Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk DOI Creative Commons
Elaine Guo Yan Chew, Zhehao Liu, Zheng Li

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that increasing in incidence globally because of population aging. We hypothesized the landscape rare, protein-altering variants could provide further insights into pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases 5,512 controls Asian ancestry. showed GBA1 SMPD1 were significantly associated with risk, replication a 5,585 5,642 controls. refined variant classification using vitro assays reduced enzymatic activity display strongest association (<44% activity, odds ratio (OR) = 2.24, P 1.25 × 10−15) risk. Moreover, 80.5% carriers harbored Asian-specific p.Pro332Arg (OR 2.16; 4.47 10−8). Our findings highlight utility performing exome diverse ancestry groups to identify rare genes previously unassociated disease. Using assays, Chew, Liu, Li, Chung et al. identified protein-coding associate risk across cohorts descent.

Language: Английский

Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease DOI Creative Commons
Thomas P Spargo,

Chloe F. Sands,

Isabella R. Juan

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 115355 - 115355

Published: March 1, 2025

Highlights•ITSN1 haploinsufficiency confers a ∼10-fold increased risk of Parkinson's disease (PD)•Effect size surpasses other well-established loci, including GBA1 and LRRK2•In vivo in vitro studies suggest an interaction between ITSN1 α-synuclein•Findings implicate synaptic vesicle trafficking dysfunction PD pathogenesisSummaryDespite its significant heritability, the genetic basis (PD) remains incompletely understood. Here, analyzing whole-genome sequence data from 3,809 cases 247,101 controls UK Biobank, we discover that protein-truncating variants confer substantially (p = 6.1 × 10−7; odds ratio [95% confidence interval] 10.5 [5.2, 21.3]). We replicate this association three independent datasets totaling 8,407 413,432 (combined p 4.5 10−12). Notably, has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, find loss ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity motor deficits, assays further physical α-synuclein. These results firmly establish as gene effect exceeding previously established vesicular pathogenesis, potentially open new avenues for therapeutic development.Graphical abstract

Language: Английский

Citations

1
Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk DOI Creative Commons
Elaine Guo Yan Chew, Zhehao Liu, Zheng Li

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that increasing in incidence globally because of population aging. We hypothesized the landscape rare, protein-altering variants could provide further insights into pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases 5,512 controls Asian ancestry. showed GBA1 SMPD1 were significantly associated with risk, replication a 5,585 5,642 controls. refined variant classification using vitro assays reduced enzymatic activity display strongest association (<44% activity, odds ratio (OR) = 2.24, P 1.25 × 10−15) risk. Moreover, 80.5% carriers harbored Asian-specific p.Pro332Arg (OR 2.16; 4.47 10−8). Our findings highlight utility performing exome diverse ancestry groups to identify rare genes previously unassociated disease. Using assays, Chew, Liu, Li, Chung et al. identified protein-coding associate risk across cohorts descent.

Language: Английский

Citations

3