Table 2.
Plasma protein biomarkers significantly associated with future onset of Parkinson’s disease
| Protein | HR (95% CI) | p | q | Replication | Cross-disease | Prior evidence |
|---|---|---|---|---|---|---|
| 2–28 years of follow-up | ||||||
| VAMP3 | 1.26 (1.16–1.36) | 1.46E-08 | 1.07E-04 | moderate | ||
| TPPP2 | 0.70 (0.61–0.80) | 7.06E-08 | 3.15E-04 | strong | ||
| HPGDS | 0.73 (0.65–0.82) | 8.59E-08 | 2.09E-04 | strong | AD | |
| ALPLcap | 1.25 (1.15–1.36) | 1.30E-07 | 3.16E-04 | strong | ||
| FCAR | 1.34 (1.20–1.50) | 3.48E-07 | 6.34E-04 | suggestive | Irmady et al., 202344 | |
| CERS5 | 1.23 (1.12–1.34) | 5.64E-06 | 6.85E-03 | suggestive | ALS | |
| MFAP5cap | 0.73 (0.64–0.84) | 1.14E-05 | 1.38E-02 | strong | ||
| RSPO2 | 1.19 (1.10–1.29) | 2.09E-05 | 2.10E-02 | suggestive | AD, ALS | |
| CD3G | 1.19 (1.10–1.29) | 2.30E-05 | 2.10E-02 | suggestive | ||
| GTF2A2cap | 1.22 (1.11–1.34) | 2.30E-05 | 2.40E-02 | moderate | ||
| LTF | 1.28 (1.14–1.43) | 3.21E-05 | 2.34E-02 | AD | ||
| NAMPTcap | 1.28 (1.14–1.44) | 4.51E-05 | 3.65E-02 | ALS | Santiago et al., 201645 | |
| OGFR | 0.77 (0.68–0.87) | 5.04E-05 | 3.67E-02 | strong | AD | |
| FGF8 | 1.21 (1.10–1.33) | 5.75E-05 | 3.46E-02 | moderate | ||
| PSG6 | 1.25 (1.12–1.39) | 6.17E-05 | 3.46E-02 | |||
| ACAD8 | 1.18 (1.09–1.28) | 7.05E-05 | 3.65E-02 | strong | AD | |
| CRYGD | 1.20 (1.10–1.32) | 7.52E-05 | 3.65E-02 | |||
| 2–10 years of follow-up | ||||||
| TIMP1cap | 0.72 (0.62–0.83) | 4.52E-06 | 1.65E-02 | moderate | ||
| IL11 | 1.30 (1.15–1.47) | 2.04E-05 | 4.23E-02 | |||
| TCL1A | 0.71 (0.61–0.83) | 2.23E-05 | 4.23E-02 | strong | Kedmi et al., 201146 | |
| 10–20 years of follow-up | ||||||
| GUCA1Bcap | 1.31 (1.18–1.45) | 3.95E-07 | 1.44E-03 | |||
| UBE2L3|UBBcap | 1.29 (1.16–1.42) | 6.08E-07 | 1.48E-03 | |||
| DCAF12 | 1.24 (1.12–1.37) | 2.63E-05 | 2.47E-02 | |||
| GPC4cap | 1.26 (1.13–1.40) | 2.80E-05 | 3.33E-02 | strong | Tatenhorst et al., 202447 | |
| BECN1 | 1.26 (1.13–1.40) | 2.92E-05 | 2.47E-02 | Miki et al., 201848 | ||
| HEPACAM2cap | 1.25 (1.12–1.39) | 3.05E-05 | 3.33E-02 | suggestive | ||
| F13A1|F13Bcap | 1.34 (1.17–1.54) | 3.20E-05 | 3.33E-02 | |||
| ABHD12 | 1.25 (1.12–1.38) | 3.37E-05 | 2.47E-02 | moderate | ||
| IRAG2 | 1.24 (1.12–1.37) | 3.38E-05 | 2.47E-02 | AD | ||
| TAFA4cap | 1.25 (1.12–1.39) | 5.93E-05 | 3.93E-02 | |||
| GSTA3 | 1.23 (1.11–1.37) | 6.08E-05 | 3.69E-02 | strong | AD | |
| SPASTcap | 1.24 (1.11–1.38) | 7.94E-05 | 4.45E-02 | AD, ALS | ||
| CUL4B | 1.32 (1.15–1.51) | 9.85E-05 | 4.22E-02 | Yao et al., 202233 | ||
| OSTF1 | 1.30 (1.14–1.49) | 9.92E-05 | 4.22E-02 | |||
| PYDC1 | 1.24 (1.11–1.38) | 1.07E-04 | 4.22E-02 | AD, ALS | D. Torshizi et al., 202418 | |
| LCN2 | 1.30 (1.14–1.49) | 1.10E-04 | 4.22E-02 | strong | Fan et al., 202430 | |
| OTX2 | 1.27 (1.13–1.44) | 1.10E-04 | 4.22E-02 | AD | ||
| MAGEA8 | 0.66 (0.54–0.82) | 1.16E-04 | 4.22E-02 | |||
| ZNF41 | 1.22 (1.10–1.35) | 1.32E-04 | 4.57E-02 | |||
| Men | ||||||
| RS1 | 1.42 (1.22–1.65) | 4.34E-06 | 9.10E-03 | AD | ||
| KRAScap | 1.34 (1.17–1.53) | 1.30E-05 | 1.89E-02 | strong | ||
| LYZcap | 1.37 (1.19–1.59) | 2.06E-05 | 2.50E-02 | |||
| GBA3cap | 1.33 (1.16–1.52) | 3.91E-05 | 3.17E-02 | AD | ||
| GJA1 | 1.32 (1.16–1.50) | 3.70E-05 | 3.37E-02 | strong | AD | |
| AMN | 1.40 (1.19–1.64) | 5.07E-05 | 3.69E-02 | moderate | ALS | Elango et al., 202331 |
| Women | ||||||
| ITGA6 | 1.27 (1.14–1.42) | 1.87E-05 | 4.29E-02 | suggestive | ||
| CXCL11 | 0.69 (0.58–0.82) | 2.34E-05 | 5.67E-02 | moderate | Hepp et al., 202332 | |
This table presents all plasma proteins showing significant (false discovery rate [FDR]=0.05) association with incident Parkinson’s disease (PD) in Cox proportional hazard regressions in the EPIC4PD case-cohort stratified for center, sex (where non-sex-stratified) and 5-year age categories. Analyses were conducted for the entire follow-up period (2–28 years), as well as for proximal (2–10 years) and distal (10–20 years) time windows before disease onset or censoring, and additionally analyzed per sex stratum over the full follow-up. Strong evidence for replication: At least one nominally significant replication (for SomaScan in the same effect direction; for Olink, direction not required), and all additional SomaScan-based datasets showing effect estimates in the same direction. Moderate evidence for replication: Effects observed in the same direction in all (at least two) SomaScan datasets datasets, but non-significant results, or alternatively, one nominally significant SomaScan-based replication result (same direction), another SomaScan dataset showing the same and one showing an opposite direction. Suggestive evidence for replication: One nominally significant replication result (same direction for SomaScan, for Olink, direction not required) but heterogeneous effect directions among remaining datasets, or only two SomaScan datasets with consistent (but non-significant) effects. Cross-disease=at least nominally significant (uncorrected p<0.05) associations with instantaneous risk of Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) based on EPIC4AD and EPIC4ALS, respectively. Prior evidence: publications describing differential protein and/or mRNA levels in blood in (always prevalent) PD patients compared to controls. Note that these were always in line with effect directions in EPIC4PD. HR=hazard ratio; CI=95% confidence interval; q=FDR-adjusted p-value (FDR=0.05). Bolded words for ‘cross-disease’ indicate significance at FDR=0.05. Note that from both outlier handling approaches, i.e., excluding outliers beyond 5 standard deviations from the log-mean or capping these outliers at the value of 5 standard deviations (indicated as “cap”), only the more significant result (smaller q) is shown. However, in all instances, at least nominally significant evidence was also observed for the alternative outlier removal method.