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Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor

Mitochondrial DNA (mtDNA), a potential source of mitochondrial dysfunction, has been implicated in Parkinson’s disease (PD). However, many previous studies investigating associations between mtDNA population variation and PD reported inconsistent or contradictory findings. Here, we investigated an a...

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Autores principales: Müller-Nedebock, Amica C., Pfaff, Abigail L., Pienaar, Ilse S., Kõks, Sulev, van der Westhuizen, Francois H., Elson, Joanna L., Bardien, Soraya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330142/
https://www.ncbi.nlm.nih.gov/pubmed/35912088
http://dx.doi.org/10.3389/fnagi.2022.921412
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author Müller-Nedebock, Amica C.
Pfaff, Abigail L.
Pienaar, Ilse S.
Kõks, Sulev
van der Westhuizen, Francois H.
Elson, Joanna L.
Bardien, Soraya
author_facet Müller-Nedebock, Amica C.
Pfaff, Abigail L.
Pienaar, Ilse S.
Kõks, Sulev
van der Westhuizen, Francois H.
Elson, Joanna L.
Bardien, Soraya
author_sort Müller-Nedebock, Amica C.
collection PubMed
description Mitochondrial DNA (mtDNA), a potential source of mitochondrial dysfunction, has been implicated in Parkinson’s disease (PD). However, many previous studies investigating associations between mtDNA population variation and PD reported inconsistent or contradictory findings. Here, we investigated an alternative hypothesis to determine whether mtDNA variation could play a significant role in PD risk. Emerging evidence suggests that haplogroup-defining mtDNA variants may have pathogenic potential if they occur “out-of-place” on a different maternal lineage. We hypothesized that the mtDNA of PD cases would be enriched for out-of-place variation in genes encoding components of the oxidative phosphorylation complexes. We tested this hypothesis with a unique dataset comprising whole mitochondrial genomes of 70 African ancestry PD cases, two African ancestry control groups (n = 78 and n = 53) and a replication group of 281 European ancestry PD cases and 140 controls from the Parkinson’s Progression Markers Initiative cohort. Significantly more African ancestry PD cases had out-of-place variants than controls from the second control group (P < 0.0125), although this association was not observed in the first control group nor the replication group. As the first mtDNA study to include African ancestry PD cases and to explore out-of-place variation in a PD context, we found evidence that such variation might be significant in this context, thereby warranting further replication in larger cohorts.
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spelling pubmed-93301422022-07-29 Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor Müller-Nedebock, Amica C. Pfaff, Abigail L. Pienaar, Ilse S. Kõks, Sulev van der Westhuizen, Francois H. Elson, Joanna L. Bardien, Soraya Front Aging Neurosci Neuroscience Mitochondrial DNA (mtDNA), a potential source of mitochondrial dysfunction, has been implicated in Parkinson’s disease (PD). However, many previous studies investigating associations between mtDNA population variation and PD reported inconsistent or contradictory findings. Here, we investigated an alternative hypothesis to determine whether mtDNA variation could play a significant role in PD risk. Emerging evidence suggests that haplogroup-defining mtDNA variants may have pathogenic potential if they occur “out-of-place” on a different maternal lineage. We hypothesized that the mtDNA of PD cases would be enriched for out-of-place variation in genes encoding components of the oxidative phosphorylation complexes. We tested this hypothesis with a unique dataset comprising whole mitochondrial genomes of 70 African ancestry PD cases, two African ancestry control groups (n = 78 and n = 53) and a replication group of 281 European ancestry PD cases and 140 controls from the Parkinson’s Progression Markers Initiative cohort. Significantly more African ancestry PD cases had out-of-place variants than controls from the second control group (P < 0.0125), although this association was not observed in the first control group nor the replication group. As the first mtDNA study to include African ancestry PD cases and to explore out-of-place variation in a PD context, we found evidence that such variation might be significant in this context, thereby warranting further replication in larger cohorts. Frontiers Media S.A. 2022-07-14 /pmc/articles/PMC9330142/ /pubmed/35912088 http://dx.doi.org/10.3389/fnagi.2022.921412 Text en Copyright © 2022 Müller-Nedebock, Pfaff, Pienaar, Kõks, van der Westhuizen, Elson and Bardien. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Müller-Nedebock, Amica C.
Pfaff, Abigail L.
Pienaar, Ilse S.
Kõks, Sulev
van der Westhuizen, Francois H.
Elson, Joanna L.
Bardien, Soraya
Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title_full Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title_fullStr Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title_full_unstemmed Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title_short Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor
title_sort mitochondrial dna variation in parkinson’s disease: analysis of “out-of-place” population variants as a risk factor
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330142/
https://www.ncbi.nlm.nih.gov/pubmed/35912088
http://dx.doi.org/10.3389/fnagi.2022.921412
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