Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder

Cai, Na, Li, Yihan, Chang, Simon, Liang, Jieqin, Lin, Chongyun, Zhang, Xiufei, Liang, Lu, Hu, Jingchu, Chan, Wharton, Kendler, Kenneth S, Malinauskas, Tomas, Huang, Guo-Jen, Li, Qibin, Mott, Richard, Flint, Jonathan (2015) Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder. Current Biology, 25 (24). pp. 3170-3177. ISSN 0960-9822

DOI: 10.1016/j.cub.2015.10.065


Summary 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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression
diseases & disorders > mental disorders > mood disorders > depression
organs, tissues, organelles, cell types and functions > organelles, types and functions > mitochondria
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Matt Covey
Date Deposited: 14 Dec 2015 20:36
Last Modified: 14 Jan 2016 20:40
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