Phenome-wide scan identifies hematologic traits associated with genetically-determined expression of cell death genes

Apoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, particularly hematologic malignancies. Understanding the impact of modulating cell death gene expression on the human phenome could inform clinical investigation of cell death pathway-modulating therapeutics in hematologic disorders by identifying novel trait associations and by detecting potential side effects profiles. To address this, we investigated the relationship between 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. 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 prosurvival BCL2 family members, trait/direction-of-effect relationships were not consistent across blood traits. These results suggest that even functionally similar and/or orthologous cell death genes play distinct roles in their contribution to human phenotypes. Apoptotic, necroptotic, and pyroptotic cell death pathways are attractive and druggable targets for many human diseases, particularly hematologic malignancies. Understanding the impact of modulating cell death gene expression on the human phenome could inform clinical investigation of cell death pathway-modulating therapeutics in hematologic disorders by identifying novel trait associations and by detecting potential side effects profiles. To address this, we investigated the relationship between 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. 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 prosurvival BCL2 family members, trait/direction-of-effect relationships were not consistent across blood traits. These results suggest that even functionally similar and/or orthologous cell death genes play distinct roles in their contribution to human phenotypes.