Effects of polygenic risk of schizophrenia on interhemispheric callosal white matter integrity and frontotemporal functional connectivity in first-episode schizophrenia

Abstract Background Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported. Methods Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts. Results Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)–left inferior temporal gyrus (ITG), right IFG–left ITG, right IFG–left middle frontal gyrus (MFG), and right IFG–right MFG in the FES group. Conclusion Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

Download Full-text

S171. EFFECT OF DAOA GENETIC VARIATION ON WHITE MATTER ALTERATION IN CORPUS CALLOSUM IN PATIENTS WITH FIRST-EPISODE SCHIZOPHRENIA

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.237 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S102-S102

Author(s):

Wenjun Su ◽

Tianyuan Zhu ◽

Lihua Xu ◽

Yanyan Wei ◽

Botao Zeng ◽

...

Keyword(s):

Working Memory ◽

Genetic Variation ◽

Cognitive Function ◽

White Matter ◽

Corpus Callosum ◽

White Matter Integrity ◽

First Episode ◽

Healthy Controls ◽

Corona Radiata ◽

First Episode Schizophrenia

Abstract Background D-amino acid oxidase activator (DAOA) gene, which plays a key role in glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. In this study, we aimed to investigate whether the variation of DAOA rs2391191 could be associated with alterations in white matter integrity in first episode schizophrenia patients, and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Methods Forty-six patients with first-episode schizophrenia and forty-nine sex, age and education-matched healthy controls underwent diffusion tensor imaging (DTI) and were genotyped for SNP DAOA rs2391191. Tract-based spatial statistics (TBSS) was used to delineate the major fiber tracts that showed significant group difference. Patients underwent pathophysiological assessments using Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function assessments were performed by Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). Results Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD) mainly spreading over corpus callosum and corona radiata compared with healthy controls (FWE-corrected p<0.05). Compared with patients carrying G allele, patients with AA genotype showed lower FA in body of corpus callosum, and higher RD in genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. But there were no significant FA or RD differences between two genotype groups in healthy controls. In patients carrying G allele, mean FA values in body of corpus callosum were positively correlated with working memory, mean RD values in genu of corpus callosum were negatively associated with speed of processing, working memory and composite score of MATRICS Consensus Cognitive Battery (MCCB), whilst there were no significant correlations found in AA homozygotes. Discussion Abnormal white matter integrity in corpus callosum and corona radiata were replicated among our sample of first episode schizophrenia. Genetic variation of DAOA rs2391191 was associated with this abnormality, with AA homozygotes showing less white matter integrity in corpus callosum. Our findings also suggested that rs2391191influenced the association between white matter integrity and cognitive function of schizophrenia patients. Such results might be due to the process of glutamatergic neurotransmission and mitochondrial function DAOA involves in as pinpointed by previous in vitro studies.

Download Full-text

DNA Methylation Basis in the Effect of White Matter Integrity Deficits on Cognitive Impairments and Psychopathological Symptoms in Drug-Naive First-Episode Schizophrenia

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.777407 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaofen Zong ◽

Qinran Zhang ◽

Changchun He ◽

Xinyue Huang ◽

Jiangbo Zhang ◽

...

Keyword(s):

Dna Methylation ◽

White Matter ◽

Cognitive Impairments ◽

Digit Span ◽

Critical Role ◽

Anterior Cingulate ◽

White Matter Integrity ◽

First Episode ◽

Brain White Matter ◽

First Episode Schizophrenia

Background: Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. However, few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits.Methods: We performed DTI scans in 42 treatment-naïve first-episode schizophrenia patients and 38 healthy controls. Voxel-based method of fractional anisotropy (FA) derived from DTI was used to assess WM integrity. Participants' peripheral blood genomic DNAm status, quantified by using Infinium® Human Methylation 450K BeadChip, was examined in parallel with DTI scanning. Participants completed Digit Span test and Trail Making test, as well as Positive and Negative Syndrome Scale measurement. We acquired genes that are differentially expressed in the brain regions with abnormal FA values according to the Allen anatomically comprehensive atlas, obtained DNAm levels of the corresponding genes, and then performed Z-test to compare the differential epigenetic-imaging associations (DEIAs) between the two groups.Results: Significant decreases of FA values in the patient group were in the right middle temporal lobe WM, right cuneus WM, right anterior cingulate WM, and right inferior parietal lobe WM, while the significant increases were in the bilateral middle cingulate WM (Ps < 0.01, GRF correction). Abnormal FA values were correlated with patients' clinical symptoms and cognitive impairments. In the DEIAs, patients showed abnormal couple patterns between altered FA and DNAm components, for which the enriched biological processes and pathways could be largely grouped into three biological procedures: the neurocognition, immune, and nervous system.Conclusion: Schizophrenia may not cause widespread neuropathological changes, but subtle alterations affecting local cingulum WM, which may play a critical role in positive symptoms and cognitive impairments. This imaging-epigenetics study revealed for the first time that DNAm of genes enriched in neuronal, immunologic, and cognitive processes may serve as the basis in the effect of WM deficits on clinical behaviors in schizophrenia.

Download Full-text

Pretreatment abnormalities in white matter integrity predict one-year clinical outcome in first episode schizophrenia

Schizophrenia Research ◽

10.1016/j.schres.2020.12.011 ◽

2021 ◽

Vol 228 ◽

pp. 241-248

Author(s):

Jiaxin Zeng ◽

Wenjing Zhang ◽

Yuan Xiao ◽

Gui Fu ◽

Lu Liu ◽

...

Keyword(s):

White Matter ◽

Clinical Outcome ◽

White Matter Integrity ◽

First Episode ◽

One Year ◽

First Episode Schizophrenia

Download Full-text

POLYGENIC RISK SCORE ANALYSES OF SYMPTOMS AND TREATMENT RESPONSE IN A FIRST EPISODE SCHIZOPHRENIA COHORT

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2017.08.159 ◽

2019 ◽

Vol 29 ◽

pp. S869

Author(s):

Marcos Santoro ◽

Vanessa Ota ◽

Simone de Jong ◽

Cristiano Noto ◽

Fernanda Talarico ◽

...

Keyword(s):

Treatment Response ◽

Risk Score ◽

First Episode ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

First Episode Schizophrenia

Download Full-text

Polygenic effects of schizophrenia on hippocampal grey matter volume and hippocampus–medial prefrontal cortex functional connectivity

The British Journal of Psychiatry ◽

10.1192/bjp.2019.127 ◽

2019 ◽

Vol 216 (5) ◽

pp. 267-274 ◽

Cited By ~ 2

Author(s):

Shu Liu ◽

Ang Li ◽

Yong Liu ◽

Hao Yan ◽

Meng Wang ◽

...

Keyword(s):

Prefrontal Cortex ◽

Functional Connectivity ◽

Medial Prefrontal Cortex ◽

Grey Matter ◽

Grey Matter Volume ◽

Polygenic Risk Score ◽

Polygenic Inheritance ◽

Polygenic Risk ◽

Matter Volume ◽

A Genome

BackgroundSchizophrenia is a complex mental disorder with high heritability and polygenic inheritance. Multimodal neuroimaging studies have also indicated that abnormalities of brain structure and function are a plausible neurobiological characterisation of schizophrenia. However, the polygenic effects of schizophrenia on these imaging endophenotypes have not yet been fully elucidated.AimsTo investigate the effects of polygenic risk for schizophrenia on the brain grey matter volume and functional connectivity, which are disrupted in schizophrenia.MethodGenomic and neuroimaging data from a large sample of Han Chinese patients with schizophrenia (N = 509) and healthy controls (N = 502) were included in this study. We examined grey matter volume and functional connectivity via structural and functional magnetic resonance imaging, respectively. Using the data from a recent meta-analysis of a genome-wide association study that comprised a large number of Chinese people, we calculated a polygenic risk score (PGRS) for each participant.ResultsThe imaging genetic analysis revealed that the individual PGRS showed a significantly negative correlation with the hippocampal grey matter volume and hippocampus–medial prefrontal cortex functional connectivity, both of which were lower in the people with schizophrenia than in the controls. We also found that the observed neuroimaging measures showed weak but similar changes in unaffected first-degree relatives of patients with schizophrenia.ConclusionsThese findings suggested that genetically influenced brain grey matter volume and functional connectivity may provide important clues for understanding the pathological mechanisms of schizophrenia and for the early diagnosis of schizophrenia.

Download Full-text

Reduced white matter integrity and facial emotion perception in never-medicated patients with first-episode schizophrenia: A diffusion tensor imaging study

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2017.03.025 ◽

2017 ◽

Vol 77 ◽

pp. 57-64 ◽

Cited By ~ 1

Author(s):

Xiaoxin Zhao ◽

Yuxiu Sui ◽

Jingjing Yao ◽

Yiding Lv ◽

Xinyue Zhang ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Diffusion Tensor ◽

Imaging Study ◽

Facial Emotion ◽

White Matter Integrity ◽

First Episode ◽

First Episode Schizophrenia ◽

Diffusion Tensor Imaging Study ◽

Facial Emotion Perception

Download Full-text

Classification of first-episode schizophrenia spectrum disorders and controls from whole brain white matter fractional anisotropy using machine learning

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.2122 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S191-S191 ◽

Cited By ~ 1

Author(s):

P. Mikolas ◽

J. Hlinka ◽

Z. Pitra ◽

A. Skoch ◽

T. Frodl ◽

...

Keyword(s):

Machine Learning ◽

White Matter ◽

Fractional Anisotropy ◽

Classification Performance ◽

Classification Model ◽

First Episode ◽

Support Vector ◽

Brain White Matter ◽

First Episode Schizophrenia

BackgroundSchizophrenia is a chronic disorder with an early onset and high disease burden in terms of life disability. Its early recognition may delay the resulting brain structural/functional alterations and improve treatment outcomes. Unlike conventional group-statistics, machine-learning techniques made it possible to classify patients and controls based on the disease patterns on an individual level. Diagnostic classification in first-episode schizophrenia to date was mostly performed on sMRI or fMRI data. DTI modalities have not gained comparable attention.MethodsWe performed the classification of 77 FES patients and 77 healthy controls matched by age and sex from fractional anisotropy data from using linear support-vector machine (SVM). We further analyzed the effect of medication and symptoms on the classification performance using standard statistical measures (t-test, linear regression) and machine learning (Kernel–Ridge regression).ResultsThe SVM distinguished between patients and controls with significant accuracy of 62.34% (P = 0.005). There was no association between the classification performance and medication nor symptoms. Group level statistical analysis yielded brain-wide significant differences in FA.ConclusionThe SVM in combination with brain white-matter fractional anisotropy might help differentiate FES from HC. The performance of our classification model was not associated with symptoms or medications and therefore reflects trait markers in the early course of the disease.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Download Full-text