Genetic Contributors to Postoperative Delirium and Their Implications for Dementia Outcomes.
BACKGROUND: Postoperative delirium (POD) is a perioperative neurocognitive disorder that substantially impairs patient recovery. Unfortunately, its genetic risk profile and relationship with subsequent dementia remain unclear. This study aimed to elucidate genetic contributors to POD identified via Hospital Episode Statistics codes and to examine its association with subsequent dementia. METHODS: The study included 230,179 noncardiac and 21,254 cardiac surgery subjects from the UK Biobank, defining POD using delirium codes from the International Classification of Diseases (10th revision) recorded within the first 7 postoperative days. Genome-wide association studies were performed in the noncardiac and cardiac cohorts and their prespecified subgroups, followed by functional annotation, gene prioritization and drug-target analyses. Associations between POD and subsequent dementia were estimated using Cox models. RESULTS: In the noncardiac cohort, one genome-wide significant locus was identified at the APOE region, with rs429358 as the lead variant ( P = 5.00 × 10 -28 ). Integrative gene prioritization analyses highlighted multiple genes within this locus. Exploratory drug-target analyses suggested potential subgroup-specific drug-target enrichment. In the cardiac cohort, no genome-wide significant signals were detected. POD was associated with all-cause dementia after both noncardiac (hazard ratio, 6.45; 95% CI, 5.45 to 7.63) and cardiac (hazard ratio, 2.95; 95% CI, 1.71 to 5.08) surgeries. CONCLUSIONS: This study demonstrates APOE as a genetic risk locus for International Classification of Diseases-coded POD in the noncardiac surgery setting and confirms an association between POD and subsequent dementia.