A recent study identified 3 novel loci that are associated with Parkinson disease progression to dementia: RIMS2, TMEM108, and WWOX.
Ganqiang Liu, PhD
A recent study has developed a polygenic hazard score for predicting progression of Parkinson disease (PD) over time to dementia (PDD).1
Researchers clarified the genetic architecture of progression and prognosis of PD and identified 5 genetic loci associated with progression. The loci are RIMS2 (hazard ratio [HR], 4.77; P = 2.78 × 10−11), TMEM108 (HR, 2.86; P = 2.09 × 10−8), WWOX (HR, 2.12; P = 2.37 × 10−8), GBA (HR, 1.93; P = .0002) and APOE (HR, 1.48; P = .001).
"The patients who come to see me in the clinic are concerned about their future, rather than their past risk factors," said senior author Clemens Scherzer, MD, director, Center for Advanced Parkinson Research, and director, Brigham Precision Neurology Program, Brigham and Women’s Hospital, in a statement.2 "They want to know how they will be doing in the future and need medications designed to stop the disease from rapidly progressing.”
He continued, saying, “this is the central question in our study: Which genes determine whether a patient will have an aggressive or benign course, and which variants influence who will develop dementia?"
Scherzer and colleagues, including first author Ganqiang Liu, PhD, neurology instructor, Harvard Medical School, and research fellow, Ann Romney Center for Neurological Disease, Brigham and Women’s Hospital, performed a genome-wide survival study of 11.2 million genetic variants in 3821 patients with PD from 15 cohorts over 31,578 longitudinal study visits between 1986 and 2017 as part of an international initiative.
The team found that 5 loci were associated with time to PDD. These included 3 novel loci: RIMS2, a gene involved in synaptic vesicle docking associated with an HR of PDD of 4.77 (P = 2.78 × 10−11); TMEM108 (HR, 2.86; P = 2.09 × 10−8); and WWOX (HR, 2.12; P = 2.37 × 10−8). The researchers also confirmed previous findings of GBA (HR, 1.93; P = .0002) and APOE4 (HR, 1.48; P = .001) as progression loci. RIMS2 variants had a more than 2.5-times stronger effect on cognitive prognosis than GBA and APOE4.
A generalized linear mixed model meta-analysis of serial Mini Mental State Exam (MMSE) scores confirmed that patients carrying the lead RIMS2 variant declined more rapidly over time compared to patients who were non-carriers (P = .0014) after adjusting for fixed covariates of age, sex, disease duration upon enrollment, years of education, 10 principal components, and random effects. RIMS2 was not found to be associated with motor progression in the study. Similarly, patients with the WWOX variant (P = .009) or APOE4 allele (β = −0.078; P = .0003) had a more rapid decline in MMSE scores than non-carriers.
The investigators tested the polygenic risk score (PRS) of developing PD, consisting of 90 gene-wide association study-derived susceptibility loci and found no statistically significant association between PRS and progression to PDD in the Cox analysis (HR, 0.95 [95% CI, 0.80-1.13]; P = .57). The area under the curve (AUC) for 10-year prediction of PDD was 0.496 (95% CI, 0.4440-0.548).
None of the 90 loci that made up the PRS were significantly associated with PDD or motor progression as measured by transition to Hoehn and Yahr stage 3 or Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale part 3 subscore. Overall, these data suggest that genetic variants and scores linked to susceptibility to PD are not significantly associated with cognitive progression.
Scherzer and colleagues developed a cognitive polygenic hazard score (PHS) to predict PDD using the lead variants from the 3 novel loci. The HR was 2.54 (95% CI, 2.10-3.08; P = 4.51 × 10−20) for a one-unit value increase in PHS. The PHS was associated with prediction of PDD with a 10-year cumulative AUC of 0.589 (95% CI, 0.552-0.626). In the study, 688 (18%) carried at least 1 of the 3 novel alleles (rs182987047, rs138073281, rs8050111); 639 cases carried 1 (PDD HR, 2.79 [95% CI, 2.12-3.67]; P = 2.70 × 10−13), 47 cases carried 2 (HR, 5.65 [95% CI, 3.27-9.74]; P = 4.81 × 10−10), and 2 cases carried 3 risk alleles (HR, 30.4; 95% CI, 3.77-245.4).
The most robust PHS took into account GBA and APOE alleles in addition to the 3 novel loci (AUC, 0.623; 95% CI, 0.576-0.670). It was significantly more accurate in estimating whether a patient will develop PDD within 10 years from disease onset than chance alone (P = 2.68 × 10−22) or compared to the PRS (P = .0009). Cox-adjusted survival curves also showed that 89.6% of patients with a low (0) PHS had no PDD at 10 years after PD onset, while 73.3% of patients in the highest quartile of the PHS remained free of PDD for 10 years after onset of PD. The researchers confirmed the predicted power of the PHS in 3 independent cohorts, EPIPARK, De Novo Parkinson Cohort, and HBS2.
"This is a different way to think about the disease and drug development," said Scherzer. "Disease-modifying drugs that target the genetic drivers of disease progression should be prime targets for turning fast progressors into slow progressors and improve patients' lives."