Effects of DTNBP1 genotype on brain development in children Stefania Tognin, 1 Essi Viding, 2,3 Eamon J. McCrory, 3 Lauren Taylor, 1 Michael C. O’Donovan, 4 Philip McGuire, 1 and Andrea Mechelli 1 1 Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London; 2 Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London; 3 Division of Psychology and Language Sciences, University College London, London; 4 Department of Clinical Neuroscience, Division of Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff, UK Background: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly understood. The present investigation examined for the first time the effects of DTNBP1 on brain structure in children. Our hypothesis was that a genetic variation in DTNBP1 (i.e., the single nucleotide polymorphism rs2619538) would be associated with differences in both gray and white matter brain regions previously implicated in schizophrenia. Methods: Magnetic resonance imaging and voxel-based morphometry were used to examine brain structure in 52 male children aged between 10 and 12 years. Statistical inferences on the effects of DTNBP1 genotype on gray and white matter volume (GMV and WMV) were made at p < .05 after family-wise error correction for multiple comparisons across the whole brain. Results: Individuals homozygous for the schizophrenia high-risk allele (AA) compared with those homozygous for the low-risk allele (TT) expressed reduced GMV in the left anterior cingulate gyrus and reduced WMV in the left medial frontal area. Conclu- sions: Our results suggest that genetic variation in DTNBP1 is associated with differences in gray and white matter; and that these effects are already evident in children as young as 10–12 years. These findings are consistent with the notion that the DTNBP1 genotype influences brain development and may thereby modulate vulnerability to schizophrenia. Keywords: Dysbindin, children, vulnerability, schizophrenia, voxel-based morphometry. Background Schizophrenia is a developmental disorder with a strong genetic component (Harrison & Weinberger, 2005), such that genes are thought to increase sus- ceptibility through the disruption of typical neuro- developmental processes (Weinberger, 1987). The identification of specific susceptibility genes has been problematic because of the complexity of the phenotype and the mode of transmission com- patible with a multilocus model. However, recent association studies have provided converging evi- dence in favor of a number of positional gene linkage regions; among the candidates is the gene encoding for the dystrobrevin-binding protein 1 (DTNBP1), otherwise known as dysbindin (Owen, Craddock, & O’Donovan, 2005). Located on chromosome 6p22.3, the DTNBP1 gene has been associated with schizophrenia risk in sev- eral independent samples (Numakawa et al., 2004; van den Oord et al., 2003; Schwab et al., 2003; Tochigi et al., 2006; Van Den Bogaert et al., 2003; Williams et al., 2004). While these studies typically focused on adult participants, Gornick et al. (2005) also found an association between DTNBP1 and childhood-onset psychosis. Although the nature of DTNBP1 function in the healthy brain remains still poorly understood, a number of protein and gene expression studies have presented evidence of DTNBP1 involvement in glutamate neurotransmis- sion (Numakawa et al., 2004). For example, studies involving knock-down of endogenous DTNBP1 with small interfering RNA have shown a reduction of glutamate levels in neurons culture (Ross, Margolis, Reading, Pletnikov, & Coyle, 2006) suggesting a possible synaptic consequence for reductions in DTNBP1 levels (Numakawa et al., 2004). Given the possible association between the DTNBP1 gene and schizophrenia, it is important to elucidate how this gene may, through its influence on brain develop- ment, increase vulnerability to the disorder. Struc- tural magnetic resonance imaging (MRI) studies have revealed several abnormalities in the brain of patients with schizophrenia and individuals at high genetic risk, particularly in the lateral and medial temporal cortices, anterior cingulate gyrus, pre- frontal and parietal association cortices and thala- mus (Bearden, van Erp, Thompson, Toga, & Cannon, 2007; Ettinger et al., 2007; Narr et al., 2009). These brain regions may be affected by susceptibility genes for schizophrenia during neurodevelopment, and may serve as endophenotypes for genetic predispo- sition (Narr et al., 2002; Seidman et al., 2003). The Conflict of interest statement: No conflicts declared. Journal of Child Psychology and Psychiatry **:* (2011), pp xx–xx doi:10.1111/j.1469-7610.2011.02427.x Ó 2011 The Authors. Journal of Child Psychology and Psychiatry Ó 2011 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA