Low-activity allele of Catechol-O-Methyltransferase (COMT L ) is associated with increased lateral ventricles in patients with first episode non-affective psychosis Benedicto Crespo-Facorro a, ⁎ , Roberto Roiz-Santiáñez a , José María Pelayo-Terán a , Rocío Pérez-Iglesias a , Eugenio Carrasco-Marín b , Ignacio Mata a , Andrés González-Mandly c , Ricardo Jorge d , José Luis Vázquez-Barquero a a University Hospital Marqués de Valdecilla, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain b University Hospital Marqués de Valdecilla, Department of Immunology, School of Medicine, University of Cantabria, Santander, Spain c University Hospital Marqués de Valdecilla, Department of Neuroradiology, Santander, Spain d Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA Received 8 May 2007; received in revised form 4 July 2007; accepted 4 July 2007 Available online 18 July 2007 Abstract Background: Structural brain anomalies are present at early phases of psychosis. The objective was to examine the impact of Catechol-O- Methyltransferase (COMT) gene variations on brain morphology in first-episode non-affective psychosis. We hypothesized that the low activity-COMT (COMT L ) allele would be associated with the presence of structural brain changes as assessed by quantitative magnetic resonance imaging (MRI). Methods: Fifty-two males and 23 females underwent COMT genotyping and MRI. Patients were categorized into three genetic subgroups: COMT H/H , COMT L/H and COMT L/L . MRI data were analyzed using BRAINS2. Global and lobar volumes of grey matter (GM) and cerebrospinal fluid (CSF) were compared among the three groups after controlling for total intracranial volume and age of illness onset. Results: COMT L carriers showed a significant enlargement of the lateral ventricles (F = 7.13, p = 0.009), right lateral ventricle (F = 5.99, p = 0.017) and left lateral ventricle (F = 6.22, p = 0.015). No other significant differences in any of the brain structures were found among subgroups. Conclusions: Our findings suggest that genetic variations of COMT can contribute to the enlargement of the lateral ventricles described in early phases of non-affective psychosis. © 2007 Elsevier Inc. All rights reserved. Keywords: Brain morphology; COMT; Genetic studies; Grey matter; Schizophrenia; Structural MRI 1. Introduction Schizophrenia is a common brain disorder with complex genetic basis and phenotypes. Lateral ventricular enlargement is the most consistently verified change in first episode schizo- phrenia (Vita et al., 2006). The increase of ventricular volume at an early age may reflect disturbances of neurodevelopment processes (Fannon et al., 2000) affecting contiguous frontal, temporal and thalamic structures (Gaser et al., 2004; Malla et al., 2002). Our group has recently found abnormally large lateral ventricles in a sample of minimally medicated first- episode non-affective psychotic patients (unpublished data). Heritability estimates are high for volume (Reveley, 1985) and shape (Styner et al., 2005) of the lateral ventricles. However, little has been investigated regarding the influence of specific genes on these brain abnormalities. The characterization of gene effects is a challenging strategy to identify biologically based phenotypes in complex psychiatric disorders (Meyer-Linden- berg and Weinberger, 2006). Imaging genetic studies at illness Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1514 – 1518 www.elsevier.com/locate/pnpbp Abbreviations: ANOVA, analysis of variance; COMT, Catechol-O-Methyl- transferase; CSF, cerebrospinal fluid; DUP, duration of untreated psychosis; EMBL, European Molecular Biology Laboratory; ICV, intracranial volume; GM, grey matter; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PRODH, proline dehydrogenase. ⁎ Corresponding author. Hospital Universitario Marqués de Valdecilla. Department of Psychiatry. Planta 2 a , Edificio 2 de Noviembre. Avda. Valdecilla s/n, 39008, Santander. Spain. Tel.: +34 942 202537; fax: +34 942 203447. E-mail address: bcfacorro@humv.es (B. Crespo-Facorro). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.07.011