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

Abstract 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.