Association Between a Functional Catechol O-Methyltransferase Gene Polymorphism and Schizophrenia: Meta-Analysis of Case-Control and Family-Based Studies
Glatt SJ, Faraone SV and Tsuang MT;
Commented by , 30 Mar 2003
Aim of the study
There is strong evidence that schizophrenia is in part a genetic disorder. Relatives of patients with schizophrenia are at higher risk of developing the disorder than the general population, and this risk is correlated with the degree of kinship to the individual with schizophrenia.
However, efforts to identify susceptibility genes have been largely unsuccessful. One reason for this is that probably many genes combine to cause the disorder and that each confers only a small degree of risk.
One major target of genetic research has been the gene for catechol O-methyltransferase (COMT) because it codes for one of the major enzymes catalyzing the metabolism of dopamine. However, the results of individual studies were equivocal. Genetic research requires high case numbers, but many of the individual studies were rather small.
Meta-analysis is a method to statistically combine the results of individual trials to increase statistical power. The authors used this method to re-evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia.
Method
Relevant case-control and family-based association studies were searched for in the electronic database MEDLINE using the search terms “schizophrenia” and “COMT”. The results of the studies were combined in a meta-analysis using odds ratios as an effect size measure and a random effects model. Study heterogeneity was analysed with a chi-square test and publication bias was analysed with a funnel-plot method.
Results
14 case-control studies and 5 family-based association studies were found. In the overall analysis of the case-control studies there was no statistically significant association between COMT alleles and schizophrenia. The family-based studies showed only modest evidence that the Val allele is associated with schizophrenia risk.
However, the results of the single studies were statistically significantly heterogeneous and this heterogeneity was due to the ethnicity of the sample. When studies with only European samples were analysed, there was a significant association between Val allele and schizophrenia risk in both case-control and family-based studies.
Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association.
Discussion
Although the results of several studies were pooled and thus statistical power increased, overall there was no statistically significant association between COMT genes and the risk for schizophrenia.
However, a more differentiated analysis suggested that the Val allele of COMT might be a small but reliable risk factor for schizophrenia for people of European ancestry, whereas the influence of this polymorphism on risk in Asian populations remained unclear.
Other factors such as age, gender and the overrepresentation of violent patients or schizoaffective patients in some studies did not have any obvious effects on the results.
It is thus possible that different COMT alleles confer risk to different ethnic groups or that the COMT genotype is a universal risk factor of such small magnitude that its attributable fraction in the Asian population is negligible.
Given the methodological superiority of family-based approaches, the authors suggest that in the future family-based studies should be undertaken to confirm the association between COMT and schizophrenia.