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

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 Alzheimers disease, including the APOE ϵ4 allele). Methods A 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. Results The GWAS (1016 cases, 139,148 controls) identified six 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 ϵ4 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). Conclusions We identified genetic variants associated with increased risk of postoperative delirium. We also found evidence of shared genetic liability with Alzheimers disease suggesting that individuals with genetic risk of Alzheimers disease, even without symptoms, may be at higher risk of postoperative delirium.