Molecular signatures of major depression.
Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual's somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10(-42), odds ratio 1.33 [95% confidence interval [CI] = 1.29-1.37]) and telomere length (p = 2.84 × 10(-14), odds ratio 0.85 [95% CI = 0.81-0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Na
N
Cai
Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC.
Simon
S
Chang
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Yihan
Y
Li
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Qibin
Q
Li
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Jingchu
J
Hu
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Jieqin
J
Liang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Li
L
Song
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Warren
W
Kretzschmar
Department of Comparative Developmental Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linne-Weg 10, Cologne 50829, Germany.
Xiangchao
X
Gan
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Jerome
J
Nicod
Centro de Investigacion Medica en Red de Salud Mental, CIBERSAM-University of Granada, Granada, Spain; MRC SGDP Centre, Institute of Psychiatry at King's College, De Crespigny Park, London SE5 8AF, UK; National Institute for Health Research, Biomedical Research Centre for Mental Health, Institute of Psychiatry at King's College, De Crespigny Park, London SE5 8AF, UK.
Margarita
M
Rivera
Mental Health Center of West China Hospital of Sichuan University, No. 28 South Dianxin Street, Wuhou District, Chengdu, Sichuan 610000, China.
Hong
H
Deng
Hebei Mental Health Center, No. 572 Dongfeng Road, Baoding, Hebei 71000, China.
Bo
B
Du
Hebei Mental Health Center, No. 572 Dongfeng Road, Baoding, Hebei 71000, China.
Keqing
K
Li
Hebei Mental Health Center, No. 572 Dongfeng Road, Baoding, Hebei 71000, China.
Wenhu
W
Sang
Zhejiang Traditional Chinese Medical Hospital, No. 54 Youdian Road, Hangzhou, Zhejiang 310000, China.
Jingfang
J
Gao
Ningbo Kang Ning Hospital, No. 1 Zhuangyu Road, Zhenhai District, Ningbo, Zhejiang 315000, China.
Shugui
S
Gao
Liaocheng No. 4 Hospital, No. 47 North Huayuan Road, Liaocheng, Shandong 252000, China.
Baowei
B
Ha
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC.
Hung-Yao
HY
Ho
No. 3 Hospital of Heilongjiang Province, No. 135 Jiaotong Road, Beian, Heilongjiang 164000, China.
Chunmei
C
Hu
Harbin Medical University, No. 23 Youzheng Street, Nangang District, Haerbin, Heilongjiang 150000, China.
Jian
J
Hu
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Zhenfei
Z
Hu
Sichuan Mental Health Center, No. 190, East Jiannan Road, Mianyang, Sichuan 621000, China.
Guoping
G
Huang
Chongqing Mental Health Center, No. 102 Jinzishan, Jiangbei District, Chongqing, Chongqing 404100, China.
Guoqing
G
Jiang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Tao
T
Jiang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Wei
W
Jin
Mental Health Institute of Jining Medical College, Dai Zhuang, Bei Jiao, Jining, Shandong 272000, China.
Gongying
G
Li
Mental Hospital of Jiangxi Province, No. 43 Shangfang Road, Nanchang, Jiangxi 330000, China.
Kan
K
Li
Wuhan Mental Health Center, No. 70, Youyi Road, Wuhan, Hubei 430000, China.
Yi
Y
Li
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Yingrui
Y
Li
No. 1 Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, Henan 450000, China.
Youhui
Y
Li
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC.
Yu-Ting
YT
Lin
Shandong Mental Health Center, No. 49 East Wenhua Road, Jinan, Shandong 250000, China.
Lanfen
L
Liu
Shenzhen Key Lab for Psychological Healthcare, Kangning Hospital, No. 1080, Cuizhu Street, Luohu District, Shenzhen, Guangdong 518000, China.
Tiebang
T
Liu
The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, Liaoning 110001, China.
Ying
Y
Liu
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Yuan
Y
Liu
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Yao
Y
Lu
Psychiatric Hospital of Henan Province, No. 388 Middle Jianshe Road, Xinxiang, Henan 453000, China.
Luxian
L
Lv
No. 1 Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, Chongqing 400016, China.
Huaqing
H
Meng
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Puyi
P
Qian
Changchun Mental Hospital, No. 4596 Beihuan Road, Changchun, Jilin 130000, China.
Hong
H
Sang
Tianjin Anding Hospital, No. 13 Liulin Road, Hexi District, Tianjin, Tianjin 300000, China.
Jianhua
J
Shen
Xian Mental Health Center, No. 15 Yanyin Road, New Qujiang District, Xian, Shaanxi 710000, China.
Jianguo
J
Shi
Brain Hospital of Nanjing Medical University, No. 264 Guangzhou Road, Nanjing, Jiangsu 210000, China.
Jing
J
Sun
Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318 Chaowang Road, Hangzhou, Zhejiang 310000, China.
Ming
M
Tao
Beijing Anding Hospital of Capital University of Medical Sciences, No. 5 Ankang Hutong, Deshengmen wai, Xicheng District, Beijing, Beijing 100000, China.
Gang
G
Wang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Guangbiao
G
Wang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Jian
J
Wang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Linmao
L
Wang
First Hospital of Hebei Medical University, No. 89 Donggang Road, Shijiazhuang, Hebei 50000, China.
Xueyi
X
Wang
ShengJing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning 110001, China.
Xumei
X
Wang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Huanming
H
Yang
Jilin Brain Hospital, No. 98 West Zhongyang Road, Siping, Jilin 136000, China.
Lijun
L
Yang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Ye
Y
Yin
No. 3 Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510000, China.
Jinbei
J
Zhang
No. 1 Hospital of Shanxi Medical University, No. 85 South Jiefang Road, Taiyuan, Shanxi 30000, China.
Kerang
K
Zhang
No. 1 Hospital of Shanxi Medical University, No. 85 South Jiefang Road, Taiyuan, Shanxi 30000, China.
Ning
N
Sun
Daqing No. 3 Hospital of Heilongjiang Province, No. 54 Xitai Road, Ranghulu District, Daqing, Heilongjiang 163000, China.
Wei
W
Zhang
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Xiuqing
X
Zhang
No. 4 Hospital of Jiangsu University, No. 246 Nanmen Street, Zhenjiang, Jiangsu 212000, China.
Zhen
Z
Zhang
Anhui Mental Health Center, No. 316 Huangshan Road, Hefei, Anhui 230000, China.
Hui
H
Zhong
MRC SGDP Centre, Institute of Psychiatry at King's College, De Crespigny Park, London SE5 8AF, UK; National Institute for Health Research, Biomedical Research Centre for Mental Health, Institute of Psychiatry at King's College, De Crespigny Park, London SE5 8AF, UK.
Gerome
G
Breen
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China; Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark; Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China; Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Jun
J
Wang
Department of Statistics, University of Oxford, Oxford, Oxfordshire OX1 3TG, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Jonathan
J
Marchini
CTSU, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, Oxfordshire OX3 7LF, UK.
Yiping
Y
Chen
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10005, China.
Qi
Q
Xu
BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China.
Xun
X
Xu
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK.
Richard
R
Mott
Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC.
Guo-Jen
GJ
Huang
Dept Psychiatry MCV, Virginia Commonwealth University, Richmond, VA 23298, USA.
Kenneth
K
Kendler
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK; East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: jf@well.ox.ac.uk.
Jonathan
J
Flint
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002650:Child Abuse, Sexual; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008016:Life Change Events; D008297:Male; D008810:Mice, Inbred C57BL; D013315:Stress, Psychological / Q000378:metabolism*; D059506:Telomere Shortening
D015415:Biomarkers; D004272:DNA, Mitochondrial; D005938:Glucocorticoids