Abstract
BACKGROUND: Postoperative 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 Alzheimer's disease, including the APOE ε4 allele). METHODS AND FINDINGS: A case-control GWAS was performed in the UK Biobank to identify genetic variants associated with postoperative delirium, adjusted for age, sex, genetic chip, and the first 10 principal components. 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) Alzheimer's disease. The GWAS (1,016 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 Alzheimer's disease (rho 0.68, 95% CI [0.46, 0.81]; p < 0.001). After adjustment for age and sex, the APOE ε4 isoform had a dose-response effect on risk (odds ratios for one and two copies: 1.75, 95% CI [1.53, 2.0], and 4.19, 95% CI [3.25, 5.41], respectively; p < 0.001). The main limitations of the study include the reliance upon clinical coding for outcome definition and limited statistical power to detect small or modest genetic effects. CONCLUSIONS: We identified genetic variants associated with increased risk of postoperative delirium. We also found evidence of shared genetic liability with Alzheimer's 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 Alzheimer's disease risk.