Transcriptome-wide association study and fly experiments uncover the role of CoA synthase in ageing across species.
While significant progress has been made in understanding the genetic architecture of ageing in model organisms, our understanding of human ageing remains limited. We performed a multi-tissue Transcriptome-wide association study (TWAS) on human lifespan, integrating GWAS data from >1 million parental lifespans with gene expression prediction models derived from reference transcriptomic datasets; followed by replication using healthspan and longevity phenotypes as additional readouts of ageing. The TWAS uncovered 563 significant gene associations, of which 139 replicated. TOMM40, encoding a component of the mitochondrial outer membrane translocase that is fundamental for mitochondrial function, had the strongest association with parental lifespan and longevity and was fine-mapped as a putatively causal lifespan gene at the APOE-TOMM40 region. Uniquely in our study, we identified fly orthologues of replicating genes and examined if modulating their expression impacts Drosophila longevity. The nine novel associations with all three ageing outcomes included COASY, encoding Coenzyme A synthase. Knocking down its fly orthologue, Ppat-dpck, resulted in significant lifespan extension in flies. Hence, in addition to discovering new genes associated with human ageing, by combining human TWAS with experimental Drosophila work, we provide evidence for the role of COASY (Ppat-dpck) in ageing across species. Significance statementExtensive research on ageing has been conducted in Drosophila and C.elegans due to their short lifespan and experimental tractability. However, in human genetic research, only a few loci have been consistently replicated. To bridge this gap, we conducted a transcriptome-wide association study (TWAS) followed by experimental validation in Drosophila. TWAS revealed 139 significant and replicating gene associations, including COASY. Knockdown of its fly orthologue (Ppat-dpck) significantly extended fly lifespan, validating its roles in ageing across species. Thus, integrating multiple ageing outcomes through TWAS in human genetic research can uncover robust associations and highlight genes involved in fundamental ageing mechanisms.