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

Abstract

Identifying 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.

Competing Interest Statement

JBR's institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. He is the CEO of 5 Prime Sciences (www.5primesciences.com), which provides research services for biotech, pharma and venture capital companies for projects unrelated to this research.

Funding Statement

This work is supported by the CIHR (JDSW CIHR 476575). BQC19 was funded by the Fonds de recherche du Quebec - Sante, Genome Quebec and the Public Health Agency of Canada. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR: 365825; 409511, 100558, 169303), the McGill Interdisciplinary Initiative in Infection and Immunity (MI4), the Lady Davis Institute of the Jewish General Hospital, the Jewish General Hospital Foundation, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK, Genome Quebec, the Public Health Agency of Canada, McGill University, Cancer Research UK [grant number C18281/A29019] and the Fonds de Recherche Quebec Sante (FRQS). JBR is supported by a FRQS Merite Clinical Research Scholarship. Support from Calcul Quebec and Compute Canada is acknowledged. These funding agencies had no role in the design, implementation or interpretation of this study.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Soskic et al. biological samples were ethically sourced and used in research under an institutional review board-approved protocol (Soskic et al. 2022). BQC19 received ethical approval from the Jewish General Hospital research ethics board (2020-2137) and the Centre Hospitalier de l'Universite de Montreal institutional ethics board (MP-02-2020-8929, 19.389). Specimens collected by GTEx were sourced per protocol for an institutional review board (GTEx Consortium 2020).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data Availability

Data from Soskic et al. are available through Zenodo (doi:10.5281/zenodo.6006796). BQC-19 data, including expression data, is available by application: https://www.bqc19.ca/. GTEx release 8 data is available from: https://www.gtexportal.org/home/. COVID-19 HGI summary statistics are available from: https://www.covid19hg.org/.

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