ECLIPSER: identifying causal cell types and genes for complex traits through single cell enrichment of e/sQTL-mapped genes in GWAS loci

Abstract

SummaryECLIPSER was developed to identify pathogenic cell types and cell type-specific genes that may affect complex disease susceptibility and trait variation by integrating single cell data with known GWAS loci. ECLIPSER maps genes to GWAS loci for a given complex trait based on expression and splicing quantitative trait loci (e/sQTLs) and other functional data, and tests whether the mapped genes are enriched for cell type-specific expression in particular cell types using single-cell/nucleus RNA-seq data from one or more tissues of interest. A Bayesian Fisher’s exact test is used to compute fold-enrichment significance. We demonstrate the application of ECLIPSER on various skin diseases and traits using snRNA-seq of healthy human skin samples.Availability and ImplementationThe source code and documentation for ECLIPSER and a Jupyter notebook for generating output tables and figures are available at https://github.com/segrelabgenomics/ECLIPSER. The source code for GWASvar2gene that maps genes to GWAS loci based on e/sQTLs is available at https://github.com/segrelabgenomics/GWASvar2gene. The analysis presented here used data from GTEx (https://gtexportal.org/home/datasets) and Open Targets Genetics (https://genetics-docs.opentargets.org/data-access/graphql-api), but can also be applied to other GWAS variant lists and QTL studies. Data used to reproduce the results of the paper are available in Supplementary data.

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

“…1b and Methods). Next, to identify key pathogenic cell types through which the colocalizing genes may be mediating their effect on POAG and IOP, we extended a method we recently developed, ECLIPSER 36, 37 to the GWAS-e/sQTL colocalizing genes (Fig. 1c and Methods).…”

“…To further relate the implicated genes to pathogenic mechanisms and cell types, we next tested whether the expression of the e/sGenes that colocalized with POAG or IOP or that mapped to GWAS loci of several other related traits (listed in Supplementary Table 27) was enriched in specific cell types in key eye tissues implicated in the pathophysiology of POAG: the anterior segment of the eye, where impaired aqueous humor outflow can lead to elevated IOP, the retina, where death or dysfunction of RGCs lead to POAG, and the optic nerve head, where local compression can cause axonopathy. We first applied ECLIPSER 36, 37 (see Methods) to 228, 118, and 279 e/sGenes that colocalized with POAG CA, POAG EUR and IOP GWAS loci, respectively (Supplementary Table 8), and to cell type-specific expression from single nucleus (sn) RNA-seq of (i) 6 tissues from the anterior segment: central cornea, corneoscleral wedge (CSW), trabecular meshwork (TM) and Schlemm’s canal, iris, ciliary body (CB), and lens 28 , (ii) the peripheral and macular retina, and (iii) the optic nerve head (ONH) and adjacent retina 41 , all taken from non-diseased human eyes (see Methods and Supplementary Tables 28-30). The cell type enrichment results are summarized in Supplementary Table 31.…”

“…To identify ocular cell types that are enriched for cell type-specific expression of genes mapped to GWAS loci of POAG, IOP and several related traits, we extended a method we recently developed called ECLIPSER (Enrichment of Causal Loci and Identification of Pathogenic cells in Single Cell Expression and Regulation data) 36, 37 , to e/sQTL colocalizing genes. ECLIPSER assesses whether genes mapped to a set of GWAS loci for a given complex disease or trait are enriched for cell type- specific expression compared to the cell type specificity of genes mapped to a background (null) set of GWAS loci associated with hundreds of unrelated traits.…”

“…(iii) LD clumping of loci. We collapsed GWAS variants that were in LD with each other (R 2 >0.8) or that shared a mapped gene into a single locus for the GWAS locus set of each ocular trait and for the null set, separately, to avoid inflating the cell type enrichment results due to LD 37 . (iv) Cell type specificity locus score.…”

“…These genes were enriched in both previously proposed and new biological processes that may influence POAG risk. To identify key ocular cell types for POAG pathogenesis, through which the proposed POAG or IOP genes may be exerting their causal effect, we extended a method we recently developed, called ECLIPSER (Enrichment of Causal Loci and Identification of Pathogenic cells in Single Cell Expression and Regulation data) 36, 37 , to e/sQTL-colocalizing genes. ECLIPSER tests whether genes mapped to GWAS loci of a given complex disease or trait are enriched for cell type-specific expression in single cell RNA-seq data of a given tissue, compared to thousands of GWAS loci of unrelated traits.…”