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

ABSTRACT: 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.

SUBMITTER: Muller-Nedebock A

PROVIDER: S-EPMC9330142 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function.ObjectiveThe objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.MethodsWe employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions.ResultsUsing the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ).ConclusionsOur results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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

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