Genetik depressiver Störungen
Abstract
Zusammenfassung: Depressive Störungen gehören weltweit zu den häufigsten psychiatrischen Erkrankungen, die die psychische und psychosoziale Entwicklung der Erkrankten nachhaltig beeinflussen. Meist beginnen die Erkrankungen im Kindes- und Jugendalter. Anhand der Symptomatik, des Verlaufs und der Ursachen werden unipolare Depressionen von bipolaren Störungen, die durch depressive und manische Erkrankungsphasen gekennzeichnet sind, unterschieden. Für die Entstehung dieser Erkrankungen spielen genetische Faktoren eine entscheidende Rolle. Familien- und Zwillingsstudien konnten das erhöhte Erkrankungsrisiko von Kindern in betroffenen Familien und die hohe Heritabilität, insbesondere von bipolaren Störungen, eindrücklich nachweisen. Die Suche nach prädisponierenden Krankheitsgenen mittels Kopplungs- und Assoziationsanalysen konnte in den vergangenen Jahren beachtliche Fortschritte erzielen. Insbesondere das s-Allel des Serotonintransportergens wurde wiederholt als Risikofaktor bestätigt. Meta-Analysen deuten allerdings auf relativ begrenzte Effekte einzelner Gene hin. Neben genetischen Komponenten sind Umweltfaktoren maßgeblich an der Krankheitsgenese beteiligt: Bei unipolaren Depressionen wird die Erkrankungswahrscheinlichkeit bei entsprechender genetischer Disposition wesentlich durch protektive oder pathogene Umweltfaktoren im Sinne einer engen Gen-Umwelt-Interaktion moduliert.
Summary: Among the most common severe psychiatric disorders worldwide, depressive disorders are a leading cause of morbidity, the onset usually occurring during childhood or adolescence. Symptomatology, prevalence, outcome and treatment differentiate depressive disorder nosologically as being either unipolar depression or bipolar disorder, which is characterized by one or more episodes of mania with or without episodes of depression. Genetic factors decisively influence the susceptibility to depressive disorders. Family studies and twin studies have been essential in defining the magnitude of familial risk and liability to heritability, particularly in the case of bipolar disorder. In recent years, linkage and association studies have made great strides towards identifying candidate genes. Particularly the s-allele of the serotonin transporter has been repeatedly confirmed to be a risk factor. Meta-analyses suggest, however, that the genetic contributions of the ascertained loci are relatively small. Along with genetic factors, environmental factors are heavily involved. Gene-environment action plays a pivotal role, particularly in unipolar depression. The genetic disposition seems to be modulated by a protective or pathogenic environment. Early-onset disorders must be further investigated in future as studies to date are somewhat limited.
Literatur
2006). he G72/G30 gene locus in psychiatric disorders: a challenge to diagnostic boundaries? . Schizophrenia Bulletin, 32, 599– 608
(2004). Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica, 109, 21– 27
(2005). Family, twin, adoption, and molecular genetic studies of juvenile bipolar disorder. Bipolar Disorders, 7, 598– 609
(1998). Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychological Medicine, 28, 51– 61
(1966). Zur Ätiologie und Nosologie endogener depressiver Psychosen. Eine genetische, soziologische und klinische Studie. Monographien aus dem Gesamtgebiet der Neurologie und Psychiatrie. Bd. 112. Berlin Heidelberg New York Tokyo: Springer
(2002). Serotonin brain circuits involved in major depression and suicide. Progress in Brain Research, 136, 443– 453
(2002). Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Molecular Psychiatry, 7, 405– 411
(2004). Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biological Psychiatry, 55, 733– 738
(1996). Childhood and adolescent depression: a review of the past 10 years. Part I.. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1427– 1439
(1993). Psychiatric impact of the loss of an adolescent sibling to suicide. Journal of Affective Disorders, 28, 249– 256
(2007). Development of a retrospective interview measure of parental maltreatment using the Childhood Experience of Care and Abuse (CECA) instrument - A life-course study of adult chronic depression - 1.. Journal of Affective Disorders,
(1999). Childhood abuse and neglect: specificity of effects on adolescent and young adult depression and suicidality. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 1490– 1496
(2006). Neural correlates of epigenesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 16033– 16038
(2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386– 389
(2007). Genome-wide scan of bipolar disorder and investigation of population stratification effects on linkage: Support for susceptibility loci at 4q21, 7q36, 9p21, 12q24, 14q24, and 16p13. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144B, 791– 801
(2007). The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort. Molecular Psychiatry, 12, 748– 755
(2007). No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144,, 561– 565
(2007). Die Genetik der bipolaren Störung. Medizinische Genetik, 19, 335– 341
(1993). An epidemiological study of disorders in late childhood and adolescence - I. Age- and gender-specific prevalence. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 34, 851– 867
(2006). Genetics of affective (mood) disorders. European Journal of Human Genetics, 14, 660– 668
(2006). G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biological Psychiatry, 60, 106– 114
(2006). Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. British Journal of Psychiatry, 188, 216– 222
(2001). Uses and abuses of meta-analysis. Clinical Medicine, 1, 478– 484
(2007). The genetics of bipolar affective disorder. Current Opinion in Psychiatry, 20, 8– 12
(2000). Cardiff depression study. A sib-pair study of life events and familiality in major depression. British Journal of Psychiatry, 176, 150– 155
(1996). Childhood sexual abuse and psychiatric disorder in young adulthood: II. Psychiatric outcomes of childhood sexual abuse. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1365– 1374
(1990). Epidemiology of childhood depressive disorders: a critical review. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 571– 580
(2005). The relations among maternal depression, maternal criticism, and adolescents’ externalizing and internalizing symptoms. Journal of Abnormal Child Psychology, 33, 1– 11
(2003). Genetic epidemiology of self-reported lifetime DSM-IV major depressive disorder in a population-based twin sample of female adolescents. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 44, 988– 996
(2007). Is it time to reassess the BDNF hypothesis of depression?. Molecular Psychiatry,
(1970). Suicide and primary affective disorders. British Journal of Psychiatry, 117, 437– 438
(2004). Family discord and stress predictors of depression and other disorders in adolescent children of depressed and nondepressed women. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 994– 1002
(2006). Psychopathology in the young offspring of parents with bipolar disorder: a controlled pilot study. Psychiatry Research, 145, 155– 167
(2007). Genetics of recurrent early-onset major depression (GenRED): final genome scan report. American Journal of Psychiatry, 164, 248– 258
(2004). Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. American Journal of Human Genetics, 74, 1154– 1167
(2003). Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology, 48, 186– 189
(2005). Prevalence and genetic architecture of Child Behavior Checklist-juvenile bipolar disorder. Biological Psychiatry, 58, 562– 568
(2007). Molecular genetics of bipolar disorder and depression. Psychiatry and Clinical Neurosciences, 61, 3– 19
(2006). Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry, 59, 673– 680
(2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the United States of America, 101, 17316– 17321
(1994). Depression: a long-term illness. British Journal of Psychiatry, 26, 9– 15
(2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62, 593– 602
(1989). Depressive disorders in childhood. IV. A longitudinal study of comorbidity with and risk for anxiety disorders. Archives of General Psychiatry, 46, 776– 782
(2005). Review and meta-analysis of the phenomenology and clinical characteristics of mania in children and adolescents. Bipolar Disorders, 7, 483– 496
(2004). No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biological Psychiatry, 56, 376– 378
(2005). Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology, 180, 95– 99
(1959). Aufteilung der endogenen Psychosen. Berlin: Akademie Verlag
(1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527– 1531
(2007). The poor prognosis of childhood-onset bipolar disorder. Journal of Pediatrics, 150, 485– 490
(2005). Meta-analysis in psychiatric genetics. Current Psychiatry Reports, 7, 143– 151
(2006). The genetics of depression: a review. Biological Psychiatry, 60, 84– 92
(2007). Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers. American Journal of Psychiatry, 164, 259– 264
(2003). The symptomatic expression of major depressive disorder in adolescents and young adults. Journal of Abnormal Psychology, 112, 244– 252
(1998). Major depressive disorder in older adolescents: prevalence, risk factors, and clinical implications. Clinical Psychology Review, 18, 765– 794
(2002). Parental major depression and the risk of depression and other mental disorders in offspring: a prospective-longitudinal community study. Archives of General Psychiatry, 59, 365– 374
(2004). Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatric Genetics, 14, 121– 129
(2004). Genetik der Depression. Gegenwärtiger Erkenntnisstand und Perspektiven. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, 47, 487– 492
(2003). Genetics of depression. In: S. Kaspar, J. A. Den Boer & J. M. A. Sitsen (Eds.), Handbook of depression and anxiety (Aufl. 2; 165-187). New York: Dekker
(2000). Genetik affektiver Störungen. In: H. Helmchen, F. Henn, H. Lauter & N. Sartorius (Eds.), Schizophrene und affektive Störungen 373-407. Berlin: Springer
(2005). Whole genome linkage scan of recurrent depressive disorder from the depression network study. Human Molecular Genetics, 14, 3337– 3345
(2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry, 60, 497– 502
(2005). Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. American Journal of Human Genetics, 77, 582– 595
(2002). Future of genetics of mood disorders research. Biological Psychiatry, 52, 457– 477
(2007). Molecular studies of major depressive disorder: the epigenetic perspective. Molecular Psychiatry, 12, 799– 814
(2001). Child sexual abuse and subsequent psychopathology: results from the National Comorbidity Survey. American Journal of Public Health, 91, 753– 760
(2006). Familial aggregation of illness chronicity in recurrent, early-onset major depression pedigrees. American Journal of Psychiatry, 163, 1554– 1560
(1997). Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet, 349, 1498– 1504
(2003). Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neuroscience Letters, 337, 17– 20
(2002). The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. American Journal of Human Genetics, 71, 651– 655
(2004). Fortschritte in der Ursachenforschung affektiver und schizophrener Störungen. Deutsches Ärzteblatt, 101, A3343– 3347
(2004). Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 129, 34– 35
(1966). A study of bipolar (manic-depressive) and unipolar recurrent depressive psychoses. I. Genetic investigation. Acta Psychiatrica Scandinavica, 194, 15– 44
(2005). Initial conditions of psychotropic drug response: studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 29, 1046– 1061
(1993). Prevalence of psychiatric disorders in a community population of older adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 369– 377
(2006). Multiaxiales Klassifikationsschema für psychische Störungen des Kindes- und Jugendalters nach ICD-10 der WHO. 5. Aufl. Bern: Verlag Hans Huber
(2007). Childhood-onset bipolar disorder: Evidence for increased familial loading of psychiatric illness. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 197– 204
(2003). Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. American Journal of Human Genetics, 73, 49– 62
(2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology, 28, 397– 401
(2004). Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World Journal of Biological Psychiatry, 5, 215– 220
(2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Molecular Psychiatry, 7, 579– 593
(2007). Does pretreatment testing for serotonin transporter polymorphisms lead to earlier effects of drug treatment in patients with major depression? A decision-analytic model. Clinical Therapeutics, 29, 691– 702
(2004). Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review. Molecular Psychiatry, 9, 433– 441
(2007). Depressionen im Kindes- und Jugendalter. Die unsichtbare Erkrankung. Deutsches Ärzteblatt, 9, 424– 426
(2005). Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample. Molecular Psychiatry, 10, 861– 867
(2004). Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 131, 16– 19
(2000). Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry, 157, 1552– 1562
(2006). Twin studies in pediatric depression. Child and Adolescent Psychiatric Clinics of North America, 15, 869– 881 viii
(2002). Etiology and genetics of early-onset mood disorders. Child and Adolescent Psychiatric Clinics of North America, 11, 499– 518
(2007). The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Molecular Psychiatry,
(2006). Genetik psychischer Erkrankungen und Entwicklungsstörungen mit Beginn im Kindes- und Jugendalter. Medizinische Genetik, 18, 142– 144
(2006). Offspring of depressed parents: 20 years later. American Journal of Psychiatry, 163, 1001– 1008
(2005). Families at high and low risk for depression: a 3-generation study. Archives of General Psychiatry, 62, 29– 36
(2007). The BDNF Val66Met × 5-HTTLPR × child adversity interaction and depressive symptoms: An attempt at replication. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics,
(2000). Selecting early onset MDD probands for genetic studies: results from a longitudinal high-risk study. American Journal of Medical Genetics, 96, 93– 101
(2005). A genetic epidemiologic perspective on comorbidity of depression and anxiety. Child and Adolescent Psychiatric Clinics of North America, 14, 707– 726 viii
(2000). Epidemiologie affektiver Störungen. In: H. Helmchen, F. Henn, H. Lauter & N. Sartorius (Eds.), Schizophrene und affektive Störungen (pp. 357-372). Berlin: Springer
(2000). Erscheinungsformen, Häufigkeit und Versorgung von Depressionen. Ergebnisse des bundesweiten Gesundheitssurveys «Psychische Störungen». Fortschritte der Medizin, 118, 4– 10
(2003). Chronische Depression. Grundlagen, praktische Erfahrungen und Empfehlungen. Lengerich, Berlin, Bremen, Riga, Rom, Viernheim, Wien, Zagreb: Pabst Science Publishers
(2006a). Depressive disorders in childhood and adolescence: an overview: epidemiology, clinical manifestation and risk factors. Child and Adolescent Psychiatric Clinics of North America, 15, 827– 841 vii
(2006b). Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. American Journal of Psychiatry, 163, 1588– 1593
(2001). Malignancy of recurrent, early-onset major depression: a family study. American Journal of Medical Genetics, 105, 690– 699
(