Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder

Background: Obsessive-compulsive disorder (OCD) is a common and severe psyc hiatric illness that affects 1-3% of the population and presents a well-est ablished comorbidity with major depressive disorder (MDD). Twin and family studies have suggested a generic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implica tes both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-m ethyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA) , another gene modulating monoamine metabolism. Methods: A sample of 110 nuclear OCD families was collected and lifetime di agnoses,were ascertained using the Diagnostic interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO gene s, and allele inheritance was examined using the Transmission Disequilibriu m Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) rest. Results: We provide evidence supporting the previously reported sexually di morphic association between low COMT enzymatic activity and OCD. We also pr ovide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic acti vity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD pro bands with co-morbid MDD, who represent more than 50% of our male OCD sampl e. Conclusions: Our analysis indicates that variants of two genes modulating m onoamine metabolism contribute significantly to OCD susceptibility. Most im portantly, an unexpected sexually dimorphic pattern of genetic susceptibili ty to OCD is revealed and suggests the possibility that profound gender dif ferences in genetic predisposition may exist not only for other OCD suscept ibility genes, but for an array of other psychiatric disorders as well. (C) 1999 Society of Biological Psychiatry.