Dataset Information

Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1.

ABSTRACT: Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness.

SUBMITTER: Chen J

PROVIDER: S-EPMC6293216 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1.

Chen Jiayu J Calhoun Vince D VD Lin Dongdong D Perrone-Bizzozero Nora I NI Bustillo Juan R JR Pearlson Godfrey D GD Potkin Steven G SG van Erp Theo G M TGM Macciardi Fabio F Ehrlich Stefan S Ho Beng-Choon BC Sponheim Scott R SR Wang Lei L Stephen Julia M JM Mayer Andrew R AR Hanlon Faith M FM Jung Rex E RE Clementz Brett A BA Keshavan Matcheri S MS Gershon Elliot S ES Sweeney John A JA Tamminga Carol A CA Andreassen Ole A OA Agartz Ingrid I Westlye Lars T LT Sui Jing J Du Yuhui Y Turner Jessica A JA Liu Jingyu J

Schizophrenia bulletin 20190101 1

Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume ...[more]

PMID: 29474680

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Project description:INTRODUCTION: Substantial heterogeneity remains across studies investigating changes in gray matter in schizophrenia. Differences in methodology, heterogeneous symptom patterns and symptom trajectories may contribute to inconsistent findings. To address this problem, we recently proposed to group patients by symptom dimensions, which map on the language, the limbic and the motor systems. The aim of the present study was to investigate whether patients with prevalent symptoms of emotional dysregulation would show structural neuronal abnormalities in the limbic system. METHOD: 43 right-handed medicated patients with schizophrenia were assessed with the Bern Psychopathology Scale (BPS). The patients and a control group of 34 healthy individuals underwent structural imaging at a 3T MRI scanner. Whole brain voxel-based morphometry (VBM) was compared between patient subgroups with different severity of emotional dysregulation. Group comparisons (comparison between patients with severe emotional dysregulation, patients with mild emotional dysregulation, patients with no emotional dysregulation and healthy controls) were performed using a one way ANOVA and ANCOVA respectively. RESULTS: Patients with severe emotional dysregulation had significantly decreased gray matter density in a large cluster including the right ventral striatum and the head of the caudate compared to patients without emotional dysregulation. Comparing patients with severe emotional dysregulation and healthy controls, several clusters of significant decreased GM density were detected in patients, including the right ventral striatum, head of the caudate, left hippocampus, bilateral thalamus, dorsolateral prefrontal and orbitofrontal cortex. The significant effect in the ventral striatum was lost when patients with and without emotional dysregulation were pooled and compared with controls. DISCUSSION: Decreased gray matter density in a large cluster including the right ventral striatum was associated with severe symptoms of emotional dysregulation in patients with schizophrenia. The ventral striatum is an important part of the limbic system, and was indicated to be involved in the generation of incentive salience and psychotic symptoms. Only patients with severe emotional dysregulation had decreased gray matter in several brain structures associated with emotion and reward processing compared to healthy controls. The results support the hypothesis that grouping patients according to specific clinical symptoms matched to the limbic system allows identifying patient subgroups with structural abnormalities in the limbic network.

Project description:Prior postmortem studies have shown gray matter (GM) microstructural abnormalities in schizophrenia. However, few studies to date have examined GM microstructural integrity in schizophrenia in vivo. Here, we employed diffusion kurtosis imaging (DKI) to test for differences in GM microstructure in eighteen schizophrenia (SZ) patients versus nineteen healthy controls (HC). GM microstructure was characterized in each participant using DKI-derived metrics of mean kurtosis (MK) and mean diffusivity (MD). Individual T1-weighted images were used to create subject-specific cortically-labelled regions of interest (ROIs) of the four cortical lobes and sixty-eight cortical GM regions delineated by the Desikan-Killiany atlas, and to derive the associated cortical thickness and area measures. The derived ROIs were also registered to the diffusion space of each subject and used to generate region-specific mean MK and MD values. We additionally administered the Wisconsin Card Sorting Test (WCST), Stroop test, and Trail Making Test part B (Trails-B) to test the relationship between GM metrics and executive function in SZ. We found significantly increased MK and MD in SZ compared to HC participants in the temporal lobe, sub-lobar temporal cortical regions (fusiform, inferior temporal, middle temporal and temporal pole), and posterior cingulate cortex after correcting for multiple comparisons. Correlational analyses revealed significant associations of MK and MD with executive function scores derived from the WCST, Stroop, and Trails-B tests, along with an inverse relationship between MK and MD and cortical thickness and area. A hierarchical multiple linear regression analysis showed that up to 85% of the inter-subject variability in cognitive function in schizophrenia measured by the WCST could be explained by MK in combination with either GM thickness or area. MK and MD appear to be sensitive to GM microstructural pathology in schizophrenia and may provide useful biomarkers of abnormal cortical microstructure in this disorder.

Project description:A failure of adaptive inference-misinterpreting available sensory information for appropriate perception and action-is at the heart of clinical manifestations of schizophrenia, implicating key subcortical structures in the brain including the hippocampus. We used high-resolution, three-dimensional (3D) fractal geometry analysis to study subtle and potentially biologically relevant structural alterations (in the geometry of protrusions, gyri and indentations, sulci) in subcortical gray matter (GM) in patients with schizophrenia relative to healthy individuals. In particular, we focus on utilizing Fractal Dimension (FD), a compact shape descriptor that can be computed using inputs with irregular (i.e., not necessarily smooth) surfaces in order to quantify complexity (of geometrical properties and configurations of structures across spatial scales) of subcortical GM in this disorder. Probabilistic (entropy-based) information FD was computed based on the box-counting approach for each of the seven subcortical structures, bilaterally, as well as the brainstem from high-resolution magnetic resonance (MR) images in chronic patients with schizophrenia (n = 19) and age-matched healthy controls (n = 19) (age ranges: patients, 22.7-54.3 and healthy controls, 24.9-51.6 years old). We found a significant reduction of FD in the left hippocampus (median: 2.1460, range: 2.07-2.18 vs. median: 2.1730, range: 2.15-2.23, p<0.001; Cohen's effect size, U3 = 0.8158 (95% Confidence Intervals, CIs: 0.6316, 1.0)), the right hippocampus (median: 2.1430, range: 2.05-2.19 vs. median: 2.1760, range: 2.12-2.21, p = 0.004; U3 = 0.8421 (CIs: 0.5263, 1)), as well as left thalamus (median: 2.4230, range: 2.40-2.44, p = 0.005; U3 = 0.7895 (CIs: 0.5789, 0.9473)) in schizophrenia patients, relative to healthy individuals. Our findings provide in-vivo quantitative evidence for reduced surface complexity of hippocampus, with reduced FD indicating a less complex, less regular GM surface detected in schizophrenia.

Dataset Information

Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1.

Publications

Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1.

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