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Reduced 3‐O‐methyl‐dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele

The catechol‐O‐methyltransferase (COMT) gene is considered as a candidate gene in obsessive–compulsive disorder (OCD). Specifically, the COMT low‐activity M158 allele has been suggested to be associated with OCD. However, there is no study reporting that COMT activity is decreased in OCD patients and that the decrease is mediated by the V158M polymorphism. Therefore, the purpose of our study was to assess COMT activity in OCD by measuring plasma levels of 3‐O‐methyl‐dopa (3‐OMD), which result from the methylation of levodopa by COMT, and to investigate the relationship between 3‐OMD levels and the V158M polymorphism. We also examined whether 3‐OMD levels represented an endophenotype, associated with the genetic liability to OCD, by assessing unaffected relatives of OCD patients. We assessed plasma 3‐OMD levels in a sample of drug‐free OCD probands (n = 34) and their unaffected parents (n = 63), and compared them with controls (n = 85). The COMT V158M polymorphism was genotyped in all participants. Lower plasma 3‐OMD levels were found in OCD probands and their unaffected parents compared to controls. The COMT M158 allele was associated with reduced plasma 3‐OMD levels in a co‐dominant manner, both in OCD probands and their relatives, but not in controls. Our results suggest that COMT activity could act as a limiting factor for the production of 3‐OMD in OCD patients and in their relatives. These findings further support a role of COMT in the susceptibility to OCD and provide evidence that 3‐OMD levels could represent an endophenotype in OCD. © 2009 Wiley‐Liss, Inc.