Zusammenfassung
Die hohe pathogenetische Relevanz hereditärer Faktoren bei Schizophrenien steht aufgrund
der Ergebnisse epidemiologischer Untersuchungen außer Zweifel. Bei komplexem Vererbungsmodus
bilden in der Regel mehrere Gene mit jeweils schwachem bis moderatem Effekt gemeinsam
eine individuell durchaus unterschiedliche genetische Basis zur Vulnerabilität für
Schizophrenie. Weitere organische sowie psychosoziale Faktoren spielen zusätzlich
eine individuell unterschiedliche, u. U. bedeutende Rolle in der Krankheitsentstehung,
so dass ätiopathogenetisch ein oligo-/polygenes multifaktorielles Modell angenommen
wird. An molekulargenetischen Methoden werden Kopplungs- und Assoziationsanalysen
durchgeführt. Positive Kopplungsbefunde häufen sich besonders für die Chromosomen
1q, 6p, 8p, 13q und 22q. Einzelne Mutationen, für sich genommen, tragen vermutlich
in der Mehrzahl der Fälle nur wenig zur Bandbreite schizophrener Merkmalsausprägungen
bei, Hauptgeneffekte konnten, von einzelnen Subtypen abgesehen, bislang nicht repliziert
werden. Aus der großen Zahl möglicher Kandidatengene lieferten Untersuchungen zu DRD3,
DRD2 und HTR2A zwar positive Ergebnisse, jedoch bei geringen Effektgrößen. Weniger
eindeutig ist die Befundlage für Allele von Dysbindin, Neuregulin 1, DAO, COMT, PRODH,
ZDHHC und DISC. Die Suche nach schizophrenierelevanten Mutationen wird durch die Möglichkeit
eines heterogenen Phänotyps Schizophrenie bei einheitlichem Genotyp ebenso erschwert
wie durch die Möglichkeit interindividuell homogener phänotypischer Ausprägungen bei
dahinter stehender schizophrenierelevanter Heterotypie im Genom. Mit dem Konzept der
an neurobiologischen Phänomenen orientierten Endophänotypen könnte ein direkterer
Weg beschritten werden, der von relevanten Mutationen bis hin zum Risiko für Schizophrenien
führt. Wenn neurobiologische Aspekte an die Stelle schizophrener Alienation gesetzt
werden, entstehen aber Erklärungsschwierigkeiten für diese komplexen Störungsbilder.
Schizophrene Erkrankungen bedürfen eines Erklärungsansatzes, der auch persönlichkeits-
und entwicklungspsychologische Aspekte von allem Anfang an beinhaltet, sollen nicht
Topoi schizophrenen Krankseins ausschließlich auf Loci molekulargenetischer Veränderungen
eingegrenzt werden.
Abstract
The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt
based on the findings of epidemiological studies. By means of a complex mode of transmission,
it is likely that several genes with weak to moderate effect jointly constitute a
genetic basis for a vulnerability to schizophrenia that may well vary for different
individuals. Other organic and psychosocial factors also play an individually different
- in some cases significant - role in terms of pathogenesis, as a result of which
an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics.
Molecular genetic methods consist in linkage analyses and association analyses. Positive
linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q.
By themselves, individual mutations contribute little to the range of schizophrenic
feature characteristics, it was not possible - irrespective of some subtypes - to
replicate genes of major effect. From the large number of possible candidate genes,
although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes
of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT,
PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations
is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case
of a homogeneous genotype as much as by the possibility of inter-individually homogeneous
phenotypical characteristics in case of schizophrenia-relevant heterotypy in the genome.
With the aid of the concept of endophenotypes, based on neurobiological phenomena,
it might be possible to take a more direct approach that leads from relevant mutations
to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological
aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic
diseases require an explanatory approach that also incorporates personality and developmental
psychological aspects from the outset, if the aim is not to restrict topoi of schizophrenic
disease exclusively to loci of molecular genetic changes.
Literatur
- 1
Gottesman I I, Shields J A.
A polygenic theory of schizophrenia.
Proc Nat Acad Sci (USA).
1967;
58 (11)
199-205
- 2
Maier W, Lichtermann D, Rietschel M, Held T, Falkai P, Wagner M, Schwab S.
Genetik schizophrener Störungen. Neue Konzepte und Befunde.
Nervenarzt.
1999;
70
955-969
- 3
Owen M J, Williams N M, O'Donovan M C.
The molecular genetics of schizophrenia: new findings promise new insights.
Mol Psychiatry.
2004;
9 (1)
14-27
- 4 Gottesman I I. Schizophrenia genesis: the origins of madness. New York: Freedman
1991
- 5
Luxenburger H.
Vorläufiger Bericht über psychiatrische Serienuntersuchungen an Zwillingen.
Z ges Neurol Psychiat.
1928;
116
297-326
- 6
Gottesman I I, Shields J.
Schizophrenia in twins: 16 years consecutive admissions to a psychiatric clinic.
Br J Psychiatry.
1966;
112
809-818
- 7
Fischer M.
Genetic and environmental factors in schizophrenia.
Acta Psychiatr Scand.
1973;
(Suppl 238) 49
1-158
- 8
Kringlen E.
Twins - still our best method.
Schizophr Bull.
1976;
2
429-433
- 9
Farmer A E, McGuffin P, Gottesman I I.
Twin concordance for DSM-III schizophrenia: scrutinizing the validity of the definition.
Arch Gen Psychiatry.
1987;
44
634-641
- 10
Onstad S, Skre I, Torgersen S, Kringlen E.
Twin concordance for DSM-III-R schizophrenia.
Acta Psychiatr Scand.
1991;
83
395-401
- 11
Franzek E, Beckmann H.
Die genetische Heterogenität der Schizophrenie. Ergebnisse einer systematischen Zwillingsstudie.
Nervenarzt.
1996;
67
583-594
- 12
Cannon T D, Kaprio J, Lönnqvist J, Huttunen M, Koskenvuo M.
The genetic epidemiology of schizophrenia in a Finnish twin cohort.
Arch Gen Psychiatry.
1998;
55
67-74
- 13
Cardno A G, Marshall E J, Coid B, Macdonald A M, Ribchester T R, Davies N J, Venturi P.
et al .
Heritablity estimates for psychotic disorders: the Maudsley twin psychosis series.
Arch Gen Psychiatry.
1999;
56
162-168
- 14
Fischer M.
Psychoses in the offspring of schizophrenic monozygotic twins and their normal co-twins.
Br J Psychiatry.
1971;
118 (522)
43-52
- 15
Gottesman I I, Bertelsen A.
Confirming unexpressed genotypes for schizophrenia.
Arch Gen Psychiatry.
1989;
54
465-472
- 16
McGue M, Gottesman I I.
The genetic epidemiology of schizophrenia and the design of linkage studies.
Eur Arch Psychiatry Clin Neurosci.
1991;
240
174-181
- 17 Moises H W, Gottesman I I. Genetische Risikofaktoren bei Schizophrenie. In: Helmchen
H, Henn F, Lauter H, Sartorius N (Hrsg). Psychiatrie der Gegenwart 5. Schizophrene
und Affektive Störungen. Berlin: Springer 2000: 71-88
- 18
Basset A S, Honer W G.
Evidence for anticipation in schizophrenia. Autosomes.
Brit J Psychiatry.
1992;
161
323-334
- 19
Heiden A, Willinger U, Scharfetter J, Meszaros K, Kasper S, Aschauer H N.
Anticipation in schizophrenia.
Schizophr Res.
1999;
35
25-32
- 20
DeLisi L E, Razi K, Stewart J, Relja M, Shields G, Smith A B, Wellman N. et al .
No Evidence for a Parent-of-Origin Effect Detected in the Pattern of Inheritance of
Schizophrenia.
Biol Psychiatry.
2000;
48
706-709
- 21
Heston L L.
Psychiatric disorders in foster home reared children of schizophrenic mothers.
Br J Psychiatry.
1966;
112
819-825
- 22
Rosenthal D, Wender P H, Kety S S, Schulsinger F, Welner J, Ostergaard L.
Schizophrenic offspring raised in adoptive homes.
J Psychiatr Res.
1968;
6 (Suppl. 1)
377-391
- 23
Rosenthal D, Wender P H, Kety S S, Welner J, Schulsinger F.
The adopted-away offspring of schizophrenics.
Am J Psychiatry.
1971;
128
307-311
- 24
Kety S S, Rosenthal D, Wender P H, Schulsinger F.
Mental illness in the biological and adoptive families of adopted schizophrenics.
Am J Psychiatry.
1971;
128
302-306
- 25
Kety S S, Wender P H, Jacobsen B, Ingraham L J, Jansson L, Faber B, Kinney D K.
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
442-455
- 26
Tienari P.
Interaction between genetic vulnerability and family environment: the Finnish adoptive
family study of schizophrenia.
Acta Psychiatr Scand.
1991;
84
460-465
- 27
Kendler K S, McGuire M, Gruenberg A M, O'Hare A, Spellman M, Walsh D.
Independent diagnoses of adoptees and relatives as defined by DSM-III in the provinicial
and national samples of the Danish adoption study of schizophrenia.
Arch Gen Psychiatry.
1994;
151
27-43
- 28
Kendler K S, Diehl S R.
The genetics of schizophrenia: a current, genetic-epidemiologic perspective.
Schizophr Bull.
1993;
19
261-285
- 29
Kirov G, O'Donovan M C, Owen M J.
Finding schizophrenia genes.
J Clin Invest.
2005;
115
1440-1448
- 30
Brustowicz L M, Hodgkinson K A, Chow E W, Honer W G, Basset A S.
Location of a major susceptibility locus for familial schizophrenia on chromosome
1q21-q22.
Science.
2000;
288
678-682
- 31
Straub R E, Maclean C J, O'Neill F A, Burke J, Murphy B, Duke F, Shinkwin R. et al
.
A potential vulnerability locus for schizophrenia on chromosome 6p24 - 22 - evidence
for genetic heterogeneity.
Nat Genet.
1995;
11
287-293
- 32
Blouin J L, Dombroki B A, Nath S K, Lasseter V K, Wolyniec P S, Nestadt G, Thornquist M.
et al .
Schizophrenia susceptibility loci on chromosomes 13q32 und 8p21.
Nat Genet.
1998;
20
70-73
- 33
Badner J A, Gershon E S.
Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
Mol Psychiatry.
2002;
7
405-411
- 34
Lewis C M, Levinson D F, Wise L H, DeLisi L E, Straub R E, Hovata I, Williams N M.
et al .
Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.
Am J Hum Genet.
2003;
73
34-48
- 35
Risch N.
Linkage strategies for genetically complex traits. 1. Multilocus models.
Am J Hum Genet.
1990;
46
222-228
- 36
Risch N.
Linkage strategies for genetically complex traits. II. The power of affected relative
pairs.
Am J Hum Genet.
1990;
46
229-241
- 37
Pimm J, McQuillin A, Thirumalai S, Lawrence J, Quested D, Bass N, Lamb G. et al .
The epsin 4 gene on chromosome 5 q, which encodes the clathrin-associated protein
enthoprotin, is involved in the genetic susceptibility to schizophrenia.
Am J Hum Genet.
2005;
76
902-907
- 38
Owen M J.
Molecular genetic studies of schizophrenia.
Brain Research Reviews.
2000;
31
179-186
- 39
Propping P, Nöthen M M, Körner J, Rietschel M, Maier W.
Assoziationsuntersuchungen bei psychiatrischen Erkrankungen.
Nervenarzt.
1994;
65
725-740
- 40
Jonsson E G, Flyckt L, Crocq M A, Forslund K, Mattila-Evenden M, Rylander G, Asperg M.
et al .
Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and
meta analysis.
Psychiatr Genet.
2003;
13
1-12
- 41
Glatt S J, Faraone S V, Tsuang M T.
Meta-analysis identifies an association between the dopamine D2 receptor gene and
schizophrenia.
Mol Psychiatry.
2003;
8
911-915
- 42
Abdolmaleky H M, Faranoe S V, Glatt S J, Tsuang M T.
Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor
gene and schizophrenia.
Schizophr Res.
2004;
67
53-62
- 43
Marti S B, Cichon S, Propping P, Nothen M.
Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia
or bipolar affective disorder in the German population.
Am J Med Genet.
2002;
114
46-50
- 44
Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A. et al .
Positive associations of polymorphism in the metabotropic glutamate receptor type
3 gene (GRM3) with schizophrenia.
Psychiatr Genet.
2003;
13
71-76
- 45
Straub R E, Jiang Y, MacLean C J, Ma Y, Webb B T, Myakishev M V, Harris-Kerr C. et
al .
Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin
gene, is associated with schizophrenia.
Am J Hum Genet.
2002;
71 (2)
337-348
- 46
Schwab S G, Knapp M, Mondabon S, Hallmayer J, Borrmann-Hassenbach M, Albus M, Lerer B.
et al .
Support for association of schizophrenia with genetic variation in the 6p22.3 gene,
dysbindin, in sib-pair families with linkage and in an additional sample of triad
families.
Am J Hum Genet.
2003;
72 (1)
185-190
- 47
Bogaert A van den, Schumacher J, Schulze T G, Otte A C, Ohlraun S, Kovalenko S, Becker T.
et al .
The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history
of the disease.
Am J Hum Genet.
2003;
73
1438-1443
- 48
Morris D W, McGhee K A, Schwaiger S, Scully P, Quinn J, Meagher D, Waddington J L.
et al .
No evidence for association of the dysbindin gene (DTNBP1) with schizophrenia in an
Irish population-based study.
Schizophr Res.
2003;
60
167-172
- 49
Williams N M, Norton N, Williams H, Ekholm B, Hamshere M L, Lindblom Y, Chowdari K V.
et al .
A systematic genomewide linkage study in 353 sib pairs with schizophrenia.
Am J Hum Genet.
2003;
73
1355-1367
- 50
Corvin A P, Morris D W, McGhee K, Schwaiger S, Scully P, Quinn J, Meagher D. et al
.
Confirmation and refinement of an ‘at-risk’ haplotype for schizophrenia suggests the
EST cluster, HS 97 362, as a potential susceptibility gene at the Neuregulin-1 locus.
Mol Psychiatry.
2004;
9
208-213
- 51
Hall D, Gogos J A, Karayiorgou M.
The contribution of three strong candidate schizophrenia susceptibility genes in demographically
distinct populations.
Genes Brain Behav.
2004;
3
240-248
- 52
Thiselton D L, Webb B T, Neale B M, Ribble R C, O'Neill F A, Walsh D, Riley B P, Kendler K S.
No evidence got linkage association of neuregulin-1 (NRG1) with disease in the Irish
study of high-density schizophrenia families (ISHDSF).
Mol Psychiatry.
2004;
9
777-783
- 53
Craddock N, O'Donovan M C, Owen M J.
The genetics of schizophrenia and bipolar disorder: dissecting psychosis.
J Med Genet.
2005;
42
193-204
- 54
Ivanov D, Kirov G, Norton N, Williams H J, Williams N M, Nikolov J, Tzwetkova R. et
al .
Chromosome 22q11 deletions, velo-cardio-facial syndrome and early-onset psychosis:
molecular gnetic study.
Br J Psychiatry.
2003;
183
409-413
- 55
Blackwood D H, Fordyce A, Walker M T, Clair D M, Porteous D J, Muir W J.
Schizophrenia and affective disorders - cosegregation with a translocation at chromosome
1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a
family.
Am J Hum Genet.
2001;
69
428-433
- 56
Gottesman I I, Gould T D.
The endophenotype concept in psychiatry: etymology and strategic interventions.
Am J Psychiatry.
2003;
160
636-645
A. Univ. Prof. DDr. Hans Fabisch
Universitätsklinik für Psychiatrie · Medizinische Universität Graz
Auenbruggerplatz 31
8036 Graz, Österreich
Email: hans.fabisch@meduni-graz.at
