title: Genetic Control over mtDNA and Its Relationship to Major Depressive Disorder.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan.
authors.forename: Simon
authors.initials: S
authors.lastname: Chang
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Jieqin
authors.initials: J
authors.lastname: Liang
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Chongyun
authors.initials: C
authors.lastname: Lin
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Xiufei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liang
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Jingchu
authors.initials: J
authors.lastname: Hu
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
authors.forename: Wharton
authors.initials: W
authors.lastname: Chan
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.affiliation: Cold Spring Harbor Laboratory, Beckman Building, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Malinauskas
authors.affiliation: Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan.
authors.forename: Guo-Jen
authors.initials: GJ
authors.lastname: Huang
authors.affiliation: BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK. Electronic address: jf@well.ox.ac.uk.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002681:China; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice
chemical_list: D004272:DNA, Mitochondrial