MET 158 VARIANT OF THE CATECHOL-O-METHYLTRANSFERASE GENOTYPE IS ASSOCIATED WITH THICKER CORTEX IN ADULT BRAIN A. CERASA, a,b * A. CHERUBINI, c A. QUATTRONE, a,d M. C. GIOIA, a,b P. TARANTINO, b G. ANNESI, b F. ASSOGNA, c C. CALTAGIRONE c,e AND G. SPALLETTA c a Neuroimaging Research Unit, Institute of Neurological Sciences, Na- tional Research Council, Catanzaro, Italy b Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy c IRCCS Santa Lucia Foundation, Rome, Italy d Institute of Neurology, University “Magna Graecia,” Catanzaro, Italy e Department of Neuroscience, “Tor Vergata” University, Rome, Italy Abstract—Cortical thickness has been proposed as a new promising brain imaging endophenotype in elucidating the nature of gene– brain relationships. Here, we define the mor- phological impact of the Val 158 Met polymorphism in the cat- echol-O-methyltransferase (COMT) gene on human brain anatomy. One hundred and forty-nine adult healthy subjects (mean age: 40.716.1; ranging from 19 to 76 years) were genotyped (38 in the homozygous Val 158 group; 80 in the Val 158 Met group; 31 in the homozygous Met 158 group) for the COMT polymorphism and underwent morphological exami- nation. Surface-based analysis of the cortical mantle showed that the COMT genotype was associated with structural dif- ferences in the right superior temporal sulcus and inferior prefrontal sulcus, where the individuals carrying the Met 158 allele had a thicker cortex with respect to their Val 158 coun- terparts. Our study extends the previous evidence found on pediatric population to the adult population, demonstrating that the higher synaptic dopamine levels associated with the presence of the Met 158 allele may influence neuronal archi- tecture in brain structures important for executive and emo- tional processing. © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: COMT Val 158 Met polymorphism, cortical thick- ness, superior temporal sulcus, inferior prefrontal sulcus, imaging genetics. Imaging genetics is an emerging area of neuroscience that is proving to be effective in delineating genetic effects on individual differences in brain function/structure and on human behavior. There are few genetic polymorphisms that have demonstrated having an effect either at an inter- mediate phenotypic level (brain function and structure) and at a phenotypic level (gene-cognitive function or gene- behavioral disorder relationships). One of the most impor- tant genotypes investigated in the imaging genetics field is the Val 158 Met polymorphism (known as rs4680) of the catechol-O-methyltransferase (COMT) gene. Regulation of dopamine signaling and neurotransmission in the cortex is critically affected by COMT (Matsumoto et al., 2003), which inactivates via methylation dopamine and other cat- echolamines. COMT is widely expressed in the hippocam- pus and the prefrontal cortex (PFC) (Matsumoto et al., 2003). Of particular interest is a functional single nucleo- tide polymorphism (SNP) of the COMT gene that produces an amino acid substitution of methionine (Met) to valine (Val) at codon 158 (Val 158 Met)(Mannisto and Kaakkola, 1999), which affects dopamine regulation in the PFC (Pal- matier et al., 1999). This polymorphism alters the stability of the enzyme activity. The Met 158 allele has been asso- ciated with decreased COMT activity, resulting in higher extracellular dopamine levels, whereas the Val 158 allele has been associated with increased COMT activity, result- ing in lower synaptic levels (Lotta et al., 1995; Weinberger et al., 2001; Chen et al., 2004). Several studies have demonstrated that the Met 158 allele improves cognitive performance, compared to the Val 158 allele (Bruder et al., 2005; Egan et al., 2001; Mattay et al., 2003; Goldberg et al., 2003), resulting in a better cortical efficiency of prefron- tal activity as assessed by functional magnetic resonance technique (fMRI) (Egan et al., 2001; Mattay et al., 2003). However, despite this polymorphism being consistently linked with the measurement of brain activity, earlier data on its association with brain morphology have been con- flicting (Ohnishi et al., 2006; Taylor et al., 2007; Cerasa et al., 2008; Honea et al., 2009; Mechelli et al., 2009). Re- cently, by using an in vivo measurement of cortical thick- ness to define possible genetic factors that influence anat- omy in the human pediatric brain, Shaw et al. (2009) showed that the Val 158 Met polymorphism has a specific impact on the temporal and prefrontal cortices. In particu- lar, these authors demonstrated that the carriers of the Met 158 allele had thicker cortex with respect to their Val 158 counterparts. The aim of this study is to define, by using cortical thickness measurement, the morphological effect of the COMT genotype on a large cohort of healthy adults, in order to extend the work from Shaw et al. (2009) by adding new evidence on the genetically driven morphological vari- ations in the brain throughout the course of a human lifetime. *Correspondence to: A. Cerasa, Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, 87050, Cosenza, Italy. Tel: +39-0984-9801270; fax: +39-0984-969306. E-mail address: a.cerasa@isn.cnr.it (A. Cerasa). Abbreviations: BDNF, brain derived neurotrophic factor; COMT, cate- chol-O-methyltransferase; fMRI, functional magnetic resonance imag- ing; GLM, general linear model; Met, methionine; MMSE, Mini Mental State Examination; PCR, polymerase chain reaction; PET, positron emission tomography; SNP, single nucleotide polymorphism; Val, va- line. Neuroscience 167 (2010) 809 – 814 0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2010.02.040 809