Table_1_Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor.xlsx

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.

线粒体DNA（mtDNA）作为线粒体功能障碍的潜在诱因，已被证实与帕金森病（PD）存在关联。然而，既往诸多探讨mtDNA群体变异与PD关联的研究，所得结果往往不一致甚至相互矛盾。本研究旨在验证另一假说，以明确mtDNA变异是否会对PD发病风险产生显著影响。越来越多的证据表明，若定义单倍群的mtDNA变异在非预期的母系血统中出现位置异常，则可能具备致病潜能。我们提出假说：PD患者的mtDNA中，编码氧化磷酸化复合物组分的基因区域，其位置异常变异的富集程度更高。本研究采用一套独特的数据集验证该假说，该数据集包含70例非洲血统PD患者的全线粒体基因组序列，2组非洲血统对照人群（样本量分别为78例和53例），以及来自帕金森病进展标志物倡议（Parkinson’s Progression Markers Initiative, PPMI）队列的281例欧洲血统PD患者与140例对照的全线粒体基因组数据。与第二组对照相比，非洲血统PD患者的位置异常变异检出率显著更高（P < 0.0125）；不过这一关联在第一组对照及验证队列中均未观测到。作为首个纳入非洲血统PD患者、并在PD研究框架下探讨位置异常变异的mtDNA研究，本研究发现这类变异或与PD发病相关，因此有必要在更大规模的队列中开展进一步验证。