Association of Non‐Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank‐Based Whole‐Genome Sequencing Study

BACKGROUND: Nucleotide repeat expansions are a potential factor in Parkinson's disease (PD) risk, but previous studies were inconsistent. We investigated 14 non-coding repeat expansion genes (C9ORF72, FMR1, AFF2, ATXN8OS, ATXN10, CNBP, CSTB, DMPK, FXN, NOP56, NOTCH2NLC, PPP2R2B, RFC1, and TCF4) in a large cohort. METHODS: We used whole-genome sequencing (WGS) data from the United Kingdom (UK) Biobank, including 3588 PD cases and 388,532 controls. Repeat sizes were determined using ExpansionHunter. We also conducted a sensitivity analysis. RESULTS: After Bonferroni correction, no genes showed a statistically significant association with PD risk. However, nominal associations were found for pathogenic repeats in C9ORF72 (odds ratio [OR] = 1.780, P = 0.037) and for gray zone repeats in FMR1 (OR = 0.695, P = 0.016), which suggests a potential protective effect. CONCLUSION: Our large-scale study provides hypothesis-generating evidence. We report a nominal association linking pathogenic C9ORF72 repeats to increased PD risk and, importantly, a novel observation that FMR1 repeats may be protective. © 2025 International Parkinson and Movement Disorder Society.