Postoperative delirium following major surgery was investigated for its genetic architecture using a case-control GWAS in the UK Biobank (1,016 cases; 139,148 controls), adjusting for age, sex, genotyping chip, and the first 10 principal components. The study identified seven SNPs mapping to four genes (APOE, TOMM40, APOC1, PVRL2), with two SNPs retaining significance after removing individuals with pre-existing dementia and five after excluding those with subsequent dementia. The leading variant was rs429358, a missense change in APOE. Genetic correlation and polygenic risk score analyses suggested a shared genetic basis between postoperative delirium and both delirium of all causes and Alzheimer's disease, with a notable correlation to Alzheimer's disease (rho ≈ 0.68; 95% CI roughly 0.46–0.81). The APOE ε4 isoform exhibited a dose-dependent increase in risk for postoperative delirium (odds ratios: 1 copy ≈ 1.75; 2 copies ≈ 4.19). The results imply genetic variants, particularly in APOE, contribute to delirium risk and indicate overlap with Alzheimer’s disease liability. Uncertainty remains regarding replication and clinical translation pending validation in independent cohorts.
by Richard A. Armstrong, Paul Yousefi, Ben Gibbison, Golam M. Khandaker, Tom R. Gaunt 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 −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 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 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.