A highly significant association between a COMT haplotype and schizophrenia
Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, et al.;
Commented by , 22 Nov 2002
Aim of the study
Schizophrenia, like most psychiatric disorders, is a complex disease that cannot be explained by a single gene or a single environmental factor. Linkage studies have provided some evidence for a number of schizophrenia susceptibility loci, but there has been little success in the replication of the findings.
One enzyme which has been placed in the limelight as a candidate gene for schizophrenia is the catechol-O-methyltransferase (COMT). One reason for this is that COMT is one of the key enzymes in the metabolism of catecholamine neurotransmitters, including dopamine.
Another reason is the microdeletion on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia.
Previous linkage and association analyses about the COMT gene as a candidate risk factor for schizophrenia have failed to produce any conclusive result. Since this was partly due to methodological problems, the authors tested the association of COMT with schizophrenia by applying a more powerful approach.
Method
The authors screened the inpatients from seven medical centers in Israel to identify Ashkenazi Jews, a well-defined homogeneous population, with schizophrenia and included them in the study. All four grandparents of each subject had to be of Ashkenazi Jewish ethnic origin and diagnosis was confirmed using SCID and DSM-IV.
An attempt was made to include a large sample size - the present study is the largest case-control study performed to date in schizophrenia. The authors used a stepwise procedure in which several single nucleotide polymorphisms (SNPs) were scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs.
The results were compared with samples of healthy Ashkenazi individuals collected from volunteers in blood banks and with Ashkenazi patients with other diseases (diabetes mellitus, prostate cancer, asthma and colon cancer).
Results
Blood from more than 4000 subjects were analysed. The authors found a highly statistically significant association between schizophrenia and a COMT haplotype (P=9.5x10-8).
Discussion
This study used a sounder approach in order to identify an association between COMT polymorphisms and schizophrenia than previous works. A large sample was examined and only subjects from a relatively well-defined, homogeneous ethnic group (Ashkenazi Jews) were included.
This may have contributed to the unprecedented level of statistical significance achieved in the present study, because homogeneous populations increase gene effect and reduce the chance of false positive findings due to population stratification.
A shortcoming is the rather limited description and the limited matching of the control subjects. Furthermore, the results suggested a sex-specific genetic component which requires further explanation. Finally, the exact pathophysiological mechanism behind the association of a COMT-haplotype with the development of schizophrenia is unclear.