Molecular Genetic Association Studies with Candidate Genes for Schizophrenia

Summary

Genetic factors have been implicated in the pathophysiology of schizophrenia. With the advent of molecular genetic techniques it has been possible to investigate differences in the genome to elucidate the genetic contributions to the disease. In complex disorders, such as schizophrenia, which result from the interaction of various vulnerability genes and non genetic factors, association studies are the most efficient strategy to explore the putative contribution at candidate gene loci. From previous research, a number of potential candidate genes are suggested, e.g. genes involved in the dopamine transmission and neurodevelopment of the brain. Patients with schizophrenia and control subjects will be analyzed with regard to potential candidate genes. When techniques have evolved the material will also be analyzed with evenly spaced markers throughout the genome. This research may give help in identifying genes contributing to schizophrenia.

Background

Family, twin and adoption studies suggest that genetic factors play a role in the etiology of schizophrenia (Kendler and Diehl, 1993). However, no specific hereditary mechanism has yet been identified for the disease. More than a decade of worldwide molecular genetic studies of pedigrees with many members suffering from schizophrenia has passed by without a finding of any well-replicated locus. This makes it not likely that one single gene or any one of several genes is sufficient to determine disease susceptibility. Rather, data is compatible with the view that schizophrenia is a complex disorder involving many genes, all giving a small contribution to the disorder. The most efficient strategy to find genes of small effect is the association approach. Unrelated patients with schizophrenia are compared with control subjects. The alleles of unrelated subjects from the same population as well as the parental non-transmitted alleles may serve as controls. Theoretically a whole genome scan with an association sample is possible (Owen and McGuffin, 1993). The marker map must be very dense. A whole genome search would require the analysis of about 3500 markers. With the rapid evolution of new powerful techniques such a genome scan of an association sample may be practically possible within the near future (Daniels et al., 1998). However, so far the approach of using association studies has been restricted to candidate genes, i.e. genes hypothesized to be involved in the disease on the basis of knowledge of the pathogenesis. Examples of such candidate genes are those involved in dopamine signalling, expression and development, such as dopamine receptors and retinoic acid.

Project aims

To identify vulnerability genes for schizophrenia.

Methodology

Patients presently treated for schizophrenia or schizophrenia-like psychoses will be asked to take part in the study. Patients will be subjected to a structured clinical interview (SCID, SCAN). Parents or siblings of the patients and unrelated healthy subjects from the general population of the same geographical areas will be subjected to a similar psychiatric structured interview as the patients. Diagnosis will be made according to DSM-IV-criteria based on case-notes and interviews. Venous blood will be taken from all individuals into EDTA-containing tubes. After DNA isolation different candidate gene polymorphisms will be analyzed with the appropriate methods with regard to each polymorphism. Data will be analyzed with traditional statistical batteries. When a sufficient material is available data mining techniques will be used as well.

Results

An already available sample of about 130 schizophrenic patients and 200 controls has been subjected to analyses with regard to several candidate genes. For a few markers there were tentative associations with schizophrenia, although most analyses did not show any association (Jönsson et al., 1996; 1999a; 1999c; 1998). Control subjects was previously investigated for monoamine metabolites (MM) in the cerebrospinal fluid (CSF) or dopamine D2 receptor (DRD2) density in striatum. This made it possible to examine relationships between candidate genes involved in the regulation of monoamines and CSF MM (Jönsson et al., 2000; 1997). There were also relationships between some DRD2 gene polymorphisms and dopamine receptor density measured by positron emission tomography (Jönsson et al., 1999b).

References

Daniels, J., Holmans, P., Williams, N., Turic, D., McGuffin, P., Plomin, R., Owen, M.J., 1998. A simple method for analyzing microsatellite allele image patterns generated from DNA pools and its application to allelic association studies. American Journal of Human Genetics 62, 1189-1197.
Jönsson, E., Brené, S., Geijer, T., Terenius, L., Tylec, A., Persson, M.-L., Sedvall, G., 1996. A search for association between schizophrenia and dopamine related alleles. European Archives of Psychiatry and Clinical Neuroscience 246, 297-304.
Jönsson, E., Norton, N., Gustavsson, J.P., Oreland, L., Owen, M.J., Sedvall, G.C., 2000. A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Journal of Psychiatric Research 34, 239-244.
Jönsson, E.G., Goldman, D., Spurlock, G., Gustavsson, J.P., Nielsen, D.A., Linnoila, M., Owen, M.J., Sedvall, G.C., 1997. Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms. Relationships to monoamine metabolite concentrations in CSF of healthy volunteers. European Archives of Psychiatry and Clinical Neuroscience 247, 297-302.
Jönsson, E.G., Nimgaonkar, V.L., Zhang, X.R., Shaw, S.H., Burgert, E., Crocq, M.-A., Chakravarti, A., Sedvall, G.C., 1999a. Trend for an association between schizophrenia and D3S1310, a marker in proximity to the dopamine D3 receptor gene. American Journal of Medical Genetics 88, 352-357.
Jönsson, E.G., Nöthen, M.M., Grünhage, F., Farde, L., Nakashima, Y., Propping, P., Sedvall, G.C., 1999b. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry 4, 290-296.
Jönsson, E.G., Nöthen, M.M., Neidt, H., Forslund, K., Rylander, G., Mattila-Evenden, M., Åsberg, M., Propping, P., Sedvall, G.C., 1999c. Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia. Schizophrenia Research 40, 31-36.
Jönsson, E.G., Zhang, F., Nimgaonkar, V.L., Rudert, W.A., Sedvall, G.C., 1998. Lack of association between schizophrenia and HLA DQB1 alleles in a Swedish sample. Schizophrenia Research 29, 293-296.
Kendler, K.S., Diehl, S.R., 1993. The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophrenia Bulletin 19, 261-285.
Owen, M.J., McGuffin, P., 1993. Association and linkage: complementary strategies for complex disorders. Journal of Medical Genetics 30, 638-639.

Project leader: Erik Jönsson