Epigenetik der Depression

S. Sanwald; C. Montag; M. Kiefer

doi:10.1055/s-0038-1675697

Nervenheilkunde, Inhaltsverzeichnis

Nervenheilkunde 2018; 37(11): 792-798
DOI: 10.1055/s-0038-1675697

Universitätsklinikum Ulm

Georg Thieme Verlag KG Stuttgart · New York

Epigenetik der Depression

Epigenetics of depression

S. Sanwald

¹Klinik für Psychiatrie und Psychotherapie III, Universitätsklinikum Ulm

,

C. Montag

²Abteilung Molekulare Psychologie, Institut für Psychologie und Pädagogik, Universität Ulm

³The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China

,

M. Kiefer

¹Klinik für Psychiatrie und Psychotherapie III, Universitätsklinikum Ulm

› Institutsangaben

Abstract

Zusammenfassung

Moderne ätiologische Theorien erklären die Entstehung der Major Depression durch eine Interaktion von Genen und Umwelt. Dabei stellt die individuelle Genetik einen Risikooder Resilienzfaktor dar, der im Zusammenspiel mit den individuellen Umweltbedingungen die Depressionsentwicklung begünstigen oder der Entstehung einer Depression vorbeugen kann. Solchen Theorien fehlte bislang das Bindeglied für das Zusammenspiel zwischen Genetik und Umwelteinflüssen. Ein solches Bindeglied ist die Epigenetik, die sich in den letzten Jahren als wegweisend in der Erforschung biologischer Marker stressbedingter Psychopathologie erwiesen hat. Der am besten erforschte epigenetische Mechanismus ist die DNA-Methylierung. Diese hat sich über viele Studien hinweg als ein möglicher Mechanismus etabliert, der dazu imstande ist, die psychopathogene Wirkung von Stress auf behaviorale, endokrine und molekulare Prozesse zu erklären. Diese Arbeit soll dazu dienen, die Grundlagen der Epigenetik und der DNA-Methylierung zu erläutern, um nachfolgend eine Übersicht über die Studienlage zu stress- und depressionsassoziierten Unterschieden in den Methylierungsmustern der bekanntesten Kandidatengene zu geben.

Summary

Modern etiologic theories of major depression postulate an interaction of genes and environment. Accordingly, depression development might be catalyzed, if the stress an individual is exposed to exceeds a certain threshold. The threshold in turn is determined by an individual’s genes. Until recently, these theories lacked the link between environmental factors and the genome. Epigenetics is bridging this gap and has built a path-breaking field of research concerning the etiology of stress-related disorders. DNA-methylation is the most investigated epigenetic modification able to explain the pathogenic impact of stress on behavioral, endocrine and molecular processes. This article aims to explain the basic concepts of epigenetics as well as DNAmethylation and reviews current studies examining the interactions and interrelations of stressful life events, DNA-methylation and depression in a candidate gene approach.

Schlüsselwörter

Stress - Epigenetik - DNA-Methylierung - Ätiologie der Depression

Keywords

Stress - epigenetics - DNA-methylation - depression development

Volltext

Referenzen

Literatur
1 Üstün TB, Ayuso-Mateos JL, Chatterji S, Mathers C, Murray CJL. Global burden of depressive disorders in the year 2000. British Journal of Psychiatry 2004; 184 (05) 386-92.
2 Busch MA, Maske UE, Ryl L, Schlack R, Hapke U. Prävalenz von depressiver Symptomatik und diagnostizierter Depression bei Erwachsenen in Deutschland. Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz. 2013; 56 (5–6): 733-9.
3 Friemel S, Bernert S, Angermeyer MC, König H-H. Die direkten Kosten von depressiven Erkrankungen in Deutschland. Psychiatrische Praxis 2005; 32 (03) 113-21.
4 Lépine J-P, Briley M. The increasing burden of depression. Neuropsychiatric disease and treatment 2011; 07 (01) 3-7.
5 bAmerican Psychiatric Association. Diagnostisches und Statistisches Manual Psychischer Störungen DSM-5. Göttingen: Hogrefe Verlag; 2018
6 Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nature Neuroscience 2010; 13 (10) 1161-9.
7 Sullivan PF, Neale MC, Kendler KS. Genetic Epidemiology of Major Depression: Review and Meta-Analysis. American Journal of Psychiatry 2000; 157 (10) 1552-62.
8 Levinson DF. The Genetics of Depression: A Review. Biological Psychiatry 2006; 60 (02) 84-92.
9 Hasler G, Drevets WC, Manji HK, Charney DS. Discovering Endophenotypes for Major Depression. Neuropsychopharmacology 2004; 29 (10) 1765-81.
10 Meaney MJ. Epigenetics and the Biological Definition of Gene x Environment Interactions. Child Developmen 2010; 81 (01) 41-79.
11 Kendler KS, Karkowski LM, Prescott CA. Causal Relationship Between Stressful Life Events and the Onset of Major Depression. American Journal of Psychiatry 1999; 156 (06) 837-41.
12 Tennant C. Life Events, Stress and Depression: A Review of Recent Findings. Australian & New Zealand Journal of Psychiatry 2002; 36 (02) 173-82.
13 Kessler RC, McLaughlin KA, Green JG, Gruber MJ, Sampson NA, Zaslavsky AM. et al. Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. British Journal of Psychiatry 2010; 197 (05) 378-85.
14 Dudley KJ, Li X, Kobor MS, Kippin TE, Bredy TW. Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. Neuroscience & Biobehavioral Reviews 2011; 35 (07) 1544-51.
15 Heim C, Binder EB. Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Experimental Neurolog 2012; 233 (01) 102-11.
16 Lesch K-P, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL. et al. Organization of the human serotonin transporter gene. Journal of Neural Transmission 1994; 95 (02) 157-62.
17 Gelernter J, Kranzler H, Cubells JF. Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in Africanand European-American and Japanese populations and in alcohol-dependent subjects. Human Genetics 1997; 101 (02) 243-6.
18 Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274 (5292): 1527-31.
19 Karg K, Burmeister M, Shedden K, Sen S. The Serotonin Transporter Promoter Variant (5-HTTLPR), Stress, and Depression Meta-analysis Revisited. Archives of General Psychiatry 2011; 68 (05) 444.
20 Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR. et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Molecular Psychiatry 2009; 14 (07) 681-95.
21 Aguilera M, Arias B, Wichers M, Barrantes-Vidal N, Moya J, Villa H. et al. Early adversity and 5-HTT/BDNF genes: new evidence of gene–environment interactions on depressive symptoms in a general population. Psychological Medicine 2009; 39 (09) 1425.
22 Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. The EMBO journal 1982; 01 (05) 549-53.
23 Lu B. BDNF and activity-dependent synaptic modulation. Learning & memory 2003; 10 (02) 86-98.
24 Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nature Neuroscience 2007; 10 (09) 1089-93.
25 Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence Variants of the Brain-Derived Neurotrophic Factor (BDNF) Gene Are Strongly Associated with Obsessive-Compulsive Disorder. The American Journal of Human Genetics 2003; 73 (02) 370-6.
26 Goldberg AD, Allis CD, Bernstein E. Epigenetics: A Landscape Takes Shape. Cell 2007; 128 (04) 635-8.
27 Turner BM. Chromatin and gene regulation: mechanisms in epigenetics [Internet]. London: Blackwell Science; 2001: 284.
28 Wong AHC, Gottesman II, Petronis A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Human Molecular Genetics 2005; 14 (Suppl. 01) R11-8.
29 Bird A. Perceptions of epigenetics. Nature 2007; 447 (7143): 396-8.
30 Kim JK, Samaranayake M, Pradhan S. Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences 2009; 66 (04) 596-612.
31 Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics 2012; 13 (02) 97-109.
32 Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321 (6067): 209-13.
33 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annual Review of Biochemistry 2005; 74 (01) 481-514.
34 Lim DHK, Maher ER. DNA methylation: a form of epigenetic control of gene expression. The Obstetrician & Gynaecologist 2010; 12 (01) 37-42.
35 Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. American Association for the Advancement of Science 2001; 293 (5532): 1068-70.
36 Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A. et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997; 277 (5332): 1659-62.
37 Francis D, Diorio J, Liu D, Meaney MJ. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 1999; 286 (5442): 1155-8.
38 Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP, Kim DM. The neurobiological consequences of early stress and childhood maltreatment. Neuroscience & Biobehavioral Reviews 2003; 27 (1–2): 33-44.
39 Montag C, Panksepp J. Primary Emotional Systems and Personality: An Evolutionary Perspective. Frontiers in Psychology 2017; 08: 464.
40 MacLean P. The triune brain in evolution: Role in paleocerebral functions. New. York: Plenum Press; 1990
41 Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR. et al. Epigenetic programming by maternal behavior. 2004; 07 (08) 847-54.
42 Weaver ICG, D’Alessio AC, Brown SE, Hellstrom IC, Dymov S, Sharma S. et al. The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes. Journal of Neuroscience 2007; 27 (07) 1756-68.
43 Klengel T, Pape J, Binder EB, Mehta D. The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology 2014; 80: 115-32.
44 McGowan PO. et al. Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats. PLoS ONE 2011; 06 (02) e14739.
45 Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene. Biological Psychiatry 2009; 65 (09) 760-9.
46 Suderman M. et al. Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proceedings of the National Academy of Sciences of the USA 2012; 109 (Suppl. 02) 17266-72.
47 McGowan PO. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature 2009; 12 (03) 342-8.
48 Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008; 03 (02) 97-106.
49 Melas PA. et al. Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. The International Journal of Neuropsychopharmacology 2013; 16 (07) 1513-28.
50 Perroud N, Paoloni-Giacobino A, Prada P, Olié E, Salzmann A, Nicastro R. et al. Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Translational Psychiatry 2011; 01 (12) e59-e59.
51 Vinkers CH. et al. Traumatic stress and human DNA methylation: a critical review. Epigenomics 2015; 07 (04) 593-608.
52 Provenzi L, Giorda R, Beri S, Montirosso R. SLC6A4 methylation as an epigenetic marker of life adversity exposures in humans: A systematic review of literature. Neuroscience & Biobehavioral Reviews 2016; 71: 7-20.
53 Beach SRH, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa Adoptee sample. American Journal of Medical Genetics Part B 2010; 153B (02) 710-3.
54 Kang H. et al. Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2013; 44: 23-8.
55 Vijayendran M, Beach SRH, Plume JM, Brody GH, Philibert RA. Effects of Genotype and Child Abuse on DNA Methylation and Gene Expression at the Serotonin Transporter. Frontiers in Psychiatry 2012; 03: 55.
56 Alasaari J. et al. Environmental Stress Affects DNA Methylation of a CpG Rich Promoter Region of Serotonin Transporter Gene in a Nurse Cohort. PLoS ONE 2012; 07 (09) e45813.
57 van der Knaap LJ. et al. Adverse Life Events and Allele-Specific Methylation of the Serotonin Transporter Gene (SLC6A4) in Adolescents. Psychosomatic Medicine 2015; 77 (03) 246-55.
58 Na K-S, Chang HS, Won E, Han K-M, Choi S, Tae WS. et al. Association between Glucocorticoid Receptor Methylation and Hippocampal Subfields in Major Depressive Disorder. PLoS ONE 2014; 09 (01) e85425.
59 Bustamante AC, Aiello AE, Galea S, Ratanatharathorn A, Noronha C, Wildman DE. et al. Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression. Journal of affective disorders 2016; 206: 181-8.
60 Sanwald S, Gahr M, Widenhorn-Müller K, Proske K, Schönfeldt-Lecuona C, Connemann B. et al. Relation of promoter methylation of NR3C1 and SLC6A4 genes to course and severity of depression. not published.
61 Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics Part B 2008; 147B (05) 543-9.
62 Zhao J, Goldberg J, Bremner JD, Vaccarino V. Association between promoter methylation of serotonin transporter gene and depressive symptoms: a monozygotic twin study. Psychosomatic medicine. NIH Public Access 2013; 75 (06) 523-9.
63 Devlin AM, Brain U, Austin J, Oberlander TF. Prenatal Exposure to Maternal Depressed Mood and the MTHFR C677T Variant Affect SLC6A4 Methylation in Infants at Birth. PLoS ONE 2010; 05 (08) e12201.
64 Farrell C, O’Keane V, Harkin A, O’Leary N, Jairaj C, Booij L. et al. Association of maternal emotional abuse with decreased serotonin transporter gene (SLC6A4) methylation. European Neuropsychopharmacology 2016; 26: 177.
65 Olsson CA, Foley DL, Parkinson-Bates M, Byrnes G, McKenzie M, Patton GC. et al. Prospects for epigenetic research within cohort studies of psychological disorder: A pilot investigation of a peripheral cell marker of epigenetic risk for depression. Biological Psychology 2010; 83 (02) 159-65.
66 Kim J-M, Stewart R, Kang H-J, Kim S-W, Shin I-S, Kim H-R. et al. A longitudinal study of SLC6A4 DNA promoter methylation and poststroke depression. Journal of psychiatric research 2013; 47 (09) 1222-7.
67 Kang H-J, Kim J-M, Lee J-Y, Kim S-Y, Bae K-Y, Kim S-W. et al. BDNF promoter methylation and suicidal behavior in depressive patients. Journal of Affective Disorders 2013; 151 (02) 679-85.
68 D’Addario C, Dell’Osso B, Galimberti D, Palazzo MC, Benatti B, Di Francesco A. et al. Epigenetic Modulation of BDNF Gene in Patients with Major Depressive Disorder. Biological Psychiatry 2013; 73 (02) e6-7.
69 Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N. et al. DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF) Gene as a Potent Diagnostic Biomarker in Major Depression. PLoS ONE 2011; 06 (08) e23881.
70 Kang H-J, Kim J-M, Bae K-Y, Kim S-W, Shin I-S, Kim H-R. et al. Longitudinal associations between BDNF promoter methylation and late-life depression. Neurobiology of Aging 2015; 36 (04) 1764 e1–1764.e7.
71 Kleimann A, Kotsiari A, Sperling W, Gröschl M, Heberlein A, Kahl KG. et al. BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy. Journal of Neural Transmission 2015; 122 (06) 925-8.
72 Tadić A, Müller-Engling L, Schlicht KF, Kotsiari A, Dreimüller N, Kleimann A. et al. Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Molecular Psychiatry 2014; 19 (03) 281-3.
73 Booij L, Wang D, Lévesque ML, Tremblay RE, Szyf M. Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress-diathesis model of depression. Philosophical transactions of the Royal Society of London Series B, Biological sciences 2013; 368 (1615): 20120251.
74 Palma-Gudiel H, Córdova-Palomera A, Leza JC, Fañanás L. Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neuroscience & Biobehavioral Reviews 2015; 55: 520-35.
75 Carr CP, Martins CMS, Stingel AM, Lemgruber VB, Juruena MF. The Role of Early Life Stress in Adult Psychiatric Disorders. The Journal of Nervous and Mental Disease 2013; 201 (12) 1007-20.
76 Cao-Lei L, Leija SC, Kumsta R, Wüst S, Meyer J, Turner JD. et al. Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions. Human Genetics 2011; 129 (05) 533-43.
77 van Eijk KR, de Jong S, Boks MP, Langeveld T, Colas F, Veldink JH. et al. Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects. BMC Genomics BioMed Central 2012; 13 (01) 636.
78 Philibert RA, Plume JM, Gibbons FX, Brody GH, Beach SRH. The Impact of Recent Alcohol Use on Genome Wide DNA Methylation Signatures. Frontiers in Genetics 2012; 03: 54.
79 Feinberg AP. et al. Personalized epigenomic signatures that are stable over time and covary with body mass index. Science translational medicine 2010; 02 (49) 49ra67.
80 Lee KWK, Pausova Z. Cigarette smoking and DNA methylation. Frontiers in Genetics 2013; 04: 132.
81 Byun H-M. et al. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Human Molecular Genetics 2009; 18 (24) 4808-17.
82 Smith AK. et al. DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2015; 168 (01) 36-44.
83 Tylee DS, Kawaguchi DM, Glatt SJ. On the outside, looking in: A review and evaluation of the comparability of blood and brain “-omes.”. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2013; 162 (07) 595-603.
84 Provençal N. et al. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. The Journal of neuroscience the official journal of the Society for Neuroscience 2012; 32 (44) 15626-42.