Genetic Vulnerability to Affective Psychopathology in Childhood: A Combined Voxel-Based Morphometry and Functional Magnetic Resonance Imaging Study Andrea Mechelli, Stefania Tognin, Philip K. McGuire, Diana Prata, Giuseppe Sartori, Paolo Fusar-Poli, Stephane De Brito, Ahmad R. Hariri, and Essi Viding Background: The majority of affective psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how genetic vulnerability affects brain structure and function in childhood since the vast majority of studies published so far have been conducted on adult participants. The present investigation examined for the first time the effects of catechol- O-methyltransferase (COMT) valine (val) 158 methionine (met) (val158met) polymorphism, which has been shown to moderate predispo- sition to negative mood and affective disorders, on brain structure and function in children. Methods: Voxel-based morphometry and functional magnetic resonance imaging were used to measure gray matter volume and emo- tional reactivity in 50 children aged between 10 and 12 years. We tested the hypothesis that met158 allele affects structural brain development and confers heightened reactivity within the affective frontolimbic circuit in children. Results: The met158 allele was positively associated with gray matter volume in the left hippocampal head where genotype accounted for 59% of interindividual variance. In addition, the met158 allele was positively associated with neuronal responses to fearful relative to neutral facial expressions in the right parahippocampal gyrus where genotype accounted for 14% of the interindividual variance. Conclusions: These results indicate that the met158 allele is associated with increased gray matter volume and heightened reactivity during emotional processing within the limbic system in children as young as 10 to 12 years of age. These findings are consistent with the notion that genetic factors affect brain function to moderate vulnerability to affective psychopathology from childhood. Key Words: Affective psychopathology, childhood, COMT, emo- tional processing, hippocampus S usceptibility for affective psychopathology depends on the dynamic interplay between genetic and environmental risk factors (1,2). The catechol-O-methyltransferase (COMT) valine (val) 158 methionine (met) (val158met) polymorphism has been shown to moderate predisposition to negative mood and affective disorders. In recent years, several imaging genetic studies have demonstrated the effects of this and other risk genes on brain structure and function in healthy adult participants (3). Given that very few psychiatric illnesses arise de novo in adulthood (4), it is important to extend the current imaging genetic work to include child samples. In the present investiga- tion, we used voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) to examine the effects of COMT val158met polymorphism on brain structure and emo- tional processing in children aged between 10 and 12 years. Catechol-O-methyltransferase is an enzyme that catalyzes the O-methylation of extracellular dopamine in the brain (5) and is mainly found in its membrane-bound (MB-COMT) form in postsynaptic neurons (6,7). The most abundant expression of COMT, both in terms of messenger RNA density (7,8) and enzyme activity (8,9), is found in the prefrontal cortex and the parahippocampal gyrus. The enzymatic activity of COMT is modulated by a guanine (G) to adenine (A) single nucleotide polymorphism (SNP) change (known as val158met or rs4680) in the COMT gene. This translates into a valine to methionine amino acid change in codon 158 that causes a threefold to fourfold decrease in its molecular thermostability. The alleles have been shown to be codominant with the met158 allele associated with decreased COMT activity, resulting in higher synaptic dopamine levels; the val158 allele associated with increased COMT activity, resulting in lower synaptic levels; and the heterozygote genotype (val158/met158) associated with an intermediate level of COMT activity (8). Several studies suggest that the met158 allele is advantageous for cognitive performance (10 –15) and prefrontal function (11,15–18) not only in adults but also in children (19,20). However, a series of recent studies have also implicated the met158 allele in negative mood and affective disorders, including increased levels of anxiety in women, obsessive-compulsive disorder in men, panic disorder, alcoholism, aggressiveness, bipolar affective disorder, major depression, and higher sensitiv- ity to pain (as reviewed by Drabant et al. [21]). The met158 allele has also been associated with a high level of anxiety (22) and early-onset antisocial behavior (23) in children and adolescents, although a recent investigation of emotional symptoms in chil- dren 6 to 7 years old did not find an association (24). While the impact of the val158met polymorphism on prefron- tal function has been characterized extensively in recent years, only a few functional imaging studies have explored the rela- tionship between this polymorphism and brain activation during emotional processing (21,25–27). Smolka et al. (26) reported a From the Department of Psychology (AM), Division of Psychological Medi- cine and Psychiatry (AM, ST, PKM, DP, PF-P), Social, Genetic and Devel- opmental Psychiatry Centre (DP, EV), and Forensic Mental Health Sci- ence Department (SDB), Institute of Psychiatry, King’s College London, London, United Kingdom; Department of Psychology (GS), University of Padua, Padova, Italy; Department of Psychiatry (ARH), University of Pitts- burgh, Pittsburgh, Pennsylvania; and Division of Psychology and Lan- guage Sciences (EV), University College London, London, United King- dom. Address reprint requests to Andrea Mechelli, Ph.D., PO Box 67, Institute of Psychiatry, King’s College London, 103 Denmark Hill, London, SE5 8AF, United Kingdom; E-mail: a.mechelli@iop.kcl.ac.uk. Received September 3, 2008; revised January 30, 2009; accepted January 30, 2009. BIOL PSYCHIATRY 2009;66:231–237 0006-3223/09/$36.00 doi:10.1016/j.biopsych.2009.01.033 © 2009 Society of Biological Psychiatry. 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