Psychiatrische Genetik – Gegenwart und Perspektiven

Zusammenfassung

Psychiatrische Störungen entwickeln sich aus dem Zusammenspiel von Umwelteinflüssen und genetischen Einflüssen, die stark unterschiedlich gewichtet sein können. In den vergangenen zwei Jahrzehnten sind die relativen Anteile genetischer Faktoren intensiv erforscht worden und haben zugleich wertvolle Einblicke in die Pathophysiologie einzelner Störungen gewährt. Neben der Weiterentwicklung von genetischen Techniken und Strategien zu deren Anwendung ist dabei das Augenmerk wieder vermehrt auf die klinische Beobachtungsgabe gerichtet worden. In der vorliegenden Übersicht werden bereits bewährte und neue Methoden der psychiatrischen Genetik vorgestellt und Ergebnisse bisheriger Arbeiten zu ausgewählten Störungen referiert.

Summary

The interplay of environmental and genetic factors accounts for marked variability in liability to psychiatric disorders. Over the past two decades, the relative contribution of genetic determinants has been the object of intense research and has offered valuable pathophysiological insights. While the advancement of techniques and strategies for gene finding has clearly benefitted psychiatric genetics, recent work has alerted to the importance of clinical judgement. The present review introduces to both established and future methods in the field, and summarizes data on the genetic backbone of selected psychiatric disorders.

Schlüsselwörter

Psychiatrische Genetik - Erblichkeit - familiäre Risiken

Keywords

Psychiatric genetics - heritability - familial risks

• Literatur

• 1 Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 07: 405-11.
• 2 Baron M. Searching for complex disease genes: can it be made any easier?. Psychiatr Genet 1995; 05: 89-91.
• 3 Baysal BE. et al. Bipolar affective disorder partially cosegregates with a balanced t(9;11) (p24;q23.1) chromosomal translocation in a small pedigree. Am J Med Genet 1998; 81: 81-91.
• 4 Bergem AL, Engedal K, Kringlen E. The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 1997; 54: 264-70.
• 5 Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-depressive disorders. Br J Psychiatry 1977; 130: 330-51.
• 6 Bulik CM. et al. Significant linkage on chromosome 10p in families with bulimia nervosa. Am J Hum Genet 2003; 72: 200-7.
• 7 Bunney WE. et al. Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders. Am J Psychiatry 2003; 160: 657-66.
• 8 Burbridge D. Francis Galton on twins, heredity and social class. Br J Hist Sci 2001; 34: 323-40.
• 9 Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97: 12-7.
• 10 Clark AG. Finding genes underlying risk of complex disease by linkage disequilibrium mapping. Curr Opin Genet Dev 2003; 13: 296-302.
• 11 Cloninger CR. et al. Anxiety proneness linked to epistatic loci in genome scan of human personality traits. Am J Med Genet 1998; 81: 313-7.
• 12 Corder EH. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921-3.
• 13 Cowan WM, Kopnisky KL, Hyman SE. The human genome project and its impact on psychiatry. Annu Rev Neurosci 2002; 25: 1-50.
• 14 Devlin B. et al. Linkage analysis of anorexia nervosa incorporating behavioral covariates. Hum Mol Genet 2002; 11: 689-96.
• 15 Disse S. et al. Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2-p12.1. Am J Hum Genet 1999; 65: 1242-51.
• 16 Doyle AE, Faraone SV. Familial links between attention deficit hyperactivity disorder, conduct disorder, and bipolar disorder. Curr Psychiatry Rep 2002; 04: 146-52.
• 17 Enoch MA, Goldman D. The genetics of alcoholism and alcohol abuse. Curr Psychiatry Rep 2001; 03: 144-51.
• 18 Farrer LA. et al. Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. Hum Mol Genet 2003; 12: 415-22.
• 19 Franke P. et al. Wisconsin Card Sorting Test: an indicator of vulnerability to schizophrenia?. Schizophr Res 1992; 06: 243-9.
• 20 Freedman R. et al. The genetics of sensory gating deficits in schizophrenia. Curr Psychiatry Rep 2003; 05: 155-61.
• 21 Fu Q. et al. Shared genetic risk of major depression, alcohol dependence, and marijuana dependence: contribution of antisocial personality disorder in men. Arch Gen Psychiatry 2002; 59: 1125-32.
• 22 Gelernter J. et al. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet 2001; 105: 548-57.
• 23 Gelernter J. et al. A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol Psychiatry 2003; 08: 71-82.
• 24 Ghosh S. et al. Linkage mapping of beta 2 EEG waves via non-parametric regression. Am J Med Genet 2003; 118B: 66-71.
• 25 Goate A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349: 704-6.
• 26 Gottesman II, Shields J. Schizophrenia and Genetics: A twin study vantage point. New York: Academic Press; 1972
• 27 Gottesman II, Shields J. Schizophrenia: The epigenetic puzzle. Cambridge: Cambridge University Press; 1982
• 28 Gratacós M. et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 2001; 106: 367-79.
• 29 Greenberg SM, Bacskai BJ, Hyman BT. Alzheimer disease’s double-edged vaccine. Nat Med 2003; 09: 389-90.
• 30 Grice DE. et al. Evidence for a susceptibility gene for anorexia nervosa on chromosome 1. Am J Hum Genet 2002; 70: 787-92.
• 31 Hamilton SP. et al. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci U S A 2003; 100: 2550-5.
• 32 Hariri AR. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297: 400-3.
• 33 Hariri AR, Weinberger DR. Imaging genomics. Br Med Bull 2003; 65: 259-70.
• 34 Heston LL. Psychiatric disorders in foster home reared children of schizophrenic mothers. Br J Psychiatry 1966; 112: 819-25.
• 35 Holland AJ. et al. Anorexia nervosa: a study of 34 twin pairs and one set of triplets. Br J Psychiatry 1984; 145: 414-9.
• 36 Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33 Suppl: 245-54.
• 37 Janus C. et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000; 408: 979-82.
• 38 Japanese Schizophrenia Sib-Pair Linkage Group. Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) families. Am J Med Genet 2003; 120B: 22-8.
• 39 Kendler KS, Gruenberg AM, Tsuang MT. Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients. A family study using DSM-III criteria. Arch Gen Psychiatry 1985; 42: 770-9.
• 40 Kendler KS. The genetics of schizophrenia: a current perspective. Psychopharmacol Bull 1986; 22: 918-22.
• 41 Kendler KS, Gruenberg AM, Tsuang MT. A family study of the subtypes of schizophrenia. Am J Psychiatry 1988; 145: 57-62.
• 42 Kendler KS. et al. The genetic epidemiology of bulimia nervosa. Am J Psychiatry 1991; 148: 1627-37.
• 43 Kendler KS. et al. Marker-to-marker linkage disequilibrium on chromosomes 5q, 6p, and 8p in Irish high-density schizophrenia pedigrees. Am J Med Genet 1999a; 88: 29-33.
• 44 Kendler KS, Karkowski LM, Prescott CA. Fears and phobias: reliability and heritability. Psychol Med 1999b 29: 539-53.
• 45 Kety SS. Mental illness in the biological and adoptive relatives of schizophrenic adoptees: findings relevant to genetic and environmental factors in etiology. Am J Psychiatry 1983; 140: 720-7.
• 46 Kety SS. et al. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark. Arch Gen Psychiatry 1994; 51: 442-55.
• 47 Klar AJ. The chromosome 1;11 translocation provides the best evidence supporting genetic etiology for schizophrenia and bipolar affective disorders. Genetics 2002; 160: 1745-7.
• 48 Kluger AN, Siegfried Z, Ebstein RP. A metaanalysis of the association between DRD4 polymorphism and novelty seeking. Mol Psychiatry 2002; 07: 712-7.
• 49 Knowles JA. Genetics. In: The American Psychiatric Publishing Textbook of Clinical Psychiatry. Fourth Edition. Hales RE, Yudofsky SC. (eds). Arlington/VA: American Psychiatric Publishing; 2003: 3-65.
• 50 Larsson T, Sjögren T, Jacobson G. Senile dementia: a clinical, sociomedical and genetic study. Acta Psychiatr Scand 1963; 39 (Suppl): 167.
• 51 Lehrman S. Genetic testing for Alzheimer’s disease ‘not appropriate’. Nature 1997; 389: 898.
• 52 Lesch KP. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527-31.
• 53 Levinson DF. et al. Genetics of recurrent earlyonset depression (GenRED): Design and preliminary clinical characteristics of a repository sample for genetic linkage studies. Am J Med Genet 2003; 119B: 118-30.
• 54 Levy F. et al. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry 1997; 36: 737-44.
• 55 Levy-Lahad E. et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995; 269: 973-7.
• 56 Lewis CM. et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34-48.
• 57 Lilenfeld LR. et al. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity. Arch Gen Psychiatry 1998; 55: 603-10.
• 58 Linney YM. et al. A quantitative genetic analysis of schizotypal personality traits. Psychol Med 2003; 33: 803-16.
• 59 MacIntyre DJ. et al. Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 08: 275-87.
• 60 Maher BS. et al. Genetic segregation analysis of recurrent, early-onset major depression: evidence for single major locus transmission. Am J Med Genet 2002; 114: 214-21.
• 61 Panegyres PK. et al. Genetic testing for Alzheimer’s disease. Med J Aust 2000; 172: 339-43.
• 62 Pauls DL. et al. Linkage of bipolar affective disorders to markers on chromosome 11p is excluded in a second lateral extension of Amish pedigree 110. Genomics 1991; 11: 730-6.
• 63 Petronis A, Paterson AD, Kennedy JL. Schizophrenia: an epigenetic puzzle?. Schizophr Bull 1999; 25: 639-55.
• 64 Pittelli SJ. Genetic linkage in schizophrenia. Am J Psychiatry 2003; 160: 597.
• 65 Prasher VP. et al. Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol 1998; 43: 380-3.
• 66 Pulver AE. et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12- q13.1: Part 1. Am J Med Genet 1994; 54: 36-43.
• 67 Rutherford J. et al. Genetic influences on eating attitudes in a normal female twin population. Psychol Med 1993; 23: 425-36.
• 68 Rybakowski F. et al. Genetic factors in the etiology of anorexia nervosa. Psychiatr Pol 2001; 35: 71-80.
• 69 Sandbrink R. et al. Genes contributing to Alzheimer’s disease. Mol Psychiatry 1996; 01: 27-40.
• 70 Schöls L, Rieß O. Einführung und tabellarischer Überblick über genetisch diagnostizierbare neurologische und psychiatrische Erkrankungen. In: Neurogenetik. 2. Aufl. Rieß O, Schöls L. (Hrsg). Stuttgart: Kohlhammer; 2002: 3-16.
• 71 Schuckit MA. et al. A genome-wide search for genes that relate to a low level of response to alcohol. Alcohol Clin Exp Res 2001; 25: 323-9.
• 72 Schumacher J. et al. Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes. Nervenarzt 2002; 03: 581-92.
• 73 Schwab SG, Wildenauer DB. Chromosome 22 workshop report. Am J Med Genet 1999; 88: 276-8.
• 74 Segurado R, Gill M. Genome-wide genetic linkage studies in bipolar disorder: review and meta-analysis. Am J Med Genet 2001; 105: 580.
• 75 Segurado R. et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 2003; 73: 49-62.
• 76 Seong E, Seasholtz AF, Burmeister M. Mouse models for psychiatric disorders. Trends Genet 2002; 18: 643-50.
• 77 Shannon JR. et al. Orthostatic intolerance and tachycardia associated with norepinephrinetransporter deficiency. N Engl J Med 2000; 342: 541-9.
• 78 Sherrington R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375: 754-60.
• 79 Shprintzen RJ. et al. Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 1992; 42: 141-2.
• 80 Sklar P. Linkage analysis in psychiatric disorders: the emerging picture. Annu Rev Genomics Hum Genet 2002; 03: 371-413.
• 81 Skodol AE. et al. The borderline diagnosis II: biology, genetics, and clinical course. Biol Psychiatry 2002; 51: 951-63.
• 82 Smalley SL. et al. Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2000; 39: 1135-43.
• 83 Smidt J. et al. Formal genetic findings in attention-deficit/hyperactivity-disorder. Fortschr Neurol Psychiatr 2003; 71: 366-77.
• 84 Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506-16.
• 85 St George-Hyslop PH. et al. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 1987; 235: 885-90.
• 86 Stöber G. et al. Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. Am J Hum Genet 2000; 67: 1201-7.
• 87 Tandon K, McGuffin P. The genetic basis for psychiatric illness in man. Eur J Neurosci 2002; 16: 403-7.
• 88 Thorgeirsson TE. et al. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet 2003; 72: 1221-30.
• 89 Todd RD. et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatry 2001; 158: 1891-8.
• 90 Torgersen S. et al. A twin study of personality disorders. Compr Psychiatry 2000; 41: 416-25.
• 91 Uhl GR, Liu QR, Naiman D. Substance abuse vulnerability loci: converging genome scanning data. Trends Genet 2002; 18: 420-5.
• 92 Utermann G, Pruin N, Steinmetz A. Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. Clin Genet 1979; 15: 63-72.
• 93 van Duijn CM. et al. Familial aggregation of Alzheimer’s disease and related disorders: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 1991; 20 Suppl 2: S13-20.
• 94 Wang TL. et al. Digital karyotyping. Proc Natl Acad Sci U S A 2002; 99: 16156-61.
• 95 Weissman MM. et al. Potential panic disorder syndrome: clinical and genetic linkage evidence. Am J Med Genet 2000; 96: 24-35.
• 96 Wildenauer DB. et al. Do schizophrenia and affective disorder share susceptibility genes?. Schizophr Res 1999; 39: 107-11.
• 97 Zinn-Justin A, Abel L. Genome search for alcohol dependence using the weighted pairwise correlation linkage method: interesting findings on chromosome 4. Genet Epidemiol 1999; 17 Suppl 1: S421-6.
• 98 Zohar AH. et al. Tridimensional personality questionnaire trait of harm avoidance (anxiety proneness) is linked to a locus on chromosome 8p21. Am J Med Genet 2003; 117B: 66-9.
• 99 Zubenko GS. et al. Malignancy of recurrent, early-onset major depression: a family study. Am J Med Genet 2001; 105: 690-9.
• 100 Zubenko GS. et al. Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10cM resolution. Am J Med Genet 2002; 114: 413-22.