The broad impact of cell death genes on the human disease phenome.

Apoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, however the tissue specificity of these pathways and the relationship between these pathways and human disease is poorly characterized. Understanding the impact of modulating cell death gene expression on the human phenome could inform clinical investigation of cell death pathway-modulating therapeutics in human disorders by identifying novel trait associations and by detecting tissue-specific side effect profiles. We analyzed the expression profiles of an array of 44 cell death genes across somatic tissues in GTEx v8 and investigated the relationship between tissue-specific genetically determined expression of 44 cell death genes and the human phenome using summary statistics-based transcriptome wide association studies (TWAS) on human traits in the UK Biobank V3 (n ~500,000). We evaluated 513 traits encompassing ICD-10 defined diagnoses and hematologic traits (blood count labs). Our analysis revealed hundreds of significant (FDR<0.05) associations between cell death gene expression and diverse human phenotypes, which were independently validated in another large-scale biobank. Cell death genes were highly enriched for significant associations with blood traits versus non-cell-death genes, with apoptosis-associated genes enriched for leukocyte and platelet traits and necroptosis gene associations enriched for erythroid traits (e.g., Reticulocyte count, FDR=0.004). This suggests that immunogenic cell death pathways play an important role in regulating erythropoiesis and reinforces the paradigm that apoptosis pathway genes are critical for white blood cell and platelet development. Of functionally analogous genes, for instance pro-survival BCL2 family members, trait/direction-of-effect relationships were heterogeneous across blood traits. Overall, these results suggest that even functionally similar and/or orthologous cell death genes play distinct roles in their contribution to human phenotypes, and that cell death genes influence a diverse array of human traits.