Progression GWAS followed by functional characterization implicates E3 ubiquitin ligase TRIM2 as a potential genetic modifier of Parkinson’s disease progression
4 affiliations
- 1Genomics Research Center, AbbVie
- 2Foundational Neuroscience Center, AbbVie
- 3Global Epidemiology, AbbVie
- 4Neuroscience Development, AbbVie
Abstract
Parkinson’s Disease (PD) is a progressive neurodegenerative disorder, affecting 10 million people worldwide. While genome-wide association studies (GWAS) have identified many genetic variants associated with PD incidence, the genetics underlying PD progression are poorly understood. Here, we aim to address this gap by performing GWAS on longitudinal clinical metrics from well-defined PD cohorts. Specifically, we identify 8 novel GWAS genes for PD progression, including TRIM2, which encodes an E3 ubiquitin ligase with loss-of-function mutations that cause neuropathy. Functional genomics data suggest that the GWAS SNPs in the locus of TRIM2 regulate its expression across several PD-relevant brain regions. Further, we show that TRIM2 knockdown and overexpression in primary neurons regulate neurofilament light (NF-L) levels and α-synuclein aggregation- the primary neuropathological hallmark of PD. Peripheral proteomic analysis of a genetically defined PD patient cohort demonstrates increased NF-L protein levels in the plasma and cerebrospinal fluid of TRIM2 SNP carriers, corroborating the role of TRIM2 in NF-L regulation. Overall, by integrating PD progression GWAS with transcriptomic, eQTL analyses, and functional data in PD cellular models, we identify new targets including TRIM2 that may influence the progression rate of PD.
Related
- Pan-Cancer Analysis Identifies LUC7L2 as a Prognostic Biomarker and Potential Functional Regulator of Prostate Cancer Progression
- Mutating ubiquitin carboxy terminal hydrolase L1 cysteine 152 ameliorates white matter injury and functional deficits in experimental vascular dementia
- A Genome-Wide Meta-Analysis of Functional Dyspepsia in 1,168,899 Individuals Implicates Immune Pathways in Disease Susceptibility.
- Targeting ubiquitin-dependent mitochondrial autophagy and apoptosis in sarcopenia: the therapeutic potential of phytochemicals.
- Functional fine-mapping of the 9p21.3 cardiovascular disease locus implicates the lncRNA MIR31HG as an effector transcript in endothelial cells
BibTeX
@article{kulkarni2026progression,
title = {{Progression GWAS followed by functional characterization implicates E3 ubiquitin ligase TRIM2 as a potential genetic modifier of Parkinson’s disease progression}},
author = {Ameya S. Kulkarni and Dan Apicco and Saleh Tamim and Lauren Gibilisco and Layan Nahlawi and Rachel Lucia and Sujana Ghosh and Samantha Lent and Yanyu Liang and Saurabh Khasnavis and Laura Smith and Joshua Stender and Priyanka Vijay and Cindy Zadikoff and Justin Wade Davis and Jan Stöhr and Hyun Ji Noh},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-67630-7},
url = {https://doi.org/10.1038/s41598-026-67630-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - Progression GWAS followed by functional characterization implicates E3 ubiquitin ligase TRIM2 as a potential genetic modifier of Parkinson’s disease progression
AU - Ameya S. Kulkarni
AU - Dan Apicco
AU - Saleh Tamim
AU - Lauren Gibilisco
AU - Layan Nahlawi
AU - Rachel Lucia
AU - Sujana Ghosh
AU - Samantha Lent
AU - Yanyu Liang
AU - Saurabh Khasnavis
AU - Laura Smith
AU - Joshua Stender
AU - Priyanka Vijay
AU - Cindy Zadikoff
AU - Justin Wade Davis
AU - Jan Stöhr
AU - Hyun Ji Noh
PY - 2026
DA - 2026/09/01
JO - Scientific Reports
DO - 10.1038/s41598-026-67630-7
UR - https://doi.org/10.1038/s41598-026-67630-7
AB - Parkinson’s Disease (PD) is a progressive neurodegenerative disorder, affecting 10 million people worldwide. While genome-wide association studies (GWAS) have identified many genetic variants associated with PD incidence, the genetics underlying PD progression are poorly understood. Here, we aim to address this gap by performing GWAS on longitudinal clinical metrics from well-defined PD cohorts. Specifically, we identify 8 novel GWAS genes for PD progression, including TRIM2, which encodes an E3 ubiquitin ligase with loss-of-function mutations that cause neuropathy. Functional genomics data suggest that the GWAS SNPs in the locus of TRIM2 regulate its expression across several PD-relevant brain regions. Further, we show that TRIM2 knockdown and overexpression in primary neurons regulate neurofilament light (NF-L) levels and α-synuclein aggregation- the primary neuropathological hallmark of PD. Peripheral proteomic analysis of a genetically defined PD patient cohort demonstrates increased NF-L protein levels in the plasma and cerebrospinal fluid of TRIM2 SNP carriers, corroborating the role of TRIM2 in NF-L regulation. Overall, by integrating PD progression GWAS with transcriptomic, eQTL analyses, and functional data in PD cellular models, we identify new targets including TRIM2 that may influence the progression rate of PD.
SN - 2045-2322
ER -