Individuals with schizophrenia show widespread cortical thickness reductions throughout the brain. the relations between GAD1 genotype and cortical thickness. Our data show a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) in G allele homozygotes of GAD1 rs3749034. When we stratified our analyses according to the COMT Val158Met genotype cortical thickness reductions of G allele homozygotes were only found in the presence of the Val allele. Genetic risk variants of schizophrenia in the GABAergic system might interact with the dopaminergic system and impact brain structure and functioning. Our findings point to the importance of the GABAergic system in the pathogenesis of schizophrenia. = 163 842) per hemisphere. The Desikan-Killiany atlas was used to assign our main obtaining to the corresponding anatomical surface labels (Desikan et al. 2006 Please find more detailed information about acquisition and processing of the sMRI data in the SM part 1.1. 2.4 Statistical analyses In line with similar studies we included age gender and acquisition site into the models as covariates (Goldman et al. 2009 Kuperberg et al. 2003 Narr et al. 2005 Salat et al. 2004 Schultz et al. 2010 All cortical thickness results were corrected for multiple comparisons using a Monte-Carlo simulation. This procedure included the following actions: (1) an initial vertex-wise threshold (VWT) was set to = 0.001 to form spatially contiguous areas of association (referred to as a “cluster”). For our exploratory analyses we used an initial VWT of = 0.05. (2) The likelihood that a obtaining (cluster) of PD 150606 this size and magnitude (difference in thickness as specified by the VWT) would appear by chance i.e. when using repeated random sampling was tested using Monte-Carlo simulation with 10 000 repeats. This resulted in cluster-wise probabilities (CWP) which are reported using < 0.05. Final statistical maps are shown around the inflated surface of the standard average subject allowing visualization of data across the entire cortical surface without interference from cortical folding. In order to control for false positive results due to populace stratification or due to brain asymmetry caused by handedness we reran all models on a sample limited to the majority ethnicity (Caucasian participants = 84) and right handed participants (= 84). In additional exploratory models we tested the effects of the GAD1 polymorphism in each COMT Val158Met genotype group (= 25 for Met/Met = 44 for Val/Met and = 25 for Val/Val carriers). 3 Results 3.1 Demographics The observed genotype PD 150606 frequency of rs3749034 did not deviate from Hardy Weinberg equilibrium (χ2 = 0 df = 1 = 0.999). Demographic variables such as age sex ethnicity parental socioeconomic status (SES) intelligence as measured by the WRAT-3 and handedness according to the Annett Handedness Scale did not differ across the GAD1 genotype groups (Table 1) and Chi-square statistics Rabbit Polyclonal to Cytochrome P450 2C8/9/18/19. did not reveal any associations between genotype group and acquisition site (χ2 = 1.843 df = 3 = 0.606). As shown in Table 2 participants from MGH were on average older than those from UI. Participants from UNM showed a lower parental SES than those from MGH and UI. Otherwise participants did not differ in gender ethnicity age WRAT-3 Score parental SES and handedness across sites. Chi square statistics did not reveal any relationship between GAD1 and COMT genotype status (χ2 = 2.52 df = 2 = 0.28). For details about relationships between the COMT Val158Met polymorphism and demographic variables please refer to SM 2.1. Table 1 Basic demographics are presented according to GAD1 rs3749034 genotype. Table 2 Basic demographics are presented for the 94 healthy volunteers included in this study according to acquisition site. PD 150606 3.2 Structural MRI Overall G allele PD 150606 homozygotes of GAD1 rs3749034 showed reduced cortical gray matter thickness in an area corresponding to the left parahippocampal gyrus (PHG) compared to A carriers (Fig.1A CWP = 0.0083). The average thickness in this cluster region of A carriers (≈ 2.82 mm) was reduced by 7.54% in G allele homozygotes (≈ 2.61 mm). In order to control for brain asymmetry due to handedness and for populace stratification we performed additional analyses restricted to right-handed and white participants. The.