Shared Genetic Architecture Among Gastrointestinal Diseases, Schizophrenia, and Brain Subcortical Volumes.

BACKGROUND AND HYPOTHESIS: The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear. STUDY DESIGN: Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms. STUDY RESULTS: The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes. CONCLUSIONS: These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.

Voxel-based texture similarity networks reveal individual variability and correlate with biological ontologies.

The human brain is organized as a complex, hierarchical network. However, the structural covariance patterns among brain regions and the underlying biological substrates of such covariance networks remain to be clarified. The present study proposed a novel individualized structural covariance network termed voxel-based texture similarity networks (vTSNs) based on 76 refined voxel-based textural features derived from structural magnetic resonance images. Validated in three independent longitudinal healthy cohorts (40, 23, and 60 healthy participants, respectively) with two common brain atlases, we found that the vTSN could robustly resolve inter-subject variability with high test-retest reliability. In contrast to the regional-based texture similarity networks (rTSNs) that calculate radiomic features based on region-of-interest information, vTSNs had higher inter- and intra-subject variability ratios and test-retest reliability in connectivity strength and network topological properties. Moreover, the Spearman correlation indicated a stronger association of the gene expression similarity network (GESN) with vTSNs than with rTSNs (vTSN: r = 0.600, rTSN: r = 0.433, z = 39.784, P < 0.001). Hierarchical clustering identified 3 vTSN subnets with differential association patterns with 13 coexpression modules, 16 neurotransmitters, 7 electrophysiology, 4 metabolism, and 2 large-scale structural and 4 functional organization maps. Moreover, these subnets had unique biological hierarchical organization from the subcortex-limbic system to the ventral neocortex and then to the dorsal neocortex. Based on 424 unrelated, qualified healthy subjects from the Human Connectome Project, we found that vTSNs could sensitively represent sex differences, especially for connections in the subcortex-limbic system and between the subcortex-limbic system and the ventral neocortex. Moreover, a multivariate variance component model revealed that vTSNs could explain a significant proportion of inter-subject behavioral variance in cognition (80.0 %) and motor functions (63.4 %). Finally, using 494 healthy adults (aged 19-80 years old) from the Southwest University Adult Lifespan Dataset, the Spearman correlation identified a significant association between aging and vTSN strength, especially within the subcortex-limbic system and between the subcortex-limbic system and the dorsal neocortex. In summary, our proposed vTSN is robust in uncovering individual variability and neurobiological brain processes, which can serve as biologically plausible measures for linking biological processes and human behavior.

Selective disrupted gray matter volume covariance of amygdala subregions in schizophrenia.

Objective: Although extensive structural and functional abnormalities have been reported in schizophrenia, the gray matter volume (GMV) covariance of the amygdala remain unknown. The amygdala contains several subregions with different connection patterns and functions, but it is unclear whether the GMV covariance of these subregions are selectively affected in schizophrenia. Methods: To address this issue, we compared the GMV covariance of each amygdala subregion between 807 schizophrenia patients and 845 healthy controls from 11 centers. The amygdala was segmented into nine subregions using FreeSurfer (v7.1.1), including the lateral (La), basal (Ba), accessory-basal (AB), anterior-amygdaloid-area (AAA), central (Ce), medial (Me), cortical (Co), corticoamygdaloid-transition (CAT), and paralaminar (PL) nucleus. We developed an operational combat harmonization model for 11 centers, subsequently employing a voxel-wise general linear model to investigate the differences in GMV covariance between schizophrenia patients and healthy controls across these subregions and the entire brain, while adjusting for age, sex and TIV. Results: Our findings revealed that five amygdala subregions of schizophrenia patients, including bilateral AAA, CAT, and right Ba, demonstrated significantly increased GMV covariance with the hippocampus, striatum, orbitofrontal cortex, and so on (permutation test, P< 0.05, corrected). These findings could be replicated in most centers. Rigorous correlation analysis failed to identify relationships between the altered GMV covariance with positive and negative symptom scale, duration of illness, and antipsychotic medication measure. Conclusion: Our research is the first to discover selectively impaired GMV covariance patterns of amygdala subregion in a large multicenter sample size of patients with schizophrenia.

Exploring functional dysconnectivity in schizophrenia: alterations in eigenvector centrality mapping and insights into related genes from transcriptional profiles.

Schizophrenia is a mental health disorder characterized by functional dysconnectivity. Eigenvector centrality mapping (ECM) has been employed to investigate alterations in functional connectivity in schizophrenia, yet the results lack consistency, and the genetic mechanisms underlying these changes remain unclear. In this study, whole-brain voxel-wise ECM analyses were conducted on resting-state functional magnetic resonance imaging data. A cohort of 91 patients with schizophrenia and 91 matched healthy controls were included during the discovery stage. Additionally, in the replication stage, 153 individuals with schizophrenia and 182 healthy individuals participated. Subsequently, a comprehensive analysis was performed using an independent transcriptional database derived from six postmortem healthy adult brains to explore potential genetic factors influencing the observed functional dysconnectivity, and to investigate the roles of identified genes in neural processes and pathways. The results revealed significant and reliable alterations in the ECM across multiple brain regions in schizophrenia. Specifically, there was a significant decrease in ECM in the bilateral superior and middle temporal gyrus, and an increase in the bilateral thalamus in both the discovery and replication stages. Furthermore, transcriptional analysis revealed 420 genes whose expression patterns were related to changes in ECM, and these genes were enriched mainly in biological processes associated with synaptic signaling and transmission. Together, this study enhances our knowledge of the neural processes and pathways involved in schizophrenia, shedding light on the genetic factors that may be linked to functional dysconnectivity in this disorder.

Homotopic functional connectivity disruptions in schizophrenia and their associated gene expression.

It has been revealed that abnormal voxel-mirrored homotopic connectivity (VMHC) is present in patients with schizophrenia, yet there are inconsistencies in the relevant findings. Moreover, little is known about their association with brain gene expression profiles. In this study, transcription-neuroimaging association analyses using gene expression data from Allen Human Brain Atlas and case-control VMHC differences from both the discovery (meta-analysis, including 9 studies with a total of 386 patients and 357 controls) and replication (separate group-level comparisons within two datasets, including a total of 258 patients and 287 controls) phases were performed to identify genes associated with VMHC alterations. Enrichment analyses were conducted to characterize the biological functions and specific expression of identified genes, and Neurosynth decoding analysis was performed to examine the correlation between cognitive-related processes and VMHC alterations in schizophrenia. In the discovery and replication phases, patients with schizophrenia exhibited consistent VMHC changes compared to controls, which were correlated with a series of cognitive-related processes; meta-regression analysis revealed that illness duration was negatively correlated with VMHC abnormalities in the cerebellum and postcentral/precentral gyrus. The abnormal VMHC patterns were stably correlated with 1287 genes enriched for fundamental biological processes like regulation of cell communication, nervous system development, and cell communication. In addition, these genes were overexpressed in astrocytes and immune cells, enriched in extensive cortical regions and wide developmental time windows. The present findings may contribute to a more comprehensive understanding of the molecular mechanisms underlying VMHC alterations in patients with schizophrenia.

Interaction between childhood trauma experience and TPH2 rs7305115 gene polymorphism in brain gray matter volume.

BACKGROUND: Childhood trauma is one of the most extensively studied and well-supported environmental risk factors for the development of mental health problems. The human tryptophan hydroxylase 2 (TPH2) gene is one of the most promising candidate genes in numerous psychiatric disorders. However, it is now widely acknowledged that neither genetic variation nor environmental exposure alone can fully explain all the phenotypic variance observed in psychiatric disorders. Therefore, it is necessary to consider the interaction between the two factors in psychiatric research. METHODS: We enrolled a sizable nonclinical cohort of 786 young, healthy adults who underwent structural MRI scans and completed genotyping, the Childhood Trauma Questionnaire (CTQ) and behavioural scores. We identified the interaction between childhood trauma and the TPH2 rs7305115 gene polymorphism in the gray matter volume (GMV) of specific brain subregions and the behaviour in our sample using a multiple linear regression framework. We utilized mediation effect analysis to identify environment /gene-brain-behaviour relationships. RESULTS: We found that childhood trauma and TPH2 rs7305115 interacted in both behaviour and the GMV of brain subregions. Our findings indicated that the GMV of the right posterior parietal thalamus served as a significant mediator supporting relationship between childhood trauma (measured by CTQ score) and anxiety scores in our study population, and the process was partly modulated by the TPH2 rs7305115 gene polymorphism. Moreover, we found only a main effect of childhood trauma in the GMV of the right parahippocampal gyrus area, supporting the relationship between childhood trauma and anxiety scores as a significant mediator. CONCLUSIONS: Our findings suggest that early-life trauma may have a specific and long-term structural effect on brain GMV, potentially leading to altered cognitive and emotional processes involving the parahippocampal gyrus and thalamus that may also be modulated by the TPH2 gene polymorphism. This finding highlights the importance of considering genetic factors when examining the impact of early-life experiences on brain structure and function. Gene‒environment studies can be regarded as a powerful objective supplement for targeted therapy, early diagnosis and treatment evaluation in the future.

Structural covariances of prefrontal subregions selectively associate with dopamine-related gene coexpression and schizophrenia.

Evidence highlights that dopamine (DA) system dysregulation and prefrontal cortex (PFC) dysfunction may underlie the pathophysiology of schizophrenia. However, the associations among DA genes, PFC morphometry, and schizophrenia have not yet been fully clarified. Based on the brain gene expression dataset from Allen Human Brain Atlas and structural magnetic resonance imaging data (NDIS = 1727, NREP = 408), we first identified 10 out of 22 PFC subregions whose gray matter volume (GMV) covariance profiles were reliably associated with their DA genes coexpression profiles, then four out of the identified 10 PFC subregions demonstrated abnormally increased GMV covariance with the hippocampus, insula, and medial frontal areas in schizophrenia patients (NCASE = 100; NCONTROL = 102). Moreover, based on a schizophrenia postmortem expression dataset, we found that the DA genes coexpression of schizophrenia was significantly reduced between the middle frontal gyrus and hippocampus, in which 21 DA genes showed significantly unsynchronized expression changes, and the 21 genes' brain expression were enriched in brain activity invoked by working memory, reward, speech production, and episodic memory. Our findings indicate the DA genes selectively regulate the structural covariance of PFC subregions by their coexpression profiles, which may underlie the disrupted GMV covariance and impaired cognitive functions in schizophrenia.

Gene expression associated with human brain activations in facial expression recognition.

Previous studies identified some genetic loci of emotion, but few focused on human emotion-related gene expression. In this study, the facial expression recognition (FER) task-based high-resolution fMRI data of 203 subjects in the Human Connectome Project (HCP) and expression data of the six healthy human postmortem brain tissues in the Allen Human Brain Atlas (AHBA) were used to conduct a transcriptome-neuroimaging spatial association analysis. Finally, 371 genes were identified to be significantly associated with FER-related brain activations. Enrichment analyses revealed that FER-related genes were mainly expressed in the brain, especially neurons, and might be related to cell junction organization, synaptic functions, and nervous system development regulation, indicating that FER was a complex polygenetic biological process involving multiple pathways. Moreover, these genes exhibited higher enrichment for psychiatric diseases with heavy emotion impairments. This study provided new insight into understanding the FER-related biological mechanisms and might be helpful to explore treatment methods for emotion-related psychiatric disorders.

Global urbanicity is associated with brain and behaviour in young people.

Urbanicity is a growing environmental challenge for mental health. Here, we investigate correlations of urbanicity with brain structure and function, neuropsychology and mental illness symptoms in young people from China and Europe (total n = 3,867). We developed a remote-sensing satellite measure (UrbanSat) to quantify population density at any point on Earth. UrbanSat estimates of urbanicity were correlated with brain volume, cortical surface area and brain network connectivity in the medial prefrontal cortex and cerebellum. UrbanSat was also associated with perspective-taking and depression symptoms, and this was mediated by neural variables. Urbanicity effects were greatest when urban exposure occurred in childhood for the cerebellum, and from childhood to adolescence for the prefrontal cortex. As UrbanSat can be generalized to different geographies, it may enable assessments of correlations of urbanicity with mental illness and resilience globally.

The morphometry of left cuneus mediating the genetic regulation on working memory.

Working memory is a basic human cognitive function. However, the genetic signatures and their biological pathway remain poorly understood. In the present study, we tried to clarify this issue by exploring the potential associations and pathways among genetic variants, brain morphometry and working memory performance. We first carried out association analyses between 2-back accuracy and 212 image-derived phenotypes from 1141 Human Connectome Project (HCP) subjects using a linear mixed model (LMM). We found a significantly positive correlation between the left cuneus volume and 2-back accuracy (T = 3.615, p = 3.150e-4, Cohen's d = 0.226, corrected using family-wise error [FWE] method). Based on the LMM-based genome-wide association study (GWAS) on the HCP dataset and UK Biobank 33 k GWAS summary statistics, we identified eight independent single nucleotide polymorphisms (SNPs) that were reliably associated with left cuneus volume in both UKB and HCP dataset. Within the eight SNPs, we found a negative correlation between the rs76119478 polymorphism and 2-back accuracy accuracy (T = -2.045, p = .041, Cohen's d = -0.129). Finally, an LMM-based mediation analysis elucidated a significant effect of left cuneus volume in mediating rs76119478 polymorphism on the 2-back accuracy (indirect effect = -0.007, 95% BCa CI = [-0.045, -0.003]). These results were also replicated in a subgroup of Caucasians in the HCP population. Further fine mapping demonstrated that rs76119478 maps on intergene CTD-2315A10.2 adjacent to protein-encoding gene DAAM1, and is significantly associated with L3HYPDH mRNA expression. Our study suggested this new variant rs76119478 may regulate the working memory through exerting influence on the left cuneus volume.

Brain Gene Expression Pattern Correlated with the Differential Brain Activation by Pain and Touch in Humans.

Genes involved in pain and touch sensations have been studied extensively, but very few studies have tried to link them with neural activities in the brain. Here, we aimed to identify genes preferentially correlated to painful activation patterns by linking the spatial patterns of gene expression of Allen Human Brain Atlas with the pain-elicited neural responses in the human brain, with a parallel, control analysis for identification of genes preferentially correlated to tactile activation patterns. We identified 1828 genes whose expression patterns preferentially correlated to painful activation patterns and 411 genes whose expression patterns preferentially correlated to tactile activation pattern at the cortical level. In contrast to the enrichment for astrocyte and inhibitory synaptic transmission of genes preferentially correlated to tactile activation, the genes preferentially correlated to painful activation were mainly enriched for neuron and opioid- and addiction-related pathways and showed significant overlap with pain-related genes identified in previous studies. These findings not only provide important evidence for the differential genetic architectures of specific brain activation patterns elicited by painful and tactile stimuli but also validate a new approach to studying pain- and touch-related genes more directly from the perspective of neural responses in the human brain.

Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer's disease.

Genome-wide association studies (GWASs) have identified multiple susceptibility loci for Alzheimer's disease (AD), which is characterized by early and progressive damage to the hippocampus. However, the association of hippocampal gene expression with AD and the underlying neurobiological pathways remain largely unknown. Based on the genomic and transcriptomic data of 111 hippocampal samples and the summary data of two large-scale meta-analyses of GWASs, a transcriptome-wide association study (TWAS) was performed to identify genes with significant associations between hippocampal expression and AD. We identified 54 significantly associated genes using an AD-GWAS meta-analysis of 455,258 individuals; 36 of the genes were confirmed in another AD-GWAS meta-analysis of 63,926 individuals. Fine-mapping models further prioritized 24 AD-related genes whose effects on AD were mediated by hippocampal expression, including APOE and two novel genes (PTPN9 and PCDHA4). These genes are functionally related to amyloid-beta formation, phosphorylation/dephosphorylation, neuronal apoptosis, neurogenesis and telomerase-related processes. By integrating the predicted hippocampal expression and neuroimaging data, we found that the hippocampal expression of QPCTL and ERCC2 showed significant difference between AD patients and cognitively normal elderly individuals as well as correlated with hippocampal volume. Mediation analysis further demonstrated that hippocampal volume mediated the effect of hippocampal gene expression (QPCTL and ERCC2) on AD. This study identifies two novel genes associated with AD by integrating hippocampal gene expression and genome-wide association data and reveals candidate hippocampus-mediated neurobiological pathways from gene expression to AD.

Prefrontal Granule Cell-Related Genes and Schizophrenia.

Although both the granular layer of the prefrontal cortex (PFC) and schizophrenia are unique in primates, especially humans, their linkage is unclear. Here, we tested whether schizophrenia is associated with expression profiles of the granule cell (GC)-related genes in the human PFC. We identified 14 candidate GC-related genes with gradually increased expression levels along the gradient of the agranular, dysgranular, light-granular, and granular prefrontal regions based on the densely sampled gene expression data of 6 postmortem human brains, and with more than 10-fold expression in neurons than other cell types based on the single-cell RNA-sequencing data of the human PFC. These GC-related genes were functionally associated with synaptic transmission and cell development and differentiation. The identified 14 GC-related genes were significantly enriched for schizophrenia, but not for depression and bipolar disorder. The expression levels of the 4 stable schizophrenia- and GC-related genes were spatially correlated with gray matter volume differences in the PFC between patients with schizophrenia and healthy controls. This study provides a set of candidate genes for the human prefrontal GCs and links expression profiles of the GC-related genes to the prefrontal structural impairments in schizophrenia.

Genes associated with gray matter volume alterations in schizophrenia.

Although both schizophrenia and gray matter volume (GMV) show high heritability, however, genes accounting for GMV alterations in schizophrenia remain largely unknown. Based on risk genes identified in schizophrenia by the genome-wide association study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium, we used transcription-neuroimaging association analysis to test that which of these genes are associated with GMV changes in schizophrenia. For each brain tissue sample, the expression profiles of 196 schizophrenia risk genes were extracted from six donated normal brains of the Allen Human Brain Atlas, and GMV differences between patients with schizophrenia and healthy controls were calculated based on five independent case-control structural MRI datasets (276 patients and 284 controls). Genes associated with GMV changes in schizophrenia were identified by performing cross-sample spatial correlations between expression levels of each gene and case-control GMV difference derived from the five MRI datasets integrated by harmonization and meta-analysis. We found that expression levels of 98 genes consistently showed significant cross-sample spatial correlations with GMV changes in schizophrenia. These genes were functionally enriched for chemical synaptic transmission, central nervous system development, and cell projection. Overall, this study provides a set of genes possibly associated with GMV changes in schizophrenia, which could be used as candidate genes to explore biological mechanisms underlying the structural impairments in schizophrenia.

Differential Reorganization of SMA Subregions After Stroke: A Subregional Level Resting-State Functional Connectivity Study.

Background and Purpose: The human supplementary motor area (SMA) contains two functional subregions of the SMA proper and preSMA; however, the reorganization patterns of the two SMA subregions after stroke remain uncertain. Meanwhile, a focal subcortical lesion may affect the overall functional reorganization of brain networks. We sought to identify the differential reorganization of the SMA subregions after subcortical stroke using the resting-state functional connectivity (rsFC) analysis. Methods: Resting-state functional MRI was conducted in 25 patients with chronic capsular stroke exhibiting well-recovered global motor function (Fugl-Meyer score >90). The SMA proper and preSMA were identified by the rsFC-based parcellation, and the rsFCs of each SMA subregion were compared between stroke patients and healthy controls. Results: Despite common rsFC with the fronto-insular cortex (FIC), the SMA proper and preSMA were mainly correlated with the sensorimotor areas and cognitive-related regions, respectively. In stroke patients, the SMA proper and preSMA exhibited completely different functional reorganization patterns: the former showed increased rsFCs with the primary sensorimotor area and caudal cingulate motor area (CMA) of the motor execution network, whereas the latter showed increased rsFC with the rostral CMA of the motor control network. Both of the two SMA subregions showed decreased rsFC with the FIC in stroke patients; the preSMA additionally showed decreased rsFC with the prefrontal cortex (PFC). Conclusion: Although both SMA subregions exhibit functional disconnection with the cognitive-related areas, the SMA proper is implicated in the functional reorganization within the motor execution network, whereas the preSMA is involved in the functional reorganization within the motor control network in stroke patients.

Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment.

Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer's disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer's disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer's disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein-protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer's disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer's disease.

Functional and anatomical connectivity-based parcellation of human cingulate cortex.

INTRODUCTION: Human cingulate cortex (CC) has been implicated in many functions, which is highly suggestive of the existence of functional subregions. METHODS: In this study, we used resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) to parcellate the human cingulate cortex (CC) based on resting-state functional connectivity (rsFC) patterns and anatomical connectivity (AC) patterns, to analyze the rsFC patterns and the AC patterns of different subregions, and to recognize whether the parcellation results obtained by the two different methods were consistent. RESULTS: The CC was divided into six functional subregions, including the anterior cingulate cortex, dorsal anterior midcingulate cortex, ventral anterior midcingulate cortex, posterior midcingulate cortex, dorsal posterior cingulate cortex, and ventral posterior cingulate cortex. The CC was also divided into ten anatomical subregions, termed Subregion 1 (S1) to Subregion 10 (S10). Each subregion showed specific connectivity patterns, although the functional subregions and the anatomical subregions were internally consistent. CONCLUSIONS: Using different model MRI images, we established a parcellation scheme, which is internally consistent for the human CC, which may provide an in vivo guide for subregion-level studies and improve our understanding of this brain area at subregional levels.

Combination of volume and perfusion parameters reveals different types of grey matter changes in schizophrenia.

Diverse brain structural and functional changes have been reported in schizophrenia. Identifying different types of brain changes may help to understand the neural mechanisms and to develop reliable biomarkers in schizophrenia. We aimed to categorize different grey matter changes in schizophrenia based on grey matter volume (GMV) and cerebral blood flow (CBF). Structural and perfusion magnetic resonance imaging data were acquired in 100 schizophrenia patients and 95 healthy comparison subjects. Voxel-based GMV comparison was used to show structural changes, CBF analysis was used to demonstrate functional changes. We identified three types of grey matter changes in schizophrenia: structural and functional impairments in the anterior cingulate cortex and insular cortex, displaying reduction in both GMV and CBF; structural impairment with preserved function in the frontal and temporal cortices, demonstrating decreased GMV with normal CBF; pure functional abnormality in the anterior cingulate cortex and lateral prefrontal cortex and putamen, showing altered CBF with normal GMV. By combination of GMV and CBF, we identified three types of grey matter changes in schizophrenia. These findings may help to understand the complex manifestations and to develop reliable biomarkers in schizophrenia.

Modulation of APOE and SORL1 genes on hippocampal functional connectivity in healthy young adults.

Apolipoprotein E (APOE) and sortilin-related receptor (SORL1) genes act on the same metabolic pathway and have been associated with Alzheimer's disease (AD) characterized by hippocampal impairment. Although the effects of APOE on hippocampal resting-state functional connectivity (rsFC) have been reported, the main effects of SORL1 and SORL1 × APOE interactions on hippocampal rsFC in healthy subjects remain largely unknown. Here, we systematically investigated the main effects of SORL1 rs2070045, and APOE, and their interaction effects on hippocampal rsFC in healthy young adults. The main effect of APOE showed that risk ε4 carriers had decreased positive hippocampal rsFC with the precuneus/posterior cingulate cortex and subgenual anterior cingulate cortex, and increased positive hippocampal rsFC with the sensorimotor cortex compared with non-ε4 carriers. The main effect of SORL1 showed that risk G-allele carriers had decreased positive rsFC between the hippocampus and middle temporal gyrus compared with TT carriers. No significant additive interaction was observed. Instead, significant SORL1 × APOE non-additive interaction was found in negative rsFC between the hippocampus and inferior frontal gyrus. Compared with subjects with TT genotype, SORL1 G-allele carriers had a stronger negative rsFC in APOE ε4 carriers, but a weaker negative rsFC in APOE non-ε4 carriers. These findings suggest that SORL1 and APOE genes modulate different hippocampal rsFCs and have a complex interaction. The SORL1- and APOE-dependent hippocampal connectivity changes may at least partly account for their association with AD.

APOE and KIBRA Interactions on Brain Functional Connectivity in Healthy Young Adults.

Genetic variations of APOE and KIBRA have been associated with human memory and Alzheimer's disease. APOE and KIBRA can jointly modulate glutamate receptor to influence long-term potentiation; however, their interactions on brain functional connectivity remain unknown. Here, we investigated additive and epistatic interactions between APOE and KIBRA (rs17070145) on brain functional connectivity density (FCD) in 267 healthy young adults. A voxel-based FCD analysis was performed to identify brain regions with significant APOE-KIBRA interaction. Additive effects showed decreased FCD in the left parahippocampal gyrus and the right middle temporal gyrus and increased FCD in the bilateral middle occipital gyri, with the increase of the number of the risk-alleles of APOE and KIBRA. Epistatic effects showed APOE × KIBRA interaction in the FCD of the dorsolateral prefrontal cortex (DLPFC). The FCD of the DLPFC showed APOE risk-allele-dependent reduction (ε2 > Îµ3 > Îµ4) in KIBRA TT homozygotes, but APOE risk-allele-dependent increase (ε2 < Îµ3 < Îµ4) in KIBRA C-carriers. FCD differences were only significant between the 2 extreme subgroups in both additive and epistatic analyses. These findings suggest that APOE and KIBRA have region-dependent additive and epistatic interactions on brain connectivity in healthy young adults.