Table 1 Overview of follow-up analyses on proteins significantly associated with delirium through PWAS and MR

Protein	Effect direction	PWAS significance	Discovery MR (UKB)							Replication MR IVW (FinnGen)	Colocalization	Druggability tier
Protein	Effect direction	PWAS significance	IVW	IVW dementia-free	Weighted median	Maximum likelihood	MR-Egger	MR-Egger intercept test	Cochran’s Q test	Replication MR IVW (FinnGen)	Colocalization	Druggability tier
PON3	−	Nominal	✓	✓	✓	✓	✓	✓	✓	×	×	Tier 1
ADAM8	+	FDR	✓	×	✓	✓	×	✓	✓	×	×	Tier 2
GGH	+	Nominal	✓	✓	✓	✓	✓	✓	✓	✓	•	Tier 2
PVR^a	+	FDR	✓	✓	✓	✓	✓	✓	×	✓	×	Tier 3A
APOE^b	−	FDR	✓	✓	✓	✓	✓	✓	×	✓	✓	Tier 3A
DPP10	+	FDR	✓	✓	✓	✓	×	✓	✓	×	×	Tier 3B
CCL25	+	Nominal	✓	×	✓	✓	✓	✓	✓	×	×	Tier 3B
DSC2	+	Bonferroni	✓	✓	✓	✓	×	✓	✓	×	×	Not classified
NT5C1A	+	FDR	✓	✓	✓	✓	×	✓	✓	×	×	Not classified
PILRA	+	FDR	✓	×	✓	✓	✓	✓	✓	✓	×	Not classified
LAYN	+	FDR	✓	×	×	✓	×	✓	✓	×	×	Not classified

Proteins that were supported by both the PWAS logistic regression test (two-sided unadjusted P < 0.05) and MR via IVW or Wald ratio test (two-sided FDR-adjusted q < 0.05) analyses in UKB and had consistent effect direction are shown. ‘✓’ denotes significance (two-sided unadjusted P < 0.05) in the MR sensitivity analyses (WM, maximum likelihood and MR-Egger); nonsignificance in the MR-Egger intercept and Cochran’s Q tests (two-sided unadjusted P > 0.05); and PP.H4 > 0.8 in the colocalization analysis. ‘•’ denotes suggestive colocalization, 0.8 > PP.H4 > 0.5. ‘×’ denotes failure. Full summary statistics, including two-sided P values, are available in Supplementary Data 1.
^aPVR lost MR significance and showed high heterogeneity using strictly independent pQTL (r² < 0.001).
^bAPOE remained significant in MR and did not show heterogeneity evidence using strictly independent pQTL (r² < 0.001).

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