Movement disorders : official journal of the Movement Disorder Society · 2026
Cross-Ethnic Replication of Intersectin-1 as a Parkinson's Disease Susceptibility Gene in a Large Chinese Cohort.
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Li Chunyu, Ou Ruwei, Wei Qianqian, Wang Shichan, Zheng Xiaoting, Jiang Qirui, Huang Jingxuan, Wang Yuxi, Xiao Yi, Liu Xiaodie, Lin Junyu, Chen Xueping, Song Wei, Zhao Bi, Wu Ying, Shang Huifang
Аннотация
BACKGROUND: Rare loss-of-function (LoF) variants in Intersectin-1 (ITSN1) have recently been identified as strong genetic risk factors for Parkinson's disease (PD) in individuals of European ancestry.
OBJECTIVE: The aim was to determine whether this association extends to other populations.
METHODS: We analyzed whole-exome sequencing data from 2063 unrelated Chinese patients with PD and performed rare-variant burden analyses together with 3298 controls and publicly available East Asian reference datasets. Gene-based association was evaluated using optimized sequence kernel association test (SKAT-O) for rare LoF variants and predicted damaging missense variants.
RESULTS: Three previously unreported frameshift LoF variants were identified in the patients, all of which were absent from controls and classified as likely pathogenic. Gene-based burden analyses demonstrated enrichment of rare deleterious ITSN1 variants in patients with PD across multiple control datasets, supporting the contribution of ITSN1 to PD susceptibility.
CONCLUSIONS: Our findings provide the first independent evidence supporting the association between rare ITSN1 variants and PD in an East Asian population, extending previous discoveries from European cohorts. The identification of population-specific pathogenic variants further refines the genetic architecture of ITSN1 and reinforces its role as a cross-population susceptibility gene for PD. © 2026 International Parkinson and Movement Disorder Society.
OBJECTIVE: The aim was to determine whether this association extends to other populations.
METHODS: We analyzed whole-exome sequencing data from 2063 unrelated Chinese patients with PD and performed rare-variant burden analyses together with 3298 controls and publicly available East Asian reference datasets. Gene-based association was evaluated using optimized sequence kernel association test (SKAT-O) for rare LoF variants and predicted damaging missense variants.
RESULTS: Three previously unreported frameshift LoF variants were identified in the patients, all of which were absent from controls and classified as likely pathogenic. Gene-based burden analyses demonstrated enrichment of rare deleterious ITSN1 variants in patients with PD across multiple control datasets, supporting the contribution of ITSN1 to PD susceptibility.
CONCLUSIONS: Our findings provide the first independent evidence supporting the association between rare ITSN1 variants and PD in an East Asian population, extending previous discoveries from European cohorts. The identification of population-specific pathogenic variants further refines the genetic architecture of ITSN1 and reinforces its role as a cross-population susceptibility gene for PD. © 2026 International Parkinson and Movement Disorder Society.