Baseline data observation: Of the 377 patients from PPMI database, 249 were men (66.0%) and the ratio of male vs female was 1.95. The median age at diagnosis was 61 years, 351 patients (93.1%) had hyposmia, detected by UPSIT test. As for other non-motor tests, median scores of SCOPA-AUT, GDS (Short version), RBDQ were 12, 5, and 4, respectively (Table 1). There were no significant gender differences in age of onset, progression of cognitive impairment, RBD symptoms, hyposmia symptoms, autonomic dysfunction, and depressive symptoms of this PD cohort (p>0.05).
Longitudinal observation: The median UPDRS-III motor score change was 8 by the fifth year follow up in this cohort. 99 (26%) patients had fast motor progression with median UPDRS-III motor score change of 22 by the 12th visit at the 5th year. 21 patients (5.6% of the cohort) had fast cognitive decline with median MoCA change of 5. there are more male (31%) than female (17%) prone to have rapid motor progression (p<0.01), but there is no gender difference in cognitive deterioration (Table 1).
Genetic associations with longitudinaldisease progression: Four SNPs (rs11724635, rs12528068, rs591323, rs17649553 located in the loci of BST1, RIMS1, FGF20, and MAPT respectively) associated with fast cognitive decline (p=0.025, p=0.008, p=0.019, p=0.024, respectively). Three SNPs (rs823118, rs10797576, rs12456492 located in the loci of NUCKS1, SIA1L2, RIT2 respectively) were associated with faster motor progression (p=0.028, p=0.039, p=0.018, respectively) (Table 2).
Genetic associations with clinical features at the baseline: Three SNPs (ITPKB rs4653767, FGF20 rs591323, GALC rs8005172) were associated with early onset age of PD (p=0.042, p=0.014, p=0.020, respectively); IP6K2 rs12497850 and LRRK2 rs76904798 were associated with cognitive impairment (p=0.006, p=0.007, respectively); SCN2A rs353116 was associated with hyposmia (p=0.002); NDUFAF2 rs2694528 and USP25 rs2823357 were associated with RBD (p=0.021, p=0.006, respectively), SATB1 rs4073221 and GAK rs11248051 were associated with autonomic dysfunction (p=0.034, p=0.043, respectively), and FGF20 rs591323 was associated with depression (p=0.034) (Supplementary Table 2).
ROC curve analysis
ROC curve analysis was performed to evaluate the predictive values of all and significant different SNPs for the outcomes of rapid motor and cognitive dysfunction (Figure 1). AUC of fast cognitive decline is 0.772 (95% CI 0.726 to 0.813) predicted by the significantly related SNPs (rs11724635, rs12528068, rs591323, rs17649553) (Table 2), while it reaches 0.961 (95% CI 0.937 to 0.978) with all 50 SNPs information input (Figure 1). The AUC of rapid motor progression is 0.628 predicted by the significantly related SNPs (rs823118, rs10797576, rs12456492) (Table 2), and it reaches 0.736 (95% CI 0.684 to 0.776) while considering all 50 SNPs and gender.
Genetic factors also demonstrated fair predication properties (AUC=0.7-0.8) early onset age (0.744) and cognitive impairment (0.729) performances at baseline visit (Supplementary figure 1). In addition, genetic factors also associate with other quantitative traits of PD at the initial visit, such as hyposmia (0.851), RBD (0.719), autonomic dysfunction (0.711), and depression (0.756) (supplementary figure 2). p value of each ROC curve is less than 0.001.
Analysis of molecular pathways related to rapid motor and cognitive decline
STRING analysis showed the number of edges was 77 vs the expected of 11, average node degree was 3.28, and there was significant more interactions in this protein network (p< 1.0e-16). There were no direct interactive molecular pathways related to those gene products (BST1, RIMS1, FGF20 and tau) with significant implication for rapid cognitive decline, indicating they are independent risk factors. However, MAPT and FGF20 encode hub proteins with more than 5 molecular interactions (Figure 2).
Regarding to the genes related to rapid motor progression, NUCKS1, SIPA1L2 and RIT2, NUCKS1 is an independent risk factor, and SIPA1L2 and RIT2 may jointly activate the RAS type GTPase. In addition, NUCKS1 and RIT2 are hub nodes in the network (Figure 2).