Müller-Nedebock Amica C, Pfaff Abigail L, Pienaar Ilse S, Kõks Sulev, van der Westhuizen Francois H, Elson Joanna L, Bardien Soraya
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
South African Medical Research Council, Stellenbosch University Genomics of Brain Disorders Research Unit, Stellenbosch University, Cape Town, South Africa.
Front Aging Neurosci. 2022 Jul 14;14:921412. doi: 10.3389/fnagi.2022.921412. eCollection 2022.
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 ( = 78 and = 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 ( < 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.
线粒体DNA（mtDNA）是线粒体功能障碍的一个潜在来源，与帕金森病（PD）有关。然而，以前许多研究线粒体DNA群体变异与帕金森病之间关联的研究报告了不一致或相互矛盾的结果。在这里，我们研究了另一种假设，以确定线粒体DNA变异是否可能在帕金森病风险中起重要作用。新出现的证据表明，如果单倍群定义的线粒体DNA变异出现在不同的母系谱系中“位置不当”，可能具有致病潜力。我们假设帕金森病患者的线粒体DNA在编码氧化磷酸化复合物成分的基因中会富集位置不当的变异。我们用一个独特的数据集检验了这一假设，该数据集包括70例非洲裔帕金森病患者的全线粒体基因组、两个非洲裔对照组（分别为78例和53例）以及来自帕金森病进展标志物倡议队列的281例欧洲裔帕金森病患者和140例对照的复制组。与第二个对照组的对照相比，非洲裔帕金森病患者中位置不当变异的数量明显更多（P<0.0125），尽管在第一个对照组和复制组中未观察到这种关联。作为第一项纳入非洲裔帕金森病患者并在帕金森病背景下探索位置不当变异的线粒体DNA研究，我们发现有证据表明这种变异在这种背景下可能很重要，因此有必要在更大的队列中进一步验证。
