<i>TREM2</i> Variants in Parkinson’s Disease: Results from the Parkinson’s Progression Markers Initiative (PPMI) Study
Bibliographic record
Abstract
Abstract Background While TREM2 coding variants are known risk factors for Alzheimer’s disease, their contribution to Parkinson’s disease (PD) risk is less clear. We hypothesized that rare coding variants in TREM2 are associated with increased risk for Parkinson’s disease (PD), and that carriers of TREM2 coding variants represent a subtype of PD cases with different clinical characteristics and disease trajectory. Method TREM2 coding variants were obtained from the whole genome sequencing data available on LONI ( https://ida.loni.usc.edu/ ) using VCFtools and annotated using Annovar for all individuals enrolled in the Parkinson’s Progression Markers Initiative (PPMI, N=1736), a longitudinal study of biomarkers of PD onset and progression. Of the 12 coding variants obtained, 8 variants that had reported or predicted pathogenic function were further analyzed. Fischer’s Exact 2‐sided tests were used to investigate enrichment of all variant carriers, as well as enrichment of specific variants with >20 carriers in the cohort, in sporadic (non‐genetic) PD (sPD) cases compared to controls. Enriched variants were tested for association with PD‐related measures including the MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) total score, Montreal Cognitive Assessment (MoCA) score, Geriatric Depression Scale (GDS)‐15 score, and the University of Pennsylvania Smell Identification Test (UPSIT) score. Result TREM2 variant carriers (total N=77) were enriched in PD cases compared to controls (p=0.002). Within variant analysis showed enrichment of p.R62H carriers (p=0.027), but not p.R47H carriers (p=0.667) in sPD. While there was no significant difference in MDS‐UPDRS (p=0.763) or MoCA (p=0.815) at baseline between p.R62H sPD carriers and non‐carriers, p.R62H carriers were more likely to have a MoCA score <21 at a subsequent visit [HR (95% CI) = 2.78 (1.19‐6.49)], though this effect was not significant in an age‐adjusted model [HR (95% CI) = 2.28 (0.97‐5.34]. Compared to non‐carriers, p.R62H carriers showed a trend for more depressive symptoms (p=0.078) and had worse anosmia (p=0.002). Conclusion TREM2 rare coding variants are more common in PD, suggesting that TREM2 may contribute to the genetic etiology of this disease. Interestingly, p.R47H, a risk factor for Alzheimer’s disease, does not appear to contribute to sPD risk, whereas p.R62H may be a novel risk factor for PD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".