The genetic architecture of postoperative delirium after major surgery and its relationship with non-postoperative neurocognitive conditions

BackgroundPostoperative delirium is the most common postoperative complication in older individuals. Genome-wide association studies (GWAS) can provide insights into how genetic factors influence postoperative risk. We examined the genetic architecture of postoperative delirium after major surgery and its relationship with related cognitive conditions (delirium of any type and Alzheimers disease, including the APOE {varepsilon}4 allele). Methods and FindingsA GWAS was performed in UK Biobank to identify genetic variants associated with postoperative delirium. These results were then used in genetic correlation and polygenic risk score analyses to investigate shared genetic risk between postoperative delirium and a) delirium of all causes, and b) Alzheimers disease. The GWAS (1016 cases, 139,148 controls) identified seven Single Nucleotide Polymorphisms (SNPs) that mapped to four genes (APOE, TOMM40, APOC1 and PVRL2); p <5 x 10-8. Five SNPs remained significant after excluding pre-existing dementia, and two after excluding subsequent dementia. The lead SNP was rs429358, a missense variant of APOE. Genetic correlation and polygenic risk score analyses revealed evidence of shared genetic architecture and risk between postoperative delirium and Alzheimers disease (rho = 0.68, p<0.001). The APOE {varepsilon}4 isoform had a dose-response effect on risk (OR [95% CI] for one and two copies 1.75 [1.53 - 2.0] and 4.19 [3.25 - 5.41] respectively, p <0.001). ConclusionsWe identified genetic variants associated with increased risk of postoperative delirium. We also found evidence of shared genetic liability with Alzheimers disease via APOE, complementing recent large-scale studies in all-cause delirium. If validated the findings have potential clinical applications including preoperative risk stratification and early identification of pre-clinical Alzheimers disease risk. Author SummaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPostoperative delirium is the most common postoperative complication in older individuals. C_LIO_LILittle is known about the genetic basis of postoperative delirium. C_LIO_LIKnowledge of the genetic risk factors could help treatment or prevention in the future. C_LI What did the researchers do and find?O_LIWe performed a genome-wide association study of postoperative delirium including 1016 cases and 139,148 controls. C_LIO_LIWe found genetic variants associated with increased postoperative delirium risk. C_LIO_LIWe also found genetic similarity between postoperative delirium, all-cause delirium, and Alzheimers disease. C_LI What do these findings mean?O_LIPostoperative delirium has shared biology with Alzheimers disease and may represent unmasking of pre-clinical disease. C_LIO_LIIndividuals with genetic risk for Alzheimers disease have increased risk of postoperative delirium and vice versa. C_LIO_LIGiven the limitations of the data source used we were unable to identify small or modest genetic effects and any findings require validation before consideration of clinical use. C_LI