Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder.
Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder.
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DOI：
10.1016/j.cub.2015.10.065
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发表时间：
2015-12-21
期刊：
影响因子：
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通讯作者：
Flint J
中科院分区：
文献类型：
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作者：
Cai N;Li Y;Chang S;Liang J;Lin C;Zhang X;Liang L;Hu J;Chan W;Kendler KS;Malinauskas T;Huang GJ;Li Q;Mott R;Flint J
对每个细胞mtDNA分子数量的控制似乎受到严格调控，但所涉及的机制在很大程度上是未知的。线粒体DNA数量的可逆性改变是对压力的反应，这表明对线粒体DNA数量的控制与压力相关的疾病有关，包括重度抑郁症（MDD）。使用来自10，442名中国女性的低覆盖率序列数据来计算映射到线粒体基因组的标准化读取数作为mtDNA数量的代表，我们确定了两个有助于mtDNA水平的基因座：一个位于10号染色体上的TFAM基因内（rs 11006126，p值= 8.73 × 10 - 28，方差解释= 1.90%）和7号染色体上的CDK 6基因上的一个（rs 445，p值= 6.03 × 10−16，方差解释= 0.50%）。这两个位点在一个独立的队列中复制。因此，CDK 6是一种参与mtDNA控制的新分子。我们确定了女性抑郁症患者异质性的增加率，并从小鼠实验范式中表明，这种增加可能是由于压力。此外，至少有一种异质性变异与mtDNA数量的变化显著相关（位置513，p值= 3.27 × 10−9，方差解释= 0.48%），表明位点特异性异质性可能是应激和mtDNA数量增加之间的联系。这些发现表明线粒体基因组拷贝数和序列参与了生物体对压力的反应。TFAM和CDK 6附近的基因座导致线粒体DNA数量的变化在重性抑郁症患者的线粒体DNA中积累的突变动物实验表明，异质性可以由慢性应激诱导线粒体DNA的数量与位点特异性异质性相关先前已经表明，重性抑郁症患者的线粒体DNA数量增加，暴露于应激可能是负责任的，线粒体DNA数量的变化是可逆的，Cai et al.本文探讨了这种变化的遗传控制和后果，以及这与重度抑郁症的关系。
Control over the number of mtDNA molecules per cell appears to be tightly regulated, but the mechanisms involved are largely unknown. Reversible alterations in the amount of mtDNA occur in response to stress suggesting that control over the amount of mtDNA is involved in stress-related diseases including major depressive disorder (MDD). Using low-coverage sequence data from 10,442 Chinese women to compute the normalized numbers of reads mapping to the mitochondrial genome as a proxy for the amount of mtDNA, we identified two loci that contribute to mtDNA levels: one within the TFAM gene on chromosome 10 (rs11006126, p value = 8.73 × 10−28, variance explained = 1.90%) and one over the CDK6 gene on chromosome 7 (rs445, p value = 6.03 × 10−16, variance explained = 0.50%). Both loci replicated in an independent cohort. CDK6 is thus a new molecule involved in the control of mtDNA. We identify increased rates of heteroplasmy in women with MDD, and show from an experimental paradigm using mice that the increase is likely due to stress. Furthermore, at least one heteroplasmic variant is significantly associated with changes in the amount of mtDNA (position 513, p value = 3.27 × 10−9, variance explained = 0.48%) suggesting site-specific heteroplasmy as a possible link between stress and increase in amount of mtDNA. These findings indicate the involvement of mitochondrial genome copy number and sequence in an organism’s response to stress. Loci near TFAM and CDK6 contribute to variation in the amount of mtDNA Mutations accumulate in the mtDNA of cases of major depression Animal experiments show that heteroplasmy can be induced by chronic stress Amount of mtDNA is associated with site-specific heteroplasmy Having previously shown that cases of major depressive disorder have increased mtDNA, that exposure to stress is likely responsible, and that the changes in amount of mtDNA are reversible, Cai et al. investigate in this paper the genetic control and consequences of this change and how this relates to major depressive disorder.