COMT and Schizophrenia Research

Professor Daniel Weinberger discusses evidence from a number of areas of research that marks COMT as a candidate gene for schizophrenia.

Is there evidence that COMT plays a role in schizophrenia? There are two pieces of evidence that COMT is a player in the development of schizophrenia. The first is the genetic evidence. So the genetic evidence is - is COMT found in the human genome on one of the twenty-three pairs of chromosomes in a place where there seems to be a genetic signal related to schizophrenia? COMT is found in a region of the twenty-second chromosome identified by the bands that paint the chromosomes as the 22q11 region. This region of the human genome is a region that in family studies, so called genetic linkage studies, has shown evidence of harboring schizophrenia genes. The other thing that’s made COMT a candidate is that region of the twenty-second chromosome is a region that is, in about one out of every 4000 human births, deleted. There is a mistake made in the duplication of this part of the genome during the creation of sperms and eggs and it leads to a deletion. And in that deleted region is COMT. And that deleted region produces, in individuals who have the deletion, about a 30-fold increase in the likelihood of having schizophrenia. So, there’s reason to believe COMT is involved in schizophrenia by virtue of where COMT is located in the genome. Another reason that COMT is implicated as a risk gene for schizophrenia is about its function. And the function of COMT is to affect dopamine, which is an important chemical in schizophrenia. But to make it even more tantalizing, because COMT is expressed primarily in the prefrontal cortex and the hippocampus, COMT affects dopamine in these specific regions, which are also at the biological level implicated in schizophrenia. Now the third piece of evidence is the evidence that COMT itself predicts schizophrenia in individuals. The way those studies are done is to look for a variation in the gene and to see whether any one variation is more frequently found in schizophrenics. This has been the least compelling evidence for COMT. But there is weak, though I would have to say inconclusive, evidence from the so-called genetic association approach implicating COMT. From the biological approach, and from the approach of where it is in the genome, the evidence is much more compelling. From the approach of simply looking at whether one form of the gene or another is more likely to be found in schizophrenics or not, that has been a more problematic result.