Enrichment of rare variants in nuclear-encoded mitochondrial metabolism genes in patients with early-onset or familial parkinson’s disease

Bergant, Gaber (author), Van Midden, Vesna M. (author), Tsygankova, Polina (author), Laslo, Dorian (author), Rački, Valentino (author), Georgiev, Dejan (author), Papić, Eliša (author), Branković, Marija (author), Janković, Milena (author), Svetel, Marina (author), Teran, Nataša (author), Dragasević Misković, Natasa (author), Petrović, Igor N. (author), Maver, Aleš (author), Novaković, Ivana (author), Pirtošek, Zvezdan (author), Rakuša, Martin (author), Vuletić, Vladimira (author), Peterlin, Borut (author)

Introduction: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, with several proposed pathogenic mechanisms. Given the established role of mitochondrial dysfunction in PD, this study seeks to investigate the enrichment of rare genetic variants tied to mitochondrial metabolism in cases of early-onset and familial PD. Methods: We performed a retrospective analysis on 248 early-onset and familial PD patients and 1622 control individuals. We assessed both pathway-level and gene-level burden of germline rare variants detected using exome sequencing in 467 nuclear genes related to mitochondrial metabolism. Results: Gene-set mutation burden analysis indicated an increased burden in genes associated with mtDNA maintenance. In addition, gene-level analysis identified a possible association between PD and rare variant burden in 14 mitochondrial metabolism-related genes under dominant or recessive inheritance models. Conclusions: Our findings support a potential contribution of rare germline variants affecting mitochondrial metabolism to the susceptibility in early-onset and familial PD.

• Language: English
• Keywords: mitochondrial metabolism, mitochondrial variants, mutation burden analysis
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FRI - Faculty of Computer and Information Science ; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 8 str.
• Numbering: Vol. 17, iss. 4
• PID: 20.500.12556/RUL-185147
• UDC: 616.858
• ISSN on article: 2073-4425
• DOI: 10.3390/genes17040472
• COBISS.SI-ID: 276781571
• Publication date in RUL: 24.07.2026

Record is a part of a journal

• Title: Genes
• Shortened title: Genes
• Publisher: MDPI
• ISSN: 2073-4425
• COBISS.SI-ID: 523100185

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• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.