From genes to pathways: genetic convergence in early-onset Parkinson’s disease in India
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Le résumé fourni par la source
Abstract Parkinson’s 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 Parkinson’s Disease in India–Young-Onset Parkinson’s 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- From genes to pathways: genetic convergence in early-onset Parkinson’s disease in India
- Date Crossref
- 03/09/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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SciGenom Labs (India) pays non établi dans la noticeEntreprise
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Centre for Movement Disorders pays non établi dans la noticeÉtablissement de santé
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Yashoda Hospital Parkinson’s Disease and Movement Disorders Center pays non établi dans la noticeÉtablissement de santé
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Medanta The Medicity pays non établi dans la noticeÉtablissement de santé
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All India Institute of Medical Sciences Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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Shree Krishna Hospital Department of Neurology pays non établi dans la noticeÉtablissement de santé
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Pramukhswami Medical College pays non établi dans la noticeÉtablissement de santé
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Institute of Medical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Banaras Hindu University Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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Institute of Neurosciences Kolkata Department of Neurology pays non établi dans la noticeÉtablissement de santé
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Jaslok Hospital pays non établi dans la noticeÉtablissement de santé
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Bangur Institute of Neurosciences Department of Neurology pays non établi dans la noticeÉtablissement de santé
SciGenom Labs (India), Centre for Movement Disorders et Parkinson’s Disease and Movement Disorders Center — Yashoda Hospital, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.