Rare-Variant Burden Analysis of Dystonia Genes in Parkinson's Disease

Dystonia frequently coexists with Parkinson's disease (PD), yet the extent of genetic overlap remains insufficiently explored.

The aim was to examine whether rare variants in dystonia-related genes are associated with PD or early-onset PD (EOPD).

We curated 44 dystonia-related genes using the Online Mendelian Inheritance in Man (OMIM) and the Movement Disorder Society report on hereditary dystonia. Whole-genome sequencing data from 5315 PD patients, including 300 EOPD patients, and 36,902 controls across the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) and UK Biobank European cohorts were analyzed. Rare-variant burden analysis was performed using the optimized sequence kernel association test (SKAT-O) and MetaSKAT.

In the analyses of all PD patients, no association survived multiple-testing correction. Conversely, exploratory EOPD analyses identified five significant genes (ATP5MC3, DNAJC12, KMT2B, TBC1D24, TMEM151A); however, these signals were driven by small numbers of variants and were not robust to leave-one-variant-out analyses.

Rare variants in dystonia-related genes are not major contributors to overall PD risk. Signals observed in the EOPD subset require replication in larger cohorts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.