Clinical and Translational Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
Mitochondrion. 2022 Mar;63:85-88. doi: 10.1016/j.mito.2022.02.002. Epub 2022 Feb 12.
Interactions between the products of the nuclear and mitochondrial genomes are critical for the function of most eukaryotic cells. Recently the introduction of mitochondrial replacement therapy has raised the question of incompatibilities between mitochondrial and nuclear variants, and their potential influence on the genetic makeup of human populations. Such interactions could also contribute to the variability of the penetrance of pathogenic DNA variants. This led us to investigate the frequencies of combinations of nuclear and mitochondrial SNP alleles (mitonuclear combinations) in healthy individuals (n = 5375) and in a cohort of patients with Parkinson's disease (PD, n = 2210). In the unaffected population, we were not able to find associations between nuclear and mitochondrial variants with a false discovery rate below 0.05 after accounting for multiple testing (i.e., the number of combinations examined). However, in the PD cohort, five combinations surpassed this threshold. Next, after combining both cohorts, we investigated whether these associations were modulated by disease status. All five combinations were significant (p < 10 for all tests). These combinations also showed significant evidence for an effect of the interaction between the mitochondrial and nuclear variants on disease risk. Their nuclear components mapped to TBCA, NIBAN3, and GLT25D1 and an uncharacterised intergenic region. In summary, starting from a single cohort design we identified combinations of nuclear and mitochondrial variants affecting PD disease risk.
核基因组和线粒体基因组产物之间的相互作用对于大多数真核细胞的功能至关重要。最近，线粒体替换疗法的引入引发了线粒体和核变体之间不兼容性的问题，以及它们对人类群体遗传构成的潜在影响。这种相互作用也可能导致致病性 DNA 变体外显率的可变性。这促使我们研究了健康个体（n=5375）和帕金森病（PD，n=2210）患者队列中核和线粒体 SNP 等位基因（线粒体核组合）的组合频率。在未受影响的人群中，我们无法找到核变体和线粒体变体之间的关联，在考虑到多次测试后（即，检查的组合数量），其假发现率低于 0.05。然而，在 PD 队列中，有五个组合超过了这个阈值。接下来，在合并两个队列后，我们研究了这些关联是否受疾病状态的调节。所有五个组合都是显著的（所有测试的 p<10）。这些组合还显示出线粒体和核变体之间相互作用对疾病风险的影响有显著证据。它们的核组成部分映射到 TBCA、NIBAN3 和 GLT25D1 以及一个未表征的基因间区域。总之，从单个队列设计开始，我们确定了影响 PD 疾病风险的核和线粒体变体组合。
