Zusammenfassung
Es gibt mittlerweile stringente Belege aus Familien-, Zwillings- und Adoptionsstudien, die den wesentlichen genetischen Anteil der Erkrankung Schizophrenie beschreiben. Die Art der Übertragung ist allerdings sehr kompliziert und umfasst wenn überhaupt nur sehr selten ein einzelnes Gen. Vielmehr gründet sich die Schizophrenie auf zahlreiche Gene mit geringen Effekten und deren Zusammenspiel mit der Umwelt. Da aber die Gesamtgröße des genetischen Effektes für 80 % der Varianz verantwortlich ist, ist es schwierig, eindeutige Umweltfaktoren festzulegen. Lange Zeit herrschte sogar die Vorstellung vor, dass der Bereich der Umwelt vollständig aus epigenetischen bzw. stochastischen Phänomenen besteht, die mit den bekannten epidemiologischen Methoden nicht entdeckt werden könnten. Nichtsdestotrotz beeinflussen eine Vielzahl von sozialen Stressoren, z. B. „high-expressed emotion”-Verhalten bei Verwandten Schizophrener und wichtige Lebensereignisse den Verlauf der Erkrankung Schizophrenie und es ist bekannt, dass bestimmte körperliche Faktoren wie Geburtskomplikationen und Cannabismissbrauch auch zu einer Anfälligkeit für diese Erkrankung beitragen. Die jüngste Entdeckung verschiedener Kandidatengene der Schizophrenie lässt nicht nur auf ein besseres Verstehen der Neurobiologie dieser Erkrankung hoffen, sondern auch auf eine verbesserte Kenntnis hinsichtlich Risikoeinschätzung und Gen/Umwelt - Wechselwirkungen.
Abstract
There is compelling evidence from family, twin and adoption studies of a substantial genetic contribution to schizophrenia. The mode of transmission is complicated and very rarely if ever involves a single gene. Rather schizophrenia results from multiple genes of small effect and their interplay with the environment. Perhaps because the overall size of the genetic effect is large, accounting for about 80 % of variance, definite environmental factors have been difficult to pin down. It has even been suggested that „the environment” consists entirely of epigenetic or stochastic phenomena that can never be detected by a standard epidemiological methods. Nevertheless, a variety of social stressors, including high expressed emotion in relatives and life events affect the course of illness and certain physical factors such as obstetric complications and cannabis smoking have been implicated in contributing to liability to the disorder. The recent discovery of several positional candidate genes that have been replicated as being associated with liability to schizophrenia holds considerable promise not just for a better understanding of the neurobiology but also for improved knowledge about risk prediction and gene-environment interplay.
References
-
1 Gottesman I I, Shields J. The Epigenetic Puzzle. Cambridge; Cambridge University Press 1982
-
2 Gottesman I I, Shields J. Schizophrenia, a think study vantage point. London; Academic Press 1972
-
3
McGuffin P, Farmer A E, Gottesman I I, Murray R M, Reveley A M.
Twin concordance for operationally defined schizophrenia: Confirmation of familiality and heritability.
Arch Gen Psychiatry.
1984;
41
541-545
-
4
Farmer A E, McGuffin P, Gottesman I I.
Twin concordance for DSM-III schizophrenia: Scrutinising the validity of the definition.
Arch Gen Psychiatry.
1987;
44
634-641
-
5
Cardno A G, Marshall E J, Coid B, Macdonald A M, Ribchester T R, Davies N J, Venturi P, Jones L A, Lewis S W, Sham P C, Gottesman I I, Farmer A E, McGuffin P, Reveley A M, Murray R M.
Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.
Arch Gen Psychiatry.
1999;
56 (2)
162-168
-
6
Cardno A G, Gottesman I I.
Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics.
American Journal of Medical Genetics (Semin Med Genet).
2000;
97 (12)
12-17
-
7
Wender P H, Rosenthal D, Kety S S, Schulsinger F, Welner J.
Social class and psychopathology in adoptees. A natural experimental method for separating the roles of genetic and experimential factors.
Arch Gen Psychiatry.
1973;
28 (3)
318-325
-
8
Kety S S, Rosenthal D, Wender P H, Schulsinger F, Jacobsen B.
Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic.
Behaviour Genetics.
1976;
6
219-225
-
9
Kendler K S, Gruenberg A M.
An independent analysis of the Danish Adoption Study of Schizophrenia. VI. The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees.
Arch Gen Psychiatry.
1984;
41 (6)
555-564
-
10
Kendler K S, Gruenberg A M, Kinney D K.
Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish Adoption Study of Schizophrenia.
Arch Gen Psychiatry.
1994;
51 (6)
456-468
-
11
Tienari P, Wynne L C, Sorri A, Lahti I, Laksy K, Moring J, Naarala M, Nieminen P, Wahlberg K E.
Genotype-environment interaction in schizophrenia-spectrum disorder. Long-term follow-up study of Finnish adoptees.
Br J Psychiatry.
2004;
184
216-222
-
12
Wetterberg L, Farmer A E.
Clinical polydiagnostic studies in a large Swedish pedigree with schizophrenia.
European Archives of Psychiatry and Clinical Neuroscience.
1991;
240 (3)
188-190
-
13
McGuffin P, Huckle P.
Simulation of Mendelism revisted: the recessive gene for attending Medical School.
Am J Hum Gen.
1990;
46
994-999
-
14
McGue M, Gottesman I I.
The genetic epidemiology of schizophrenia and the design of linkage studies.
Eur Arch Psychiatry and Clin Neuroscience.
1991;
240 (3)
174-181
-
15
Falconer D S.
The inheritance of liability to certain diseases, estimated from the incidence among relatives.
Annals of Human Genetics.
1965;
29
51-76
-
16
Gottesman I I, Shields J.
A polygenic theory of schizophrenia.
Procedures of the National Academy of Science USA.
1967;
58
199-205
-
17
Reich T, James J W, Morris C A.
The use of multiple thresholds in determining the mode of transmission of semi-continuous traits.
Ann Hum Genetics.
1972;
36
163-184
-
18
McGuffin P, Asherson P, Owen M, Farmer A E.
The strength of the genetic effect - is there room for an evironmental influence in the aetiology of schizophrenia?.
Br J Psychiatry.
1994;
164
593-599
-
19
Murray R M, Sham P, Os J Van, Zanelli J, Cannon M, McDonald C.
A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder.
Schizophrenia Research.
2004;
71 (2 - 3)
405-416
-
20
Brown A S, Hooton J, Schaefer C A, Zhang H, Petkova E, Babulas V, Perrin M, Gorman J M, Susser E S.
Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.
Am J Psychiatry.
2004;
161 (5)
889-895
-
21
Mortensen P B, Pedersen C B, Westergaard T, Wohlfahrt J, Ewald H, Mors O, Andersen P K, Melbye M.
Effects of family history and place and season of birth on the risk of schizophrenia.
New England Journal of Medicine.
1999;
340 (8)
603-608
-
22
McGuffin P, Gottesman I I.
Risk factors for schizophrenia.
The New England Journal of Medicine.
1999;
341 (5)
370-371
-
23 Bebbington P E, Kuipers E. Schizophrenia and psychosocial stresses. In: Hirsch SR, Weinberger D (eds) Schizophrenia (2nd ed). Oxford; Blackwell 2003: 611-634
-
24
Thapar A, Harold G, McGuffin P.
Life events and depressive symptoms in childhood - shared genes or shared adversity? A research note.
Journal of Child Psychology and Psychiatry.
1998;
39 (8)
1153-1158
-
25
Farmer A, Harris T, Redman K, Sadler S, Mahmood A, McGuffin P.
The Cardiff Depression Study - A sib pair study of life events and familiality in major depression.
Br J Psychiatry.
2000;
176
150-155
-
26
Williams N M, Rees M I, Holmans P, Norton N, Cardno A G, Jones L A, Murphy K C, Sanders R D, McCarthy G, Gray M Y, Fenton I, McGuffin P, Owen M J.
A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs.
Human Molecular Genetics.
1999;
8 (9)
729-1739
-
27 Gottesman I I. Schizophrenia Genesis. New York; W. H. Freeman 1991
-
28
Badner J A, Gershon E S.
Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
Mol Psychiatry.
2002;
7 (4)
405-411
-
29 Lewis C M, Levinson D F, Wise L H, DeLisi L E, Straub R E, Hovatta I, Williams N M, Schwab S G, Pulver A E, Faraone S V, Brzustowicz L M, Kaufmann C A, Garver D L, Gurling H M, Lindholm E, Coon H, Moises H W, Byerley W, Shaw S H, Mesen A, Sherrington R, O'Neill F A, Walsh D, Kendler K S, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O'Donovan M C, Owen M J, Wildenauer D B, Maier W, Nestadt G, Blouin J L, Antonarakis S E, Mowry B J, Silverman J M, Crowe R R, Cloninger C R, Tsuang M T, Malaspina D, Harkavy-Friedman J M, Svrakic D M, Bassett A S, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T. Genome scan meta-analysis of schizophrenia and bipolar disorder. Part II: Schizophrenia. American Journal of Human Genetics Epub 2003 Jun 11 73: 34-48
-
30
Harrison P, Owen M.
Genes for schizophrenia? Recent findings and their pathophysiological implications.
Lancet.
2003;
361
417-419
-
31
McGuffin P, Tandon K, Corsico A.
Linkage and association studies of schizophrenia.
Curr Psychiatry Reports.
2203;
5
121-127
-
32
Moises H W, Zoega T, Gottesman I I.
The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.
BMC Psychiatry.
2002;
2 (1)
8
-
33
Caspi A, McClay J, Moffitt T E, Mill J, Martin J, Craig I W, Taylor A, Poulton R.
Role of genotype in the cycle of violence in maltreated children.
Science.
2002;
297 (5582)
851-854
-
34
Foley D L, Eaves L J, Wormley B, Silberg J L, Maes H H, Kuhn J, Riley B.
Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder.
Arch Gen Psychiatry.
2004;
61 (7)
738-744
-
35
Caspi A, Sugden K, Moffitt T E, Taylor A, Craig I W, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R.
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.
Science.
2003;
301 (5631)
386-389
-
36
Eley T, Sugden K, Corsico A, Gregory A, Sham P, McGuffin P, Plomin R, Craig I.
Gene-environment interaction analysis of serotonin system markers with adolescent depression.
Mol Psychiatry.
2004;
9
908-915
Prof. Peter McGuffin
Social, Genetic and Developmental Psychiatry Centre · Institute of Psychiatry London
Box PO80, De Crespigny Park, London SE5 8AF · Great Britain
