Serum ferritin and delirium risk: an integrative genomic analysis of causal inference and multi-tissue regulatory signals.

BACKGROUND

Delirium is an acute neuropsychiatric syndrome characterized by disrupted attention and cognition, often triggered by systemic inflammation and physiological stress. Elevated serum ferritin is frequently observed in patients with delirium. Since ferritin couples iron handling to inflammatory signaling during acute-phase responses, it remains unclear whether genetically influenced baseline serum ferritin is a modifiable causal risk factor for delirium, or whether ferritin elevations observed during illness mainly reflect downstream systemic states leading to brain network failure. We used genetic triangulation to assess baseline causality and identify regulatory mechanisms influencing delirium susceptibility.

RESULTS

Using harmonized GWAS summary statistics for ferritin (GCST90270865; N = 270,794) and delirium (GCST90473243; 8461 cases, 449,979 controls), we found no evidence that genetically proxied increases in ferritin causally raise delirium risk (primary MR: IVW random-effects OR = 1.09 per 1/SD ferritin, 95% CI 0.93–1.26; p = 0.282). Genome-wide overlap was limited, with weak, non-significant cross-trait genetic correlation and minimal shared polygenic signal. Mechanistic follow-up at the locus level across multi-tissue QTL resources identified widespread ferritin-linked cis-QTL signals (255 probes, 126 genes), while delirium showed sparse mediator signals (four probes, three genes), all on chromosome 19. At 19q13, ferritin strongly colocalized with an APOE plasma pQTL (PP.H4 = 0.999; SuSiE PP.H4 ≈ 1.00), whereas delirium colocalized with a cortex CEACAM19 eQTL (PP.H4 = 0.9983). Outside 19q13, ferritin colocalized with iron regulation signals at SLC11A2 whole-blood eQTL (PP.H4 = 0.853) and TF liver sQTL (PP.H4 = 0.966), with no evidence of ferritin–delirium colocalization.

CONCLUSIONS

Genetic evidence does not support baseline ferritin as a primary, modifiable causal factor for delirium risk. Instead, inherited susceptibility appears locus-specific and seems to align with brain regulatory mechanisms, including a cortical signal at 19q13, distinct from iron homeostasis. These findings emphasize the need for mechanistic and preventive research targeting brain-relevant pathways other than systemic iron management for delirium prevention.