Nature meets Nurture: Die Bedeutung der Epigenetik für die Ätiologie psychischer Erkrankungen

V. Buchholz; A. Kotsiari; S. Bleich; H. Frieling

doi:10.1055/s-0033-1335739

Fortschritte der Neurologie · Psychiatrie, Inhaltsverzeichnis

Fortschr Neurol Psychiatr 2013; 81(7): 368-380
DOI: 10.1055/s-0033-1335739

Übersicht

Nature meets Nurture: Die Bedeutung der Epigenetik für die Ätiologie psychischer Erkrankungen

Nature Meets Nurture: The Importance of Epigenetics for the Aetiology of Psychiatric Diseases

V. Buchholz

,

A. Kotsiari

,

S. Bleich

,

H. Frieling

Abstract

Zusammenfassung

Ergründung und Verständnis der Ätiologie einer Krankheit sind Voraussetzung für eine erfolgreiche Therapie. Psychische Erkrankungen stellen diesbezüglich eine besondere Herausforderung dar, da zusätzlich zu etwaigen physiologischen und genetischen Ursachen auch die Umwelt einen großen Einfluss auf deren Ausprägung hat. So hat sich mit der Epigenetik in den letzten Jahren ein Forschungszweig etabliert, der den Einfluss dieser Umweltfaktoren auf die Entwicklung psychischer Erkrankungen untersucht und der vielversprechende Ansätze für neue Diagnose- und Behandlungsmethoden zeigt.

Abstract

A successful therapy requires an understanding and investigation of the aetiology of a disease. Psychiatric diseases represent a special challenge, because environmental factors may play a crucial role in their development as well as possible physiological and genetic causes. Therefore, epigenetics has established itself to be a branch of research that studies the effect of environmental factors on the development of psychiatric diseases, leading to promising new approaches for diagnosis and therapy.

Schlüsselwörter

Epigenetik - Schizophrenie - Autismus - Essstörungen - Alkoholabhängigkeit - Depression

Key words

epigenetics - schizophrenia - autism - eating disorders - alcohol abuse - depression

Volltext

Referenzen

Literatur
1 Waddington CH. The epigenotype. Int J Epidemiol 2012; 41: 10-13
2 Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 2006; 174: 341-348
3 Horvath A, Morava E, Toth G et al. Vascular diseases, spina bifida and schizophrenia in a single family associated with the heterozygote mutation of the heat-sensitive variant of methylenetetrahydrofolate reductase. Orv Hetil 2001; 142: 1445-1448
4 Muntjewerff JW, Blom HJ. Aberrant folate status in schizophrenic patients: what is the evidence?. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1133-1139
5 Muntjewerff JW, Hoogendoorn ML, Kahn RS et al. Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study. American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2005; 135B: 69-72
6 Picker JD, Coyle JT. Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia?. Harv Rev Psychiatry 2005; 13: 197-205
7 Reif A, Pfuhlmann B, Lesch KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1162-1168
8 Doskocil J, Sorm F. Distribution of 5-methylcytosine in pyrimidine sequences of deoxyribonucleic acids. Biochim Biophys Acta 1962; 55: 953-959
9 Choudhuri S. From Waddington’s epigenetic landscape to small noncoding RNA: some important milestones in the history of epigenetics research. Toxicol Mech Methods 2011; 21: 252-274
10 Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403: 41-45
11 Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28: 1057-1068
12 Kanwal R, Gupta S. Epigenetic modifications in cancer. Clin Genet 2012; 81: 303-311
13 Sadock B, Sadock VKaplan and. Sadock’s Comprehensive Texbook of psychiatry. 9. Aufl. Philadelphia PA: Lippincott Williams & Wilkins; 2009
14 Howes OD, McDonald C, Cannon M et al. Pathways to schizophrenia: the impact of environmental factors. Int J Neuropsychopharmacol 2004; 7 (Suppl. 01) S7-S13
15 Wadhwa PD, Buss C, Entringer S et al. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med 2009; 27: 358-368
16 Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 2010; 90: 285-326
17 Davies W, Lynn PM, Relkovic D et al. Imprinted genes and neuroendocrine function. Front Neuroendocrinol 2008; 29: 413-427
18 Scarano MI, Strazzullo M, Matarazzo MR et al. DNA methylation 40 years later: Its role in human health and disease. J Cell Physiol 2005; 204: 21-35
19 Dempster EL, Pidsley R, Schalkwyk LC et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 2011; 20: 4786-4796
20 Petronis A, Gottesman II et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?. Schizophr Bull 2003; 29: 169-178
21 Pesold C, Liu WS, Guidotti A et al. Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression. Proc Natl Acad Sci U S A 1999; 96: 3217-3222
22 Costa E, Davis J, Grayson DR et al. Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability. Neurobiol Dis 2001; 8: 723-742
23 Fatemi SH, Earle JA, McMenomy T. Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 2000; 5: 654-663, 571
24 Guidotti A, Auta J, Davis JM et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061-1069
25 Veldic M, Caruncho HJ, Liu WS et al. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A 2004; 101: 348-353
26 Tochigi M, Iwamoto K, Bundo M et al. Methylation status of the reelin promoter region in the brain of schizophrenic patients. Biol Psychiatry 2008; 63: 530-533
27 Veldic M, Guidotti A, Maloku E et al. In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci U S A 2005; 102: 2152-2157
28 Abdolmaleky HM, Cheng KH, Russo A et al. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005; 134B: 60-66
29 Chen Y, Sharma RP, Costa RH et al. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 2002; 30: 2930-2939
30 Grayson DR, Jia X, Chen Y et al. Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A 2005; 102: 9341-9346
31 Grayson DR. Schizophrenia and the epigenetic hypothesis. Epigenomics 2010; 2: 341-344
32 Kalkman HO, Loetscher E. GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. J Neural Transm 2003; 110: 803-812
33 Broman S, JM F (Hrsg.) The changing nervous system. Neurobehavioral Consequences of Early Brain Disorders. Aufl: Oxford University Press: 1999
34 Geyer MA, Vollenweider FX. Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 2008; 29: 445-453
35 Lesch KP. Hallucinations: psychopathology meets functional genomics. Mol Psychiatry 1998; 3: 278-281
36 Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 2007; 12: 707-747
37 Carrard A, Salzmann A, Malafosse A et al. Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. J Affect Disord 2011; 132: 450-453
38 Gray L, Scarr E, Dean B. Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder. Psychiatry Res 2006; 143: 111-120
39 Lopez-Figueroa AL, Norton CS, Lopez-Figueroa MO et al. Serotonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression in subjects with major depression, bipolar disorder, and schizophrenia. Biol Psychiatry 2004; 55: 225-233
40 Cruz DA, Eggan SM, Azmitia EC et al. Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia. Am J Psychiatry 2004; 161: 739-742
41 Tauscher J, Kapur S, Verhoeff NP et al. Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Arch Gen Psychiatry 2002; 59: 514-520
42 Abdolmaleky HM, Faraone SV, Glatt SJ et al. Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. Schizophr Res 2004; 67: 53-62
43 Petronis A. The genes for major psychosis: aberrant sequence or regulation?. Neuropsychopharmacology 2000; 23: 1-12
44 Williams J, McGuffin P, Nothen M et al. Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 1997; 349: 1221
45 Abdolmaleky HM, Yaqubi S, Papageorgis P et al. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr Res 2011; 129: 183-190
46 Abdolmaleky HM, Cheng KH, Faraone SV et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 2006; 15: 3132-3145
47 Chen J, Lipska BK, Halim N et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004; 75: 807-821
48 Tenhunen J, Salminen M, Lundstrom K et al. Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 1994; 223: 1049-1059
49 Wang GJ, Volkow ND, Fowler JS et al. Comparison of two pet radioligands for imaging extrastriatal dopamine transporters in human brain. Life Sci 1995; 57: PL187-PL191
50 Blasi G, Mattay VS, Bertolino A et al. Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci 2005; 25: 5038-5045
51 Bruder GE, Keilp JG, Xu H et al. Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 2005; 58: 901-907
52 de Frias CM, Annerbrink K, Westberg L et al. Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults. J Cogn Neurosci 2005; 17: 1018-1025
53 Egan MF, Goldberg TE, Kolachana BS et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 2001; 98: 6917-6922
54 Galderisi S, Maj M, Kirkpatrick B et al. Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment. Neuropsychobiology 2005; 52: 83-89
55 Rosa A, Peralta V, Cuesta MJ et al. New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. Am J Psychiatry 2004; 161: 1110-1112
56 Chen WG, Chang Q, Lin Y et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 2003; 302: 885-889
57 Abdolmaleky HM, Smith CL, Zhou JR et al. Epigenetic alterations of the dopaminergic system in major psychiatric disorders. Methods Mol Biol 2008; 448: 187-212
58 Ballmaier M, Zoli M, Leo G et al. Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. Eur J Neurosci 2002; 15: 1197-1205
59 Nishikawa S, Goto S, Yamada K et al. Lack of Reelin causes malpositioning of nigral dopaminergic neurons: evidence from comparison of normal and Reln(rl) mutant mice. J Comp Neurol 2003; 461: 166-173
60 Chen Y, Zhang J, Zhang L et al. Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. Hum Genet 2011;
61 Fuke C, Shimabukuro M, Petronis A et al. Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 2004; 68: 196-204
62 Philibert RA, Beach SR, Gunter TD et al. The effect of smoking on MAOA promoter methylation in DNA prepared from lymphoblasts and whole blood. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 619-628
63 Philibert RA, Gunter TD, Beach SR et al. MAOA methylation is associated with nicotine and alcohol dependence in women. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 565-570
64 Shimabukuro M, Sasaki T, Imamura A et al. Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res 2007; 41: 1042-1046
65 DSM-IV APA. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR. 4. Aufl. Washington DC: American Psychiatric Publishing; 2000
66 Allan AM, Liang X, Luo Y et al. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum Mol Genet 2008; 17: 2047-2057
67 Jiang YH, Sahoo T, Michaelis RC et al. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet A 2004; 131: 1-10
68 Nagarajan RP, Patzel KA, Martin M et al. MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res 2008; 1: 169-178
69 Nguyen A, Rauch TA, Pfeifer GP et al. Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J 2010; 24: 3036-3051
70 Shulha HP, Cheung I, Whittle C et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry 2012; 69: 314-324
71 James SJ, Melnyk S, Jernigan S et al. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J Autism Dev Disord 2008; 38: 1966-1975
72 Bleich S, Frieling H, Hillemacher T. Elevated prenatal homocysteine levels and the risk of schizophrenia. Arch Gen Psychiatry 2007; 64: 980-981
73 James SJ, Melnyk S, Jernigan S et al. Abnormal Transmethylation/transsulfuration Metabolism and DNA Hypomethylation Among Parents of Children with Autism. J Autism Dev Disord 2008; 38: 1976
74 James SJ, Melnyk S, Jernigan S et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 947-956
75 Melnyk S, Fuchs GJ, Schulz E et al. Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord 2012; 42: 367-377
76 Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene 2002; 21: 5400-5413
77 Nagarajan RP, Hogart AR, Gwye Y et al. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 2006; 1: e1-e11
78 Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 2005; 14: 483-492
79 Thatcher KN, LaSalle JM. Dynamic changes in Histone H3 lysine 9 acetylation localization patterns during neuronal maturation require MeCP2. Epigenetics 2006; 1: 24-31
80 Hogart A, Nagarajan RP, Patzel KA et al. 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet 2007; 16: 691-703
81 Fujita N, Watanabe S, Ichimura T et al. Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J Biol Chem 2003; 278: 24132-24138
82 Jorgensen HF, Ben-Porath I, Bird AP. Mbd1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol Cell Biol 2004; 24: 3387-3395
83 Sarraf SA, Stancheva I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol Cell 2004; 15: 595-605
84 Carter CS. Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders?. Behav Brain Res 2007; 176: 170-186
85 Gregory SG, Connelly JJ, Towers AJ et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 2009; 7: 62
86 Boukhtouche F, Vodjdani G, Jarvis CI et al. Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis. J Neurochem 2006; 96: 1778-1789
87 Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology 2006; 13: 171-181
88 Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 2005; 17: 485-495
89 Fatemi SH, Halt AR. Altered levels of Bcl2 and p53 proteins in parietal cortex reflect deranged apoptotic regulation in autism. Synapse 2001; 42: 281-284
90 Bulik CM, Reba L, Siega-Riz AM et al. Anorexia nervosa: definition, epidemiology, and cycle of risk. Int J Eat Disord 2005; 37: S2-S9 discussion S20-S21
91 Frieling H, Romer KD, Scholz S et al. Epigenetic dysregulation of dopaminergic genes in eating disorders. Int J Eat Disord 2010; 43: 577-583
92 Frieling H, Bleich S, Otten J et al. Epigenetic downregulation of atrial natriuretic peptide but not vasopressin mRNA expression in females with eating disorders is related to impulsivity. Neuropsychopharmacology 2008; 33: 2605-2609
93 Jousse C, Parry L, Lambert-Langlais S et al. Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome. FASEB J 2011; 25: 3271-3278
94 Frieling H, Gozner A, Romer KD et al. Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry 2007; 12: 229-230
95 Saluz HP, Jiricny J, Jost JP. Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis. Proc Natl Acad Sci U S A 1986; 83: 7167-7171
96 Yokomori N, Moore R, Negishi M. Sexually dimorphic DNA demethylation in the promoter of the Slp (sex-limited protein) gene in mouse liver. Proc Natl Acad Sci U S A 1995; 92: 1302-1306
97 Baltatzi M, Hatzitolios A, Tziomalos K et al. Neuropeptide Y and alpha-melanocyte-stimulating hormone: interaction in obesity and possible role in the development of hypertension. Int J Clin Pract 2008; 62: 1432-1440
98 Barsh GS, Schwartz MW. Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 2002; 3: 589-600
99 Woods SC, Seeley RJ, Porte DJr et al. Signals that regulate food intake and energy homeostasis. Science 1998; 280: 1378-1383
100 Newell-Price J, King P, Clark AJ. The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression. Mol Endocrinol 2001; 15: 338-348
101 Ehrlich S, Weiss D, Burghardt R et al. Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa. J Psychiatr Res 2010; 44: 827-833
102 Rosas-Vargas H, Martinez-Ezquerro JD, Bienvenu T. Brain-derived neurotrophic factor, food intake regulation, and obesity. Arch Med Res 2011; 42: 482-494
103 Nott A, Watson PM, Robinson JD et al. S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 2008; 455: 411-415
104 Stoger R. In vivo methylation patterns of the leptin promoter in human and mouse. Epigenetics 2006; 1: 155-162
105 Stoger R. The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes?. Bioessays 2008; 30: 156-166
106 Halford JC, Cooper GD, Dovey TM. The pharmacology of human appetite expression. Curr Drug Targets 2004; 5: 221-240
107 Nestler EJ, Carlezon Jr WA. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006; 59: 1151-1159
108 Volkow ND, Fowler JS, Wang GJ et al. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 2004; 9: 557-569
109 Kaye WH, Frank GK, McConaha C. Altered dopamine activity after recovery from restricting-type anorexia nervosa. Neuropsychopharmacology 1999; 21: 503-506
110 Frank GK, Bailer UF, Henry SE et al. Increased dopamine D2 / D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and 11craclopride. Biol Psychiatry 2005; 58: 908-912
111 Bello NT, Sweigart KL, Lakoski JM et al. Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1260-R1268
112 Anderson P, Møller L, Galea G (eds.) Alcohol in the European Union Consumption, harm and policy approaches. Copenhagen: WHO Regional Office for Europe; 2012
113 Hillemacher T. Biological mechanisms in alcohol dependence – new perspectives. Alcohol and alcoholism 2011; 46: 224-230
114 Kohnke MD. Approach to the genetics of alcoholism: a review based on pathophysiology. Biochem Pharmacol 2008; 75: 160-177
115 Bleich S, Lenz B, Ziegenbein M et al. Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcoholism, clinical and experimental research 2006; 30: 587-591
116 Bonsch D, Lenz B, Reulbach U et al. Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism. Journal of neural transmission 2004; 111: 1611-1616
117 Lenz B, Bleich S, Beutler S et al. Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites. Exp Cell Res 2006; 312: 4049-4055
118 Philibert RA, Plume JM, Gibbons FX et al. The impact of recent alcohol use on genome wide DNA methylation signatures. Front Genet 2012; 3: 54
119 Bowirrat A, Oscar-Berman M. Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome. American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2005; 132B: 29-37
120 Heinz A, Schafer M, Higley JD et al. Neurobiological correlates of the disposition and maintenance of alcoholism. Pharmacopsychiatry 2003; 36 (Suppl. 03) S255-S258
121 Tupala E, Tiihonen J. Dopamine and alcoholism: neurobiological basis of ethanol abuse. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1221-1247
122 Wise RA. The neurobiology of craving: implications for the understanding and treatment of addiction. J Abnorm Psychol 1988; 97: 118-132
123 Hillemacher T, Frieling H, Hartl T et al. Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving. Journal of psychiatric research 2009; 43: 388-392
124 Heinz A, Dettling M, Kuhn S et al. Blunted growth hormone response is associated with early relapse in alcohol-dependent patients. Alcoholism, clinical and experimental research 1995; 19: 62-65
125 Wiesbeck GA, Mauerer C, Thome J et al. Alcohol dependence, family history, and D2 dopamine receptor function as neuroendocrinologically assessed with apomorphine. Drug and alcohol dependence 1995; 40: 49-53
126 Lesch OM, Benda N, Gutierrez K et al. Craving in alcohol dependence: pharmaceutical interventions. In: Judd LL, Saletu B, Filip V, (eds.) Basic and Clinical Science of Mental and Addictive Disorders. V. Aufl. Basel: Karger; 1997: 136-147
127 Modell JG, Glaser FB, Cyr L et al. Obsessive and compulsive characteristics of craving for alcohol in alcohol abuse and dependence. Alcoholism, clinical and experimental research 1992; 16: 272-274
128 Bonsch D, Greifenberg V, Bayerlein K et al. Alpha-synuclein protein levels are increased in alcoholic patients and are linked to craving. Alcoholism, clinical and experimental research 2005; 29: 763-765
129 Bonsch D, Lederer T, Reulbach U et al. Joint analysis of the NACP-REP1 marker within the alpha synuclein gene concludes association with alcohol dependence. Human molecular genetics 2005; 14: 967-971
130 Bonsch D, Reulbach U, Bayerlein K et al. Elevated alpha synuclein mRNA levels are associated with craving in patients with alcoholism. Biological psychiatry 2004; 56: 984-986
131 Sidhu A, Wersinger C, Vernier P. Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2004; 18: 637-647
132 Self DW, Nestler EJ. Molecular mechanisms of drug reinforcement and addiction. Annu Rev Neurosci 1995; 18: 463-495
133 Dodd PR, Foley PF, Buckley ST et al. Genes and gene expression in the brain of the alcoholic. Addict Behav 2004; 29: 1295-1309
134 Maler JM, Esselmann H, Wiltfang J et al. Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res 2005; 1052: 156-162
135 Tsai GE, Ragan P, Chang R et al. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. The American journal of psychiatry 1998; 155: 726-732
136 Biermann T, Bonsch D, Reulbach U et al. Dopamine and N-methyl-D-aspartate receptor expression in peripheral blood of patients undergoing alcohol withdrawal. Journal of neural transmission 2007; 114: 1081-1084
137 Little HJ. The contribution of electrophysiology to knowledge of the acute and chronic effects of ethanol. Pharmacology & therapeutics 1999; 84: 333-353
138 Popp RL, Lickteig R, Browning MD et al. Ethanol sensitivity and subunit composition of NMDA receptors in cultured striatal neurons. Neuropharmacology 1998; 37: 45-56
139 Biermann T, Reulbach U, Lenz B et al. N-methyl-D-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal. Journal of neural transmission 2009; 116: 615-622
140 Feinn R, Nellissery M, Kranzler HR. Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2005; 133B: 79-84
141 Hinckers AS, Laucht M, Schmidt MH et al. Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents. Biological psychiatry 2006; 60: 282-287
142 Kweon YS, Lee HK, Lee CT et al. Association of the serotonin transporter gene polymorphism with Korean male alcoholics. Journal of psychiatric research 2005; 39: 371-376
143 Bleich S, Bonsch D, Rauh J et al. Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence. Alcohol Alcohol 2007; 42: 509-512
144 Angelone SM, Bellini L, Di Bella D et al. Effects of fluvoxamine and citalopram in maintaining abstinence in a sample of Italian detoxified alcoholics. Alcohol and alcoholism 1998; 33: 151-156
145 Naranjo CA, Poulos CX, Bremner KE et al. Citalopram decreases desirability, liking, and consumption of alcohol in alcohol-dependent drinkers. Clin Pharmacol Ther 1992; 51: 729-739
146 Bengel D, Greenberg BD, Cora-Locatelli G et al. Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Molecular psychiatry 1999; 4: 463-466
147 Philibert RA, Sandhu H, Hollenbeck N et al. 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, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2008; 147B: 543-549
148 Park BY, Lee BC, Jung KH et al. Epigenetic changes of serotonin transporter in the patients with alcohol dependence: methylation of an serotonin transporter promoter CpG island. Psychiatry Investig 2011; 8: 130-133
149 Junghanns K, Backhaus J, Tietz U et al. Impaired serum cortisol stress response is a predictor of early relapse. Alcohol and alcoholism 2003; 38: 189-193
150 Rasmussen DD, Bryant CA, Boldt BM et al. Acute alcohol effects on opiomelanocortinergic regulation. Alcoholism, clinical and experimental research 1998; 22: 789-801
151 Richardson HN, Lee SY, O’Dell LE et al. Alcohol self-administration acutely stimulates the hypothalamic-pituitary-adrenal axis, but alcohol dependence leads to a dampened neuroendocrine state. The European journal of neuroscience 2008; 28: 1641-1653
152 Kiefer F, Wiedemann K. Neuroendocrine pathways of addictive behaviour. Addict Biol 2004; 9: 205-212
153 Newell-Price J. Proopiomelanocortin gene expression and DNA methylation: implications for Cushing’s syndrome and beyond. J Endocrinol 2003; 177: 365-372
154 Ye L, Li X, Kong X et al. Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids. J Endocrinol 2005; 185: 337-343
155 Muschler MA, Hillemacher T, Kraus C et al. DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence. Journal of neural transmission 2010; 117: 513-519
156 Antoni FA, Hunter EF, Lowry PJ et al. Atriopeptin: an endogenous corticotropin-release inhibiting hormone. Endocrinology 1992; 130: 1753-1755
157 Hillemacher T, Frieling H, Luber K et al. Epigenetic regulation and gene expression of vasopressin and atrial natriuretic peptide in alcohol withdrawal. Psychoneuroendocrinology 2009; 34: 555-560
158 Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry 2001; 62 (Suppl. 16) 26-31
159 Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997; 349: 1498-1504
160 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. Exp Neurol 2012; 233: 102-111
161 Karg K, Burmeister M, Shedden K et al. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Archives of general psychiatry 2011; 68: 444-454
162 Risch N, Herrell R, Lehner T et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. Jama 2009; 301: 2462-2471
163 Olsson CA, Foley DL, Parkinson-Bates M 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. Biol Psychol 2010; 83: 159-165
164 Philibert R, Madan A, Andersen A et al. Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. American journal of medical genetics Part B, Neuropsychiatric genetics: the official publication of the International Society of Psychiatric Genetics 2007; 144B: 101-105
165 Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Archives of general psychiatry 1997; 54: 597-606
166 Castren E. Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 2004; 4: 58-64
167 Castren E. Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection. Mol Neurobiol 2004; 29: 289-302
168 Kinnally EL, Capitanio JP, Leibel R et al. Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav 2010; 9: 575-582
169 Kaufman J, Yang BZ, Douglas-Palumberi H et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101: 17316-17321
170 Devlin AM, Brain U, Austin J et al. Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One 2010; 5: e12201
171 Koenen KC, Uddin M, Chang SC et al. SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depress Anxiety 2011; 28: 639-647
172 Rubin RT, Phillips JJ, McCracken JT et al. Adrenal gland volume in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function. Biological psychiatry 1996; 40: 89-97
173 Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci 2008; 31: 464-468
174 De Kloet ER, Vreugdenhil E, Oitzl MS et al. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998; 19: 269-301
175 Weaver IC, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nature neuroscience 2004; 7: 847-854
176 Weaver IC, D’Alessio AC, Brown SE et al. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. The Journal of neuroscience: the official journal of the Society for Neuroscience 2007; 27: 1756-1768
177 Francis D, Diorio J, Liu D et al. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 1999; 286: 1155-1158
178 Liu D, Diorio J, Tannenbaum B et al. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997; 277: 1659-1662
179 Perroud N, Paoloni-Giacobino A, Prada P 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. Transl Psychiatry 2011; 1: e59
180 McGowan PO, Sasaki A, D’Alessio AC et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature neuroscience 2009; 12: 342-348
181 Oberlander TF, Weinberg J, Papsdorf M et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics: official journal of the DNA Methylation Society 2008; 3: 97-106
182 Alt SR, Turner JD, Klok MD et al. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed. Psychoneuroendocrinology 2010; 35: 544-556
183 Murgatroyd C, Patchev AV, Wu Y et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature neuroscience 2009; 12: 1559-1566
184 Mueller BR, Bale TL. Sex-specific programming of offspring emotionality after stress early in pregnancy. The Journal of neuroscience: the official journal of the Society for Neuroscience 2008; 28: 9055-9065
185 Elliott E, Ezra-Nevo G, Regev L et al. Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nature neuroscience 2010; 13: 1351-1353
186 Raadsheer FC, Hoogendijk WJ, Stam FC et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436-444
187 Raadsheer FC, van Heerikhuize JJ, Lucassen PJ et al. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression. The American journal of psychiatry 1995; 152: 1372-1376
188 Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry 2002; 17 (Suppl. 03) 306-310
189 Duman RS, Malberg J, Nakagawa S et al. Neuronal plasticity and survival in mood disorders. Biological psychiatry 2000; 48: 732-739
190 Fossati P, Radtchenko A, Boyer P. Neuroplasticity: from MRI to depressive symptoms. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 2004; 14 (Suppl. 05) S503-S510
191 Manji HK, Quiroz JA, Sporn J et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biological psychiatry 2003; 53: 707-742
192 Tsankova NM, Berton O, Renthal W et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature neuroscience 2006; 9: 519-525
193 Roth TL, Lubin FD, Funk AJ et al. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological psychiatry 2009; 65: 760-769
194 Roth TL, Zoladz PR, Sweatt JD et al. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. Journal of psychiatric research 2011; 45: 919-926
195 Dwivedi Y, Rizavi HS, Conley RR et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Archives of general psychiatry 2003; 60: 804-815
196 Fuchikami M, Morinobu S, Segawa M et al. DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. PLoS One 2011; 6: e23881
197 Karege F, Perret G, Bondolfi G et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry research 2002; 109: 143-148
198 Ernst C, Deleva V, Deng X et al. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Archives of general psychiatry 2009; 66: 22-32
199 Keller S, Sarchiapone M, Zarrilli F et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Archives of general psychiatry 2010; 67: 258-267
200 Soubry A, Murphy S, Huang Z et al. The effects of depression and use of antidepressive medicines during pregnancy on the methylation status of the IGF2 imprinted control regions in the offspring. Clin Epigenetics 2011; 3: 2
201 Woodson K, Gillespie J, Hanson J et al. Heterogeneous gene methylation patterns among pre-invasive and cancerous lesions of the prostate: a histopathologic study of whole mount prostate specimens. Prostate 2004; 60: 25-31
202 Woodson K, Hanson J, Tangrea J. A survey of gene-specific methylation in human prostate cancer among black and white men. Cancer letters 2004; 205: 181-188
203 Duvic M, Vu J. Vorinostat in cutaneous T-cell lymphoma. Drugs Today 2007; 43: 585-599
204 Kuendgen A, Lubbert M. Current status of epigenetic treatment in myelodysplastic syndromes. Ann Hematol 2008; 87: 601-611
205 Kosaki K, McGinniss MJ, Veraksa AN et al. Prader-Willi and Angelman syndromes: diagnosis with a bisulfite-treated methylation-specific PCR method. Am J Med Genet 1997; 73: 308-313
206 Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 2009; 49: 243-263
207 Dong E, Guidotti A, Grayson DR et al. Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci U S A 2007; 104: 4676-4681
208 Kataoka S, Takuma K, Hara Y et al. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 2013; 16: 91-103
209 Boks MP, de Jong NM, Kas MJ et al. Current status and future prospects for epigenetic psychopharmacology. Epigenetics 2012; 7: 20-28
210 Ghadirivasfi M, Nohesara S, Ahmadkhaniha HR et al. Hypomethylation of the serotonin receptor type-2A Gene (HTR2A) at T102C polymorphic site in DNA derived from the saliva of patients with schizophrenia and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 536-545
211 Nohesara S, Ghadirivasfi M, Mostafavi S et al. DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. J Psychiatr Res 2011; 45: 1432-1438
212 Sterrenburg L, Gaszner B, Boerrigter J et al. Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat. PLoS One 2011; 6: e28128
213 Zhang TY, Hellstrom IC, Bagot RC et al. Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. The Journal of neuroscience: the official journal of the Society for Neuroscience 2010; 30: 13130-13137
214 Zill P, Baghai TC, Schule C et al. DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression. PLoS One 2012; 7: e40479
215 Melas PA, Rogdaki M, Lennartsson A et al. Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. The international journal of neuropsychopharmacology/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 2012; 15: 669-679
216 Cruceanu C, Alda M, Nagy C et al. H3K4 tri-methylation in synapsin genes leads to different expression patterns in bipolar disorder and major depression. The international journal of neuropsychopharmacology/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum. 2012; 1-11
217 Dyrvig M, Hansen HH, Christiansen SH et al. Epigenetic regulation of Arc and c-Fos in the hippocampus after acute electroconvulsive stimulation in the rat. Brain Res Bull 2012; 88: 507-513
218 Ernst C, Chen ES, Turecki G. Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Molecular psychiatry 2009; 14: 830-832
219 Yang X, Ewald ER, Huo Y et al. Glucocorticoid-induced loss of DNA methylation in non-neuronal cells and potential involvement of DNMT1 in epigenetic regulation of Fkbp5. Biochemical and biophysical research communications. 2012 420: 570-575
220 Uddin M, Koenen KC, Aiello AE et al. Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol Med 2011; 41: 997-1007
221 Poulter MO, Du L, Weaver IC et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biological psychiatry 2008; 64: 645-652
222 Sabunciyan S, Aryee MJ, Irizarry RA et al. Genome-wide DNA methylation scan in major depressive disorder. PLoS One 2012; 7: e34451
223 Champagne FA, Weaver IC, Diorio J et al. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 2006; 147: 2909-2915
224 Liu Y, Murphy SK, Murtha AP et al. Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements. Epigenetics: official journal of the DNA Methylation Society 2012; 7: 735-746