Please cite this article in press as: Cerasa A, et al. Morphological correlates of MAO A VNTR polymorphism: New evidence from cortical thickness measurement. Behav Brain Res (2010), doi:10.1016/j.bbr.2010.03.021 ARTICLE IN PRESS UNCORRECTED PROOF G Model BBR 6420 1–7 Behavioural Brain Research xxx (2010) xxx–xxx 1 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report 1 Morphological correlates of MAO A VNTR polymorphism: New evidence from cortical thickness measurement 2 3 Antonio Cerasa a,∗ , Andrea Cherubini d , Aldo Quattrone a,c , Maria C. Gioia a , Angela Magariello b , Maria Muglia b , Ida Manna b , Francesca Assogna d , Carlo Caltagirone d,e , Gianfranco Spalletta d 4 5 a Neuroimaging Research Unit, Institute of Neurological Sciences, National Research Council, Catanzaro, Italy 6 b Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy 7 c Institute of Neurology, University “Magna Graecia”, Catanzaro, Italy 8 d IRCCS Santa Lucia Foundation, Rome, Italy 9 e Tor Vergata” University, Dept. of Neuroscience, Rome, Italy 10 11 article info 12 13 Article history: 14 Received 21 December 2009 15 Received in revised form 24 February 2010 16 Accepted 11 March 2010 17 Available online xxx 18 Keywords: 19 MAO A VNTR genotype 20 Cortical thickness 21 Imaging genetics 22 Orbitofrontal cortex 23 abstract A functional variant in the mono-amine oxidase A (MAO A) gene has been shown to impact neural function related to cognitive and affective processing and increase risk for conduct disorders. However, whether MAO A could be a candidate gene for structural variation in the human brain remains to be clarified. This study is the first to investigate the effect of this genotype on brain morphology by measuring cortical thickness. We genotyped 59 healthy male subjects (36 carrying the MAO A High-activity allele and 23 the MAO A Low-activity allele) who underwent structural MRI at 3 T. Models of the grey-white and pial surfaces were generated for each individual’s cortices, and the distance between these two surfaces was used to compute cortical thickness within a priori regions of interest of the orbitofrontal and cingulate cortices. Surface-based analysis of the cortical mantle showed that the MAO A genotype was associated with structural differences in the orbitofrontal cortex bilaterally, where the MAO A High-activity group showed the highest cortical thickness value and the MAO A Low-activity group the lowest. Otherwise, no significant difference was detected within the cingulate cortex. Thus, we confirm the hypothesis that the MAO A genotype has a specific impact on human brain morphology. In particular, thickness measurement of the orbitofrontal cortex provides new evidence about the biological impact of the MAO A genotype on neural systems relevant to the pathophysiology of behavioural disorders. © 2010 Published by Elsevier B.V. 1. Introduction 24 Mono-amine oxidase (MAO) is a mitochondrial enzyme that 25 degrades the neurotransmitters serotonin (5-HT) and (to a lesser 26 extent) noradrenaline and dopamine [50]. There are two distinct 27 forms of the enzyme: A and B. MAO A provides the major enzymatic 28 clearing step for serotonin and norepinephrine during brain devel- 29 opment [50]. The MAO A coding gene (Xp11.4–Xp11.3) presents a 30 well-characterized variable number tandem repeat (VNTR) func- 31 tional polymorphism in the promoter region, which has two 32 Abbreviations: MAO A, mono-amine oxidase A; MRI, magnetic resonance imag- ing; VBM, voxel-based morphometry; 5-HT, serotonin; VNTR, variable number tandem repeat; ROIs, regions of interest; PUs, parcellation units; GLM, general linear model; DOSS, different offsets same slopes; DODS, different offsets different slopes; ICV, intracranial volume. ∗ Corresponding author at: 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). common alleles that selectively influence protein transcription and, 33 hence, enzymatic activity. Enzyme expression is relatively high for 34 carriers of 3.5 or 4 repeats (MAO A High) and lower for carriers of 35 2, 3 or 5 repeats (MAO A Low) [48]. 36 The presence of this functional polymorphism has stimulated 37 several studies on its association at an intermediate phenotypic 38 level (gene-brain function or gene-brain structure relationships) or 39 at phenotypic level (gene-cognitive function or gene-behavioural 40 disorder relationships). Unfortunately, major parts of this research 41 were characterized by conflicting findings. Whereas the association 42 of this genotype with antisocial behaviour in human cross-sectional 43 studies underlined the role of the MAO A High-activity allele in 44 males as a risk factor [36], population studies investigating the 45 gene-by-environment interaction defined a clear and pronounced 46 effect of the MAO A Low variant to predict conduct disorders 47 in males with adverse early experiences [6,23]. Similarly, several 48 imaging genetic studies investigating the neurofunctional correlate 49 of the MAO A VNTR polymorphism presented different interpre- 50 tations as to whether the High- or Low-activity allelic variant is 51 the risk factor. One study highlighted the under-activation of the 52 0166-4328/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.bbr.2010.03.021