Genome-wide association study identifies protective genetic factors in active blood donors against multiple diseases

The healthy donor effect (HDE) refers to the lower mortality observed among blood donors compared to the general population. While HDE arises due to healthier individuals being more likely to donate, the extent to which it is influenced by genetic differences remains unclear. To elucidate the genetic basis of HDE, we conducted a genome-wide association study (GWAS) involving 53,688 active blood donors with extensive donation histories and 228,060 controls from biobank cohorts within the FinnGen project. We identified 46 fine-mapped genome-wide significant loci associated with several health-related endpoints, plasma protein levels and laboratory measurements. Genetic correlation analyses across FinnGen endpoints revealed that blood donors are genetically protected against several diseases beyond those affecting donation eligibility. Using the correlated endpoints as exposures in multivariable Mendelian randomization (MVMR) to inform priors for Bayesian GWAS, we found that 25 of the fine-mapped loci exert a direct effect on blood donorship (BD) rather than acting through disease mediation, suggesting a genetic contribution to maintaining a health state conducive to long-term donation. We also performed MVMR analyses of laboratory traits. The results indicated that normal liver function, blood glucose, and low inflammation independently increase the likelihood of becoming a blood donor, while iron levels showed no causal relationship. Functional enrichments among the proteins regulated by the 46 fine-mapped variants included mainly red cell antigen-related cell adhesion processes. In conclusion, our findings demonstrate that HDE is partly explained by genetic factors, involving both direct health-promoting effects and indirect eligibility selection.