diseases and complex traits (average N=341K) in conjunction with 16 scRNA-seq data sets spanning 1.3 million cells from 31 tissues and organs. At the cell type level, scDRS broadly recapitulated known links between classical cell types and disease, and also produced novel biologically plausible findings. At the individual cell level, scDRS identified subpopulations of disease-associated cells that are not captured by existing cell type labels, including subpopulations of CD4+ T cells associated with inflammatory bowel disease, partially characterized by their effector-like states; subpopulations of hippocampal CA1 pyramidal neurons associated with schizophrenia, partially characterized by their spatial location at the proximal part of the hippocampal CA1 region; and subpopulations of hepatocytes associated with triglyceride levels, partially characterized by their higher ploidy levels. At the gene level, we determined that genes whose expression across individual cells was correlated with the scDRS score (thus reflecting co-expression with GWAS disease genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.

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