From genes to pathways: genetic convergence in early-onset Parkinsons disease in India
- 1Parkinson's Disease and Movement Disorders Clinic, Bangalore, India.
Abstract
Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India-Young-Onset Parkinsons Disease project (GOPI-YOPD).
The cohort included 668 participants (463 males-69.3%) with a mean age at motor onset of 39.4{+/-}8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole-genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS-associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local-network clusters. Terms meeting a Benjamini-Hochberg false-discovery-rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene-to-pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations.
At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy-related processes (228/336, 67.9%) and regulation of synaptic-vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway-phenotype association remained significant after correction for multiple testing.
Genetic findings in this Indian cohort converged across an interconnected mitochondrial-autophagic-lysosomal-vesicular network, with different contributions from P/LP-associated and VUS-associated gene sets. This study provides the first pathway-resolved South Asian genetic profile and a framework for comparative studies across populations.
Related
- Identification of Key Genes and Pathways in Parkinson’s Disease Through Bioinformatics Analysis
- Thoracic Aortic Disease in Genetic Syndromes Beyond Established Aortopathy Genes
- Levodopa Preferentially Reorganizes Dorsal Subthalamic Activity in Parkinsons Disease
- Explainable machine learning identifies predictors for postural instability and cognitive impairment in early Parkinsons Disease
- Per- and polyfluoroalkyl substances and kidney disease: Genetic associations and computational prioritization of candidate toxicogenomic pathways
BibTeX
@misc{menon2026from,
title = {{From genes to pathways: genetic convergence in early-onset Parkinsons disease in India}},
author = {R. Menon and A. I. Khan and D. Elangovan and R. M. Kandadai and V. Goyal and S. D. Desai and D. Joshi and H. Kumar and P. M. Wadia and A. Mukherjee and N. Kumar and S. Mehta and T. S. Geetha and C. Sandeep and S. Murugan and M. Ayathu Venkat and H. S. Shah and V. Paramanandam and M. v. Chandarana and R. Yadav and R. K. Dhamija and P. K. Pal and A. Biswas and R. Gupta and R. Borgohain and R. L. Vedam and P. L. Kukkle},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.26361762},
url = {https://www.medrxiv.org/content/10.64898/2026.08.31.26361762v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - From genes to pathways: genetic convergence in early-onset Parkinsons disease in India
AU - R. Menon
AU - A. I. Khan
AU - D. Elangovan
AU - R. M. Kandadai
AU - V. Goyal
AU - S. D. Desai
AU - D. Joshi
AU - H. Kumar
AU - P. M. Wadia
AU - A. Mukherjee
AU - N. Kumar
AU - S. Mehta
AU - T. S. Geetha
AU - C. Sandeep
AU - S. Murugan
AU - M. Ayathu Venkat
AU - H. S. Shah
AU - V. Paramanandam
AU - M. v. Chandarana
AU - R. Yadav
AU - R. K. Dhamija
AU - P. K. Pal
AU - A. Biswas
AU - R. Gupta
AU - R. Borgohain
AU - R. L. Vedam
AU - P. L. Kukkle
PY - 2026
DA - 2026/08/31
PB - medRxiv
DO - 10.64898/2026.08.31.26361762
UR - https://www.medrxiv.org/content/10.64898/2026.08.31.26361762v1
AB - Parkinsons disease (PD) arises through disruption of multiple interconnected cellular processes, but the genetic contributions to these processes may differ across ancestries. We investigated functional convergence among genes harboring pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUS) in a multicenter Indian cohort recruited through the Genetics of Parkinsons Disease in India-Young-Onset Parkinsons Disease project (GOPI-YOPD). The cohort included 668 participants (463 males-69.3%) with a mean age at motor onset of 39.4{+/-}8.8 years. P/LP variants and VUS identified through previously reported whole-exome or whole-genome sequencing were retained as separate evidential categories. The P/LP-associated gene set comprised 11 unique genes and the VUS-associated set comprised 40 unique genes. Separate STRING functional-enrichment analyses evaluated Gene Ontology Biological Process, Molecular Function and Cellular Component terms, KEGG pathways, WikiPathways and STRING local-network clusters. Terms meeting a Benjamini-Hochberg false-discovery-rate threshold of <0.05 were organized into eight non-mutually-exclusive ontology/pathway categories. Gene-to-pathway mappings were subsequently projected to individual participants to estimate pathway representation and examine clinical associations. At least one reportable P/LP variant or VUS was identified in 336/668 participants (50.3%): 35 had a P/LP variant alone, 282 had VUS alone and 19 had a P/LP variant together with VUS in one or more additional genes. The most frequently represented categories were mitochondrial organization (247/336, 73.5%), autophagy-related processes (228/336, 67.9%) and regulation of synaptic-vesicle transport (201/336, 59.8%). PRKN was the most frequent P/LP-associated gene, occurring in 29/54 P/LP carriers, followed by PLA2G6 and PINK1. Lysosomal transport was represented exclusively by VUS-associated genes, particularly GBA1, VPS13C and LRRK2. Among P/LP carriers, additional VUS in distinct genes were not associated with age at onset (P = 0.81) or family history (52.6% versus 31.4%; P = 0.15). No pathway-phenotype association remained significant after correction for multiple testing. Genetic findings in this Indian cohort converged across an interconnected mitochondrial-autophagic-lysosomal-vesicular network, with different contributions from P/LP-associated and VUS-associated gene sets. This study provides the first pathway-resolved South Asian genetic profile and a framework for comparative studies across populations.
ER -