Integrative transcriptomic, evolutionary, and causal inference framework for region-level analysis: Application to COVID-19.
NPJ Genom Med
Springer Science and Business Media LLC
MetadataShow full item record
Zhou, D., & Gamazon, E. R. (2022). Integrative transcriptomic, evolutionary, and causal inference framework for region-level analysis: Application to COVID-19.. NPJ Genom Med, 7 (1) https://doi.org/10.1038/s41525-022-00296-y
We developed an integrative transcriptomic, evolutionary, and causal inference framework for a deep region-level analysis, which integrates several published approaches and a new summary-statistics-based methodology. To illustrate the framework, we applied it to understanding the host genetics of COVID-19 severity. We identified putative causal genes, including SLC6A20, CXCR6, CCR9, and CCR5 in the locus on 3p21.31, quantifying their effect on mediating expression and on severe COVID-19. We confirmed that individuals who carry the introgressed archaic segment in the locus have a substantially higher risk of developing the severe disease phenotype, estimating its contribution to expression-mediated heritability using a new summary-statistics-based approach we developed here. Through a large-scale phenome-wide scan for the genes in the locus, several potential complications, including inflammatory, immunity, olfactory, and gustatory traits, were identified. Notably, the introgressed segment showed a much higher concentration of expression-mediated causal effect on severity (0.9-11.5 times) than the entire locus, explaining, on average, 15.7% of the causal effect. The region-level framework (implemented in publicly available software, SEGMENT-SCAN) has important implications for the elucidation of molecular mechanisms of disease and the rational design of potentially novel therapeutics.
U.S. Department of Health & Human Services | National Institutes of Health (NIH) (R01HG011138, R35HG010718, R56AG068026)
NIGMS NIH HHS (R01 GM140287)
NHGRI NIH HHS (R01 HG011138, R35 HG010718)
NIA NIH HHS (R56 AG068026)
External DOI: https://doi.org/10.1038/s41525-022-00296-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336397
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/