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GCH1 genetic variation as a prognostic factor in Parkinsons disease across populations
Shin, J. H.; Perinan, M. T.; Jang, J. W.; Screven, L.; Lange, L. M.; Klein, C.; Shulman, J. M.; Gan-Or et al.. medRxiv (preprint), 2026-08-19
Topic: Brain proteins, microglia and lab models
BackgroundPathogenic variants in GCH1 have been associated with Parkinsons disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized. ObjectivesTo characterize the genetic spectrum, clinical phenotype, and longitudinal progression of GCH1-associated PD across multiple populations. MethodsWhole-genome sequencing (WGS) and clinical exome sequencing (CES) data from the Global Parkinsons Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients. Variant pathogenicity was classified according to ACMG criteria. Demographic, clinical, and longitudinal features were compared between GCH1 P/LP variant carriers and non-carrier PD patients; individuals with known pathogenic variants in PD-associated genes were excluded from both groups. ResultsIn the GP2 cohort (PD, n=22,825; controls, n=4,453), 16 pathogenic or likely pathogenic (P/LP) GCH1 variants were identified in 58 individuals, including 54 PD patients, one control, and three individuals with other neurodegenerative phenotypes (two with progressive supranuclear palsy and one with dementia with Lewy bodies). In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006). Variant frequencies in PD patients ranged from 0.121% to 0.714% across ancestries. In the CES cohort, P/LP variants were identified in 0.201% of PD patients. After integrating GP2 with additional unpublished and published datasets, 119 GCH1-associated PD patients were analyzed. Compared with non-carriers, GCH1 P/LP variant carriers had earlier disease onset (53.7 {+/-} 14.8 vs 59.2 {+/-} 11.7 years; p=8.99x10-5), lower levodopa equivalent daily dose requirements (467.5 {+/-} 331.7 vs 680.3 {+/-} 466.39mg/day; p=4.21x10-8), and more frequent family history of PD (47.6% vs 19.9%; p=1.09x10-8). Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87). ConclusionGCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications. These findings suggest that GCH1 genetic variants may serve as genetic biomarkers for patient stratification and prognosis in PD.
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APA 7th
Shin, J. H., Perinan, M. T., Jang, J. W., Screven, L., Lange, L. M., Klein, C., et al. (2026). GCH1 genetic variation as a prognostic factor in Parkinsons disease across populations. medRxiv (preprint). https://doi.org/10.64898/2026.08.14.26359677
Vancouver
Shin JH, Perinan MT, Jang JW, Screven L, Lange LM, Klein C, et al. GCH1 genetic variation as a prognostic factor in Parkinsons disease across populations. medRxiv (preprint). 2026. doi:10.64898/2026.08.14.26359677.
BibTeX
@article{shin2026-a566b431,
author = {Shin, J. H. and Perinan, M. T. and Jang, J. W. and Screven, L. and Lange, L. M. and Klein, C. and Shulman, J. M. and Gan-Or and others},
title = {{GCH1 genetic variation as a prognostic factor in Parkinsons disease across populations}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.08.14.26359677},
url = {https://doi.org/10.64898/2026.08.14.26359677}
}
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Key findings
- BackgroundPathogenic variants in GCH1 have been associated with Parkinsons disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized.
- In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006).
- Compared with non-carriers, GCH1 P/LP variant carriers had earlier disease onset (53.7 {+/-} 14.8 vs 59.2 {+/-} 11.7 years; p=8.99x10-5), lower levodopa equivalent daily dose requirements (467.5 {+/-} 331.7 vs 680.3 {+/-} 466.39mg/day; p=4.21x10-8), and more frequent family history of PD (47.6% vs 1
- Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87).
- ConclusionGCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications.
Why it matters
Pathogenic or likely pathogenic GCH1 variants were more common in Parkinson's disease patients than controls and were linked to earlier disease onset. This concerns the genetic and clinical features of Parkinson's disease, not Alzheimer's disease treatment, cure or prevention.
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Study details
- Study designlongitudinal study
- Participants22,825
- Effect size0.267%; 0.023%; OR=11.854
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 43 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 40 of the 94 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 4 / 4 | 22,825 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 0 / 4 | Last-listed author the Global Parkinson’s Genetic Program (GP2): h-index 3 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | National Institutes of Health: institution h-index 2,723 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 57 institution(s) in 20 countries |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 40 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 40 of the 94 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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