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      Molecular Signatures of Major Depression

      research-article
      1 , 50 , 2 , 50 , 1 , 50 , 3 , 3 , 3 , 3 , 1 , 4 , 1 , 5 , 6 , 7 , 8 , 9 , 9 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 3 , 16 , 17 , 3 , 3 , 18 , 19 , 20 , 3 , 21 , 22 , 23 , 24 , 25 , 3 , 3 , 26 , 27 , 3 , 28 , 29 , 30 , 31 , 32 , 33 , 3 , 3 , 3 , 34 , 35 , 3 , 36 , 3 , 37 , 38 , 38 , 39 , 3 , 40 , 41 , 6 , 7 , 3 , 42 , 43 , 44 , 45 , 1 , 46 , 47 , 3 , 1 , 51 , 2 , 51 , 48 , 51 , 1 , 49 , 51 ,
      Current Biology
      Cell Press

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          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.

          Highlights

          • Amount of mtDNA is increased, and telomeric DNA is shortened in major depression

          • Both changes can be induced with stress but are contingent on the depressed state

          • Changes are tissue specific and in part due to glucocorticoid secretion

          • Changes are in part reversible and represent switches in metabolic strategy

          Abstract

          Cai et al. found increases in mtDNA and a reduction in telomeric DNA in cases of major depression using whole-genome sequencing. Both changes are depression state dependent. Mice exposed to chronic stress or glucorticoids showed that these changes reflect switches in metabolic strategy and are tissue specific and partial reversible.

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          Most cited references43

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          Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads.

          High-volume sequencing of DNA and RNA is now within reach of any research laboratory and is quickly becoming established as a key research tool. In many workflows, each of the short sequences ("reads") resulting from a sequencing run are first "mapped" (aligned) to a reference sequence to infer the read from which the genomic location derived, a challenging task because of the high data volumes and often large genomes. Existing read mapping software excel in either speed (e.g., BWA, Bowtie, ELAND) or sensitivity (e.g., Novoalign), but not in both. In addition, performance often deteriorates in the presence of sequence variation, particularly so for short insertions and deletions (indels). Here, we present a read mapper, Stampy, which uses a hybrid mapping algorithm and a detailed statistical model to achieve both speed and sensitivity, particularly when reads include sequence variation. This results in a higher useable sequence yield and improved accuracy compared to that of existing software.
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            Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators.

            Stress begins in the brain and affects the brain, as well as the rest of the body. Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems. Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated. The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much, drinking, poor quality sleep; otherwise referred to as "lifestyle") is called allostatic overload. Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks. However, it is not clear whether prolonged stress for many months or years may have irreversible effects on the brain. The adaptive plasticity of chronic stress involves many mediators, including glucocorticoids, excitatory amino acids, endogenous factors such as brain neurotrophic factor (BDNF), polysialated neural cell adhesion molecule (PSA-NCAM) and tissue plasminogen activator (tPA). The role of this stress-induced remodeling of neural circuitry is discussed in relation to psychiatric illnesses, as well as chronic stress and the concept of top-down regulation of cognitive, autonomic and neuroendocrine function. This concept leads to a different way of regarding more holistic manipulations, such as physical activity and social support as an important complement to pharmaceutical therapy in treatment of the common phenomenon of being "stressed out". Policies of government and the private sector play an important role in this top-down view of minimizing the burden of chronic stress and related lifestyle (i.e. allostatic overload).
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              Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

              Background Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors. Results Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes. Conclusions This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.
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                Author and article information

                Contributors
                Journal
                Curr Biol
                Curr. Biol
                Current Biology
                Cell Press
                0960-9822
                1879-0445
                04 May 2015
                04 May 2015
                : 25
                : 9
                : 1146-1156
                Affiliations
                [1 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, Oxfordshire OX3 7BN, UK
                [2 ]Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC
                [3 ]BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, Yantian District, Shenzhen, Guangdong 518083, China
                [4 ]Department of Comparative Developmental Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linne-Weg 10, Cologne 50829, Germany
                [5 ]Centro de Investigacion Medica en Red de Salud Mental, CIBERSAM-University of Granada, Granada, Spain
                [6 ]MRC SGDP Centre, Institute of Psychiatry at King’s College, De Crespigny Park, London SE5 8AF, UK
                [7 ]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
                [8 ]Mental Health Center of West China Hospital of Sichuan University, No. 28 South Dianxin Street, Wuhou District, Chengdu, Sichuan 610000, China
                [9 ]Hebei Mental Health Center, No. 572 Dongfeng Road, Baoding, Hebei 71000, China
                [10 ]Zhejiang Traditional Chinese Medical Hospital, No. 54 Youdian Road, Hangzhou, Zhejiang 310000, China
                [11 ]Ningbo Kang Ning Hospital, No. 1 Zhuangyu Road, Zhenhai District, Ningbo, Zhejiang 315000, China
                [12 ]Liaocheng No. 4 Hospital, No. 47 North Huayuan Road, Liaocheng, Shandong 252000, China
                [13 ]Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC
                [14 ]No. 3 Hospital of Heilongjiang Province, No. 135 Jiaotong Road, Beian, Heilongjiang 164000, China
                [15 ]Harbin Medical University, No. 23 Youzheng Street, Nangang District, Haerbin, Heilongjiang 150000, China
                [16 ]Sichuan Mental Health Center, No. 190, East Jiannan Road, Mianyang, Sichuan 621000, China
                [17 ]Chongqing Mental Health Center, No. 102 Jinzishan, Jiangbei District, Chongqing, Chongqing 404100, China
                [18 ]Mental Health Institute of Jining Medical College, Dai Zhuang, Bei Jiao, Jining, Shandong 272000, China
                [19 ]Mental Hospital of Jiangxi Province, No. 43 Shangfang Road, Nanchang, Jiangxi 330000, China
                [20 ]Wuhan Mental Health Center, No. 70, Youyi Road, Wuhan, Hubei 430000, China
                [21 ]No. 1 Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, Henan 450000, China
                [22 ]Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan, ROC
                [23 ]Shandong Mental Health Center, No. 49 East Wenhua Road, Jinan, Shandong 250000, China
                [24 ]Shenzhen Key Lab for Psychological Healthcare, Kangning Hospital, No. 1080, Cuizhu Street, Luohu District, Shenzhen, Guangdong 518000, China
                [25 ]The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, Liaoning 110001, China
                [26 ]Psychiatric Hospital of Henan Province, No. 388 Middle Jianshe Road, Xinxiang, Henan 453000, China
                [27 ]No. 1 Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, Chongqing 400016, China
                [28 ]Changchun Mental Hospital, No. 4596 Beihuan Road, Changchun, Jilin 130000, China
                [29 ]Tianjin Anding Hospital, No. 13 Liulin Road, Hexi District, Tianjin, Tianjin 300000, China
                [30 ]Xian Mental Health Center, No. 15 Yanyin Road, New Qujiang District, Xian, Shaanxi 710000, China
                [31 ]Brain Hospital of Nanjing Medical University, No. 264 Guangzhou Road, Nanjing, Jiangsu 210000, China
                [32 ]Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318 Chaowang Road, Hangzhou, Zhejiang 310000, China
                [33 ]Beijing Anding Hospital of Capital University of Medical Sciences, No. 5 Ankang Hutong, Deshengmen wai, Xicheng District, Beijing, Beijing 100000, China
                [34 ]First Hospital of Hebei Medical University, No. 89 Donggang Road, Shijiazhuang, Hebei 50000, China
                [35 ]ShengJing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning 110001, China
                [36 ]Jilin Brain Hospital, No. 98 West Zhongyang Road, Siping, Jilin 136000, China
                [37 ]No. 3 Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510000, China
                [38 ]No. 1 Hospital of Shanxi Medical University, No. 85 South Jiefang Road, Taiyuan, Shanxi 30000, China
                [39 ]Daqing No. 3 Hospital of Heilongjiang Province, No. 54 Xitai Road, Ranghulu District, Daqing, Heilongjiang 163000, China
                [40 ]No. 4 Hospital of Jiangsu University, No. 246 Nanmen Street, Zhenjiang, Jiangsu 212000, China
                [41 ]Anhui Mental Health Center, No. 316 Huangshan Road, Hefei, Anhui 230000, China
                [42 ]Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
                [43 ]Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China
                [44 ]Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia
                [45 ]Department of Statistics, University of Oxford, Oxford, Oxfordshire OX1 3TG, UK
                [46 ]CTSU, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, Oxfordshire OX3 7LF, UK
                [47 ]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
                [48 ]Dept Psychiatry MCV, Virginia Commonwealth University, Richmond, VA 23298, USA
                [49 ]East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
                Author notes
                []Corresponding author jf@ 123456well.ox.ac.uk
                [50]

                Co-first author

                [51]

                Co-senior author

                Article
                S0960-9822(15)00322-X
                10.1016/j.cub.2015.03.008
                4425463
                25913401
                bffece65-2246-42a1-be2a-3304a380ac1f
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 6 February 2015
                : 3 March 2015
                : 6 March 2015
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                Life sciences
                Life sciences

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