Re‐evaluating Dystonia‐Linked Gene Variants in a Large European Parkinson's Disease Cohort

We read with great interest the recent article by Lange et al, “Rare but Relevant? Assessing Variants in Dystonia-Linked Genes in Parkinson's Disease,” in Movement Disorders.1 Their study successfully leveraged the GP2/AMP-PD cohorts, showing that pathogenic variants in dystonia-linked genes, notably GCH1 and VPS16, are present in 0.54% of patients with Parkinson's disease (PD). The authors concluded that GCH1 is a PD-relevant gene. Motivated by their findings, we systematically evaluated the burden of variants in the same set of dystonia-linked genes in a large, well-characterized, population-based cohort of European ancestry individuals from the UK Biobank (UKB).2, 3 Our study included 3602 PD cases and carefully selected 145,496 control subjects (age >60 years, no PD/related International Classification of Diseases, 10th Revision codes, and no family history of PD). We analyzed three variant categories (masks) using REGENIE4 and LOFTEE5: high-confidence protein-truncating variants (HC-PTVs), loss-of-function (LOF) variants, and a combined mask of LOF + missense (5/5) variants (variants consistently predicted as damaging by five in silico algorithms) (see Supporting Information Data S1). In contrast to the overall enrichment observed in the GP2/AMP-PD cohorts, our analysis of the UKB cohort did not find a significant difference in the total burden of HC-PTVs, LOF, or LOF + missense (5/5) variants across all tested dystonia-linked genes between the PD group and control subjects (P > 0.05; Table 1). At the single-gene level, we did not observe an enrichment of variants in either GCH1 or VPS16 in patients with PD compared with controls (P > 0.05 for all masks; Table 1). This suggests that, at least in this large European PD cohort, GCH1 and VPS16 pathogenic variants may not be a major risk factor for PD, necessitating a cautious, population-specific interpretation. Intriguingly, we identified a nominal enrichment of variants in the DNAJC12 gene in the PD group (Table 1). PD cases showed a higher frequency of DNAJC12 HC-PTVs (0.08% in cases vs. 0.01% in controls, odds ratio [OR; 95% confidence interval (CI)] = 7.58 [2.21–26.02], P = 1.02 × 10−2) and LOF + missense (5/5) variants (0.25% in cases vs. 0.08% in controls, OR [95% CI] = 3.28 (1.66–6.48), P = 2.63 × 10−3). DNAJC12 is linked to dystonia-parkinsonism,6 and our finding, although not surviving Bonferroni correction (1.92 × 10−3), warrants further investigation in other large-scale PD cohorts. The difference in findings between our UKB study and the GP2/AMP-PD study may be attributed to: (1) ancestry and population structure: our study was restricted to Caucasians, whereas the GP2/AMP-PD cohort included diverse ancestries; (2) cohort ascertainment: our population-based UKB cohort may reflect a different spectrum of PD; and (3) variant definition: the authors focused on ClinVar/American College of Medical Genetics and Genomics–classified pathogenic variants, whereas we assessed the burden of specific functional variant masks. In conclusion, our data suggest that the overall burden of disruptive variants in dystonia-linked genes is not significantly enriched in European PD patients. The clinical relevance of GCH1 and VPS16 may be less pronounced in this population, whereas DNAJC12 warrants further exploration as a potential PD-risk gene. These contrasting findings underscore the need for cautious, population-specific genetic interpretation. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. L.C.: 1C, 2A, 2B, 2C, 3A. J.W.: 1C, 2A, 2B, 2C, 3A. Q.Y.: 1C, 2A, 2B, 2C, 3A. Z.H.: 1A, 1B, 1C, 3A, 3B. Y.F.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B. J.L.: 1A, 1B, 1C, 3A, 3B. We express our sincere gratitude to the participants of the UK Biobank and recognize the invaluable contributions of the UK Biobank team in the collection, curation, and management of data that enabled this research. This study was supported by the National Natural Science Foundation of China (grant 82401649 to Y.F.; grants 82230040, 82071415, and 81873778 to J.L.) and the China Postdoctoral Science Foundation (grant 2024 M752018 to Y.F.). Additional support was provided by the Huangpu District Health and Medical Research Project, Shanghai (grant HLM202205). The authors declare no competing interests related to this study. Over the past 12 months, no additional financial relationships or conflicts of interest beyond those reported above were present for any author. Author disclosures are available in the Supporting Information. The UK Biobank (UKB) data are available through the UKB Access Management System (https://www.ukbiobank.ac.uk/). We will return the derived data fields following UKB policy; in due course, they will be available through the UKB Access Management System. Data S1. Supporting Information. Data S2. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.