We recently identified a gene predisposing to OCD (PNAS 1997; 94: 4572-4575).The gene for Catechol-O-methyltransferase (COMT) is involved in the inactivation of catecholamines including the neurotransmitter dopamine, and maps to the 22q11 region. It is frequently deleted in patients with 22q11 microdeletions. There are reports that patients with these microdeletions frequently manifest with OCD (among other psychiatric phenotypes), providing evidence that the 22q11 locus harbors gene(s) predisposing to OCD. Although serotonin reuptake inhibitors (SSRIs) are the first-line pharmacotherapy for OCD, complete relief of symptoms is rare, and addition of dopamine antagonists in the therapeutic regimen appears to be useful for a subset of OCD patients, thus implicating involvement of dopaminergic pathways as well in the illness.

COMT therefore because of its function and genomic location represents an attractive candidate gene for OCD.  We recently addressed the role of the COMT gene in the genetic predisposition to OCD.  We show that a common functional allele of this gene (Met at codon 158) which results in a three-to-four-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males [p=0.0002 for genotypes and alleles; approximate relative risk for Met/Met versus non-Met/Met 5.91 (2.40-14.53)].  The mechanism underlying this sex-selective association remains to be defined, and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point.

We are expanding our work to identify additional genes predisposing to OCD. Our goal is to

• understand the mode of function of COMT, and any additional genes we may identify
• understand the mode of dysfunction in disease. This effort will hopefully lead to better treatments and early intervention.