Objective: To systematically assess known disease-causing repeat expansions detectable by short-read sequencing in Parkinson’s Disease (PD) and atypical parkinsonism and examine repeat length-disease relationships to assess if expanded alleles confer PD risk.

Background: Short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, but their prevalence, penetrance, and phenotypic spectrum in PD across diverse ancestries remain incompletely characterized. Previous studies have been limited in sample size and loci, often systematically underrecognizing intermediate and pathogenic alleles.

Method: We analyzed short-read whole-genome (WGS) and clinical-exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), including 13,738 individuals with PD, 4,729 individuals with atypical parkinsonism, and 10,394 healthy controls representing 11 genetic ancestries from the Global Parkinson’s Genetics Program, the Accelerating Medicines Partnership – Parkinson’s Disease, and the Alzheimer’s Disease Sequencing Project. We genotyped twelve known disease-causing repeat expansions to evaluate carrier frequencies and repeat sequence structures. Additionally, we performed the length-dependent associations with PD risk in Europeans using Firth’s penalized logistic regression.

Results: Pathogenic repeat expansions were identified across seven loci (AR, ATXN1, ATXN2, ATXN3, CACNA1A, HTT, and THAP11), spanning seven ancestries. ATXN2 expansions were most frequently observed in PD and present in African, East Asian, European, and Middle Eastern ancestries. In Europeans, ATXN2 repeat length exhibited a strong, length-dependent association with PD risk; individuals with ≥32 repeats had a more than four-fold increased risk (OR = 4.25, P = 0.00057), with >92% of expanded carriers harboring repeat interruptions. Pathogenic expansions at other loci, such as ATXN3 and THAP11, displayed distinct ancestry-specific distributions and locus-specific sequence motifs. Clinically, ATXN2 and ATXN3 expansion carriers most often presented with typical PD but frequently showed early disease onset and a strong family history.

Conclusion: Our large-scale, multi-ancestry study comprehensively maps the genetic landscape of repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 repeats and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-ancestry-analysis-of-repeat-expansions-in-parkinsons-disease/