Objective: To replicate and validate the association between ITSN1 loss-of-function (LoF) variants and Parkinson’s disease (PD) in a Chinese population, and to assess whether this genetic risk factor is consistent across different ancestral backgrounds.

Background: LoF variants in the ITSN1 gene were previously discovered through large-scale sequencing in European-ancestry cohorts and shown to confer high risk for PD. However, whether this association holds in other populations, particularly non-European ancestries, remains unknown.

Method: We performed a gene-based rare variant burden analysis of ITSN1 in 2,063 Chinese PD patients and 3,298 controls. Whole-exome sequencing data were analyzed for rare LoF and predicted-damaging missense variants (CADD>20). Association testing was conducted using the optimized sequence kernel association test (SKAT-O), adjusted for sex and population structure.

Results: We identified four novel frameshift LoF variants in patients, all absent from control databases and unreported in European cohorts. Three were classified as Likely Pathogenic. Burden analysis revealed a significant enrichment of rare, deleterious ITSN1 variants in PD cases. The association was significant for both ultra-rare LoF variants and the combined set of LoF and damaging missense variants.

Conclusion: This study independently replicates the association between ITSN1 LoF variants and PD, confirming its role as a cross-population risk gene. The discovery of population-private variants underscores the importance of diverse cohort studies and refines the genetic architecture of PD in the Chinese population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/itsn1-loss-of-function-variants-and-parkinsons-disease-risk-in-a-chinese-cohort/