Colocalization of expression transcripts with COVID-19 outcomes is rare across cell states, cell types and organs

Abstract

AbstractIdentifying causal genes at GWAS loci can help pinpoint targets for therapeutic interventions. Expression studies can disentangle such loci but signals from expression quantitative trait loci (eQTLs) often fail to colocalize—which means that the genetic control of measured expression is not shared with the genetic control of disease risk. This may be because gene expression is measured in the wrong cell type, physiological state, or organ. We tested whether Mendelian randomization (MR) could identify genes at loci influencing COVID-19 outcomes and whether the colocalization of genetic control of expression and COVID-19 outcomes was influenced by cell type, cell stimulation, and organ. We conducted MR of cis-eQTLs from single cell (scRNA-seq) and bulk RNA sequencing. We then tested variables that could influence colocalization, including cell type, cell stimulation, RNA sequencing modality, organ, symptoms of COVID-19, and SARS-CoV-2 status among individuals with symptoms of COVID-19. The outcomes used to test colocalization were COVID-19 severity and susceptibility as assessed in the Host Genetics Initiative release 7. Most transcripts identified using MR did not colocalize when tested across cell types, cell state and in different organs. Most that did colocalize likely represented false positives due to linkage disequilibrium. In general, colocalization was highly variable and at times inconsistent for the same transcript across cell type, cell stimulation and organ. While we identified factors that influenced colocalization for select transcripts, identifying 33 that mediate COVID-19 outcomes, our study suggests that colocalization of expression with COVID-19 outcomes is partially due to noisy signals even after following quality control and sensitivity testing. These findings illustrate the present difficulty of linking expression transcripts to disease outcomes and the need for skepticism when observing eQTL MR results, even accounting for cell types, stimulation state and different organs.