Structural Endophenotypes Research Articles

Identification of genetic features that are associated with amplitude of low-frequency fluctuation changes in schizophrenia using omics analysis.

Genetic risk for schizophrenia is thought to trigger variation in clinical features of schizophrenia, but biological processes associated with neuronal activity in brain regions remain elusive. In this study, gene expression features were mapped to various sub-regions of the brain by integrating low-frequency amplitude features and gene expression data from the schizophrenia brain and using gene co-expression network analysis of the Allen Transcriptome Atlas of the human brain from six donors to identify genetic features of brain regions and important associations with neuronal features. The results indicate that changes in the dynamic amplitude of low-frequency fluctuation (dALFF) are mainly associated with transcriptome signature factors such as cortical layer synthesis, immune response, and expanded membrane transport. Further modular disease enrichment analysis revealed that the same set of signature genes associated with dALFF levels was enriched for multiple neurological biological processes. Finally, genetic profiling of individual modules identified multiple core genes closely related to schizophrenia, also potentially associated with neuronal activity. Thus, this paper explores genetic features of brain regions in the schizophrenia closely related to low-frequency amplitude ratio levels based on imaging genetics, which suggests structural endophenotypes associated with schizophrenia.

Cortical thickness and surface area in patients with obsessive compulsive disorder and their unaffected siblings.

Little is known about the underlying neurobiological mechanisms in patients with obsessive-compulsive disorder (OCD). We aimed to examine cortical thickness and surface area in individuals with OCD and their unaffected siblings, comparing them to healthy controls. 30 patients with OCD, 21 unaffected siblings (SIB) and 30 controls underwent structural magnetic resonance imaging. Structural images were analyzed using the FreeSurfer software package (version 6.0). Compared to healthy controls, both OCD and SIB groups showed significantly lower cortical thickness in the right anterior insula. Surface areas of the superior frontal gyrus, paracentral gyrus and precuneus of the right hemisphere were also reduced in OCD patients compared to controls. There were no significant differences in cortical thickness and surface area between the OCD and SIB groups. We did not detect any significant differences in subcortical volumes between groups. Lower cortical thickness in the right anterior insula in both OCD patients and unaffected siblings may represent a potential structural endophenotype for OCD.

Integrative omics analysis identifies differential biological pathways that are associated with regional grey matter volume changes in major depressive disorder.

Major depressive disorder (MDD) is accompanied by alterations in grey matter volume. However, the biological processes associated with regional structural perturbations remain elusive. We applied integrative omics analysis to investigate specialized transcriptome signatures and translational determinants associated with regional grey matter variations in 2737 MDD patients relative to 3098 controls by summarizing the results from gene co-expression network analysis of Allen human brain transcriptome profiles in six donors, enrichment analysis of gene-sets and cellular structure from rodents and mediation analysis of BrainSpan proteome profile in six donors. We found convergent alterations of grey matter volume in MDD were associated with transcriptome profiles enriched for synaptic transmission, metabolism, immune processes and transmembrane transport. Genes with abnormal expression in post-mortem tissue in MDD were also associated with transcriptome signatures. Further gene co-expression network and enrichment analysis of MDD-related genes in these signatures revealed the modules with higher neuronal expression were enriched in the medial temporal cortex and temporo-parietal junction with genes differentially associated with neuronal development and metabolism. Also, the modules with higher non-neuronal (e.g. astrocyte and oligodendrocyte) expression were concentrated in the rostral and dorsal anterior cingulate cortex and were separately associated with immune response and transmembrane transport. Moreover, proteins as the gene expression products mediated the association between transcriptome signatures and brain volume changes in the visual and dorsolateral prefrontal cortex. Our multidimensional analyses offer a novel approach to detect specific biological pathways that capture regional structural variations in MDD, which suggests structural endophenotypes associated with MDD.

Using coordinate-based meta-analyses to explore structural imaging genetics.

Imaging genetics has become a highly popular approach in the field of schizophrenia research. A frequently reported finding is that effects from common genetic variation are associated with a schizophrenia-related structural endophenotype. Genetic contributions to a structural endophenotype may be easier to delineate, when referring to biological rather than diagnostic criteria. We used coordinate-based meta-analyses, namely the anatomical likelihood estimation (ALE) algorithm on 30 schizophrenia-related imaging genetics studies, representing 44 single-nucleotide polymorphisms at 26 gene loci investigated in 4682 subjects. To test whether analyses based on biological information would improve the convergence of results, gene ontology (GO) terms were used to group the findings from the published studies. We did not find any significant results for the main contrast. However, our analysis enrolling studies on genotype × diagnosis interaction yielded two clusters in the left temporal lobe and the medial orbitofrontal cortex. All other subanalyses did not yield any significant results. To gain insight into possible biological relationships between the genes implicated by these clusters, we mapped five of them to GO terms of the category "biological process" (AKT1, CNNM2, DISC1, DTNBP1, VAV3), then five to "cellular component" terms (AKT1, CNNM2, DISC1, DTNBP1, VAV3), and three to "molecular function" terms (AKT1, VAV3, ZNF804A). A subsequent cluster analysis identified representative, non-redundant subsets of semantically similar terms that aided a further interpretation. We regard this approach as a new option to systematically explore the richness of the literature in imaging genetics.

Abnormal white matter integrity as a structural endophenotype for bipolar disorder.

Several lines of evidence suggest that bipolar disorder (BD) is associated with white matter (WM) pathology. Investigation of unaffected first-degree relatives of BD patients may help to distinguish structural biomarkers of genetic risk without the confounding effects of burden of illness, medication or clinical state. In the present study, we applied tract-based spatial statistics to study WM changes in patients with BD, unaffected siblings and controls. A total of 27 euthymic patients with BD type I, 20 unaffected siblings of bipolar patients and 29 healthy controls who did not have any current or past diagnosis of Axis I psychiatric disorders were enrolled in the study. Fractional anisotropy (FA) was significantly lower in BD patients than in the control group in the corpus callosum, fornix, bilateral superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, posterior thalamic radiation, cingulum, uncinate fasciculus, superior corona radiata, anterior corona radiata and left external capsule. In region-of-interest (ROI) analyses, we found that both unaffected siblings and bipolar patients had significantly reduced FA in the left posterior thalamic radiation, the left sagittal stratum, and the fornix compared with healthy controls. Average FA for unaffected siblings was intermediate between the healthy controls and bipolar patients within these ROIs. Decreased FA in the fornix, left posterior thalamic radiation and left sagittal stratum in both bipolar patients and unaffected siblings may represent a potential structural endophenotype or a trait-based marker for BD.

Gray matter volumes in patients with bipolar disorder and their first-degree relatives

Bipolar disorder (BD) is highly heritable. First-degree relatives of BD patient have an increased risk to develop the disease. We investigated abnormalities in gray matter (GM) volumes in healthy first-degree relatives of BD patients to identify possible brain structural endophenotypes for the disorder. 3D T1-weighted magnetic resonance images were obtained from 25 DSM-IV BD type I patients, 23 unaffected relatives, and 27 healthy controls (HC). A voxel-based morphometry protocol was used to compare differences in GM volumes between groups. BD patients presented reduced GM volumes bilaterally in the thalamus compared with HC. Relatives presented no global or regional GM differences compared with HC. Our negative results do not support the role of GM volume abnormalities as endophenotypes for BD. Thalamic volume abnormalities may be associated the pathophysiology of the disease.

White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.

The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.

'O' blood type is associated with larger grey-matter volumes in the cerebellum.

Recent evidence indicated higher incidence of cognitive deficits in ABO blood-type system 'AB' individuals. Since this statistical difference might originate from the lack of protective effects exerted by 'O' alleles on the brain via vascular or non-vascular routes, this study investigated volumetric differences in grey matter between 'O' and non-'O' adults to explore the possibility of a structural endophenotype visible in 'O' adults without cognitive impairment or neurodegeneration. A large sample of cognitively healthy adults who had previously undergone structural MRI for research purposes were contacted telephonically and enquired about their ABO blood type. Out of the 189 individuals who were able to retrieve and communicate this information, 'O' (n=76) and 'A' adults (n=65) were included in Model 1. In Model 2, all non-'O' (n=113) were instead collapsed in a single group. Voxel-Based Morphometry analyses were carried out on three-dimensional T1-weighted scans, and between-sample t tests were run to compare the maps of grey-matter volumes of the subgroups of interest, controlling for major nuisance variables. In Model 1, 'O' adults had larger grey-matter volumes in two symmetrical clusters within the posterior ventral portion of the cerebellum. This was confirmed in Model 2. Additionally, non-'O' adults showed lower volume values in temporal and limbic regions, including the left hippocampus. The cerebellar clusters were located in regions previously found to be part of a network responsible for sensorimotor integration. It is speculated that the structural reductions seen in non-'O' adults might result in a susceptibility to down-regulation of this network. This occurrence is likely to intensify along the ageing process and may contribute to foster cognitive decline. Although Model 2 seems to suggest that having a 'O' blood type might play a role in protection against those conditions in which temporal and mediotemporal volumetric loss is observed (Alzheimer's disease), additional supporting evidence is needed. A number of potential biological processes might sustain these between-group differences, including sensorimotor ontogenesis, hormonal function, and a regional impact of cerebral amyloid angiopathy. These findings identify the cerebellar tissue as a candidate for further studying ABO function, and support a general association between ABO blood type and variance in the development of the nervous system.

Brain regions associated with risk and resistance for bipolar I disorder: a voxel‐based MRI study of patients with bipolar disorder and their healthy siblings

Bipolar I disorder is a highly heritable disorder but not all siblings manifest with the illness, even though they may share similar genetic and environmental risk factors. Thus, sibling studies may help to identify brain structural endophenotypes associated with risk and resistance for the disorder. Structural magnetic resonance imaging (MRI) scans were acquired for 28 euthymic patients with bipolar disorder, their healthy siblings, and 30 unrelated healthy controls. Statistical Parametric Mapping 8 (SPM8) was used to identify group differences in regional gray matter volume by voxel-based morphometry (VBM). Using analysis of covariance, gray matter analysis of the groups revealed a group effect indicating that the left orbitofrontal cortex [Brodmann area (BA) 11] was smaller in patients with bipolar disorder than in unrelated healthy controls [F=14.83, p<0.05 (family-wise error); 7mm(3) ]. Paired t-tests indicated that the orbitofrontal cortex of patients with bipolar disorder [t=5.19, p<0.05 (family-wise error); 37mm(3) ] and their healthy siblings [t=3.89, p<0.001 (uncorrected); 63mm(3) ] was smaller than in unrelated healthy controls, and that the left dorsolateral prefrontal cortex was larger in healthy siblings than in patients with bipolar disorder [t=4.28, p<0.001 (uncorrected); 323mm(3) ] and unrelated healthy controls [t=4.36, p<0.001 (uncorrected); 245mm(3) ]. Additional region-of-interest analyses also found volume deficits in the right cerebellum of patients with bipolar disorder [t=3.92, p<0.001 (uncorrected); 178mm(3) ] and their healthy siblings [t=4.23, p<0.001 (uncorrected); 489mm(3) ], and in the left precentral gyrus of patients with bipolar disorder [t=3.61, p<0.001 (uncorrected); 115mm(3) ] compared to unrelated healthy controls. The results of this study suggest that a reduction in the volume of the orbitofrontal cortex, which plays a role in the automatic regulation of emotions and is a part of the medial prefrontal network, is associated with the heritability of bipolar disorder. Conversely, increased dorsolateral prefrontal cortex volume may be a neural marker of a resistance factor as it is part of a network of voluntary emotion regulation and balances the effects of the disrupted automatic emotion regulation system.

Local Gyrification Index in Probands with Psychotic Disorders and Their First-Degree Relatives

Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia, and are scant for psychotic bipolar and schizoaffective (SZA) disorders and for relatives of these conditions. Here, we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. Regional local gyrification index (LGI) values, as measured by FreeSurfer software, were compared between 243 control subjects, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for schizophrenia, SZA, and bipolar disorder. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. Probands exhibited significant hypogyria compared with control subjects in three brain regions and relatives with Axis II cluster A disorders showed nearly significant hypogyria in these same regions. Local gyrification index values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant hypogyria were most widespread in SZA. Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders.

COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation

Endophenotypes in genetic psychiatry may increase our understanding of the molecular mechanisms underlying disease risk and its manifestations. We sought to investigate the link between neuropsychological impairments and brain structural abnormalities associated with the COMT Val(158)Met polymorphism in patients with schizophrenia to improve understanding of the pathophysiology of this disorder. We performed a systematic review using studies identified in PubMed and MEDLINE (from the date of the first available article to July 2012). Our review examined evidence of an association between the COMT Val(158)Met polymorphism and both neuropsychological performance and brain structure in patients with psychosis, in their relatives and in healthy individuals (step 1). The review also explored whether the neuropsychological tasks and brain structures identified in step 1 met the criteria for an endophenotype (step 2). Then we evaluated evidence that the neuropsychological endophenotypes identified in step 2 are associated with the brain structure endophenotypes identified in that step (step 3). Finally, we propose a neurobiological interpretation for this evidence. A poorer performance on the n-back task and the Continuous Performance Test (CPT) and smaller temporal and frontal brain areas were associated with the COMT Val allele in patients with schizophrenia and their relatives and met most of the criteria for an endophenotype. It is possible that the COMT Val(158)Met polymorphism therefore contributes to the development of these neuropsychological and brain structural endophenotypes of schizophrenia, in which the prefrontal cortex may represent the neural substrate underlying both n-back and CPT performances. The association between a single genetic variant and an endophenotype does not necessarily imply a causal relationship between them. This evidence and the proposed interpretation contribute to explain, at least in part, the biological substrate of 4 important endophenotypes that characterize schizophrenia.

Neuroimaging Endophenotypes in Animal Models of Autism Spectrum Disorders: Lost or Found in Translation?

Autism spectrum disorder(s) (ASDs) is a neurodevelopmental disorder characterized by stereotyped behaviours and impairments in communication and social interactions. This heterogeneity has been a major obstacle in uncovering the aetiology and biomarkers of ASDs. Rodent models with genetic modifications or environmental insults have been created to study particular endophenotypes and bridge the gap between genetics and behavioural phenotypes. Translational neuroimaging modalities with their ability to screen the brain noninvasively and yield structural, biochemical and functional information provide a unique platform for discovery and evaluation of such endophenotypes in preclinical and clinical research. We reviewed literature on translational neuroimaging in rodent models of ASDs. The most prominent models will be described and the respective neuroimaging endophenotypes will be discussed with reference to human data. A perspective on future directions of translational neuroimaging in animal models of ASDs will be given. To date, we experience a proliferation of rodent models which recapitulate specific liabilities identified in ASDs patients. Translational neuroimaging in these models is emerging but is skewed towards magnetic resonance imaging (MRI) modalities. Volumetric and structural assessments of the brain are dominating and a host of endophenotypes have been reported that allude to findings in ASDs patients but with only few to converge among the models. Caveats of current studies are the diverging biological conditions related to genetic background and age of the animals. It is anticipated that longitudinal and functional assessments will gain much importance and will help elucidating mechanistic relationship between behavioural and structural endophenotypes.

Reduced right posterior hippocampal volume in women with recurrent familial pure depressive disorder

Volumetric changes in mood-relevant distributed limbic/paralimbic structures have been reported in the recent literature on the course of mood disorders. Patients with unipolar and bipolar disorders have been found to have smaller hippocampal and anterior cingulate volumes. We examined hippocampal, amygdalar and anterior cingulate cortex (ACC) volumes in female patients with recurrent familial pure depressive disorder (rFPDD). We used semi-automated software for magnetic resonance imaging (MRI) to measure the volumes of the hippocampus, amygdala, ACC and subgenual prefrontal cortex (SGPFC) in 15 female patients with familial recurrent major depression (MD) and 15 healthy female subjects. Analysis of covariance, with whole brain volume as covariate, was used to compare volumetric measurements in the two groups. Volumes of the right hippocampal body and tail were significantly smaller in female patients with familial depressive disorder than in healthy subjects. Our data provide evidence of structural lateralized hippocampal body and tail abnormalities in women with familial history and recurrent episodes of depression. Although global reduction of hippocampal volume has been widely reported, data on lateralized regional reductions in familial recurrent depression had not been previously reported. Reduced volume of the right posterior hippocampus could be a structural endophenotype for recurrent depressive disorders in women.

Heritable Variations in Gray Matter Concentration as a Potential Endophenotype for Psychopathic Traits

Genetic vulnerability to psychopathic traits is likely to also manifest at the neural level. We have recently reported increased gray matter concentration in several brain areas in boys with psychopathic traits. To explore whether these gray matter concentration differences can be regarded as endophenotypes for psychopathic traits by (1) assessing their heritability and (2) examining the etiology of the co-occurrence of psychopathic traits and increased gray matter concentration. Community twin sample. On-campus neuroimaging facility. One hundred twenty-three male twins (56 monozygotic and 67 dizygotic individuals; mean age 11.55 years; range, 10-13 years). We analyzed structural magnetic resonance imaging scans. Voxel-based morphometry analyses were used to obtain gray matter concentration values that were analyzed in a biometrical genetic twin model. Left posterior cingulate and right dorsal anterior cingulate gray matter concentrations were found to be the strongest endophenotype markers, with heritability estimates of 46% and 37%, respectively, and common genes explaining the phenotypic relationship between these regions and psychopathic traits. No significant heritabilities were found for several regions, including the right orbitofrontal cortex and insula. These findings suggest that structural endophenotypes, in the form of variations in gray matter concentration, reflect genetic vulnerability for psychopathic traits. Specifically, gray matter concentration in the left posterior cingulate and right dorsal anterior cingulate, brain areas implicated in empathy, moral processing, and introspection, are potential candidate endophenotypes for psychopathic traits.

Cognitive Performance and Grey Matter Density in Psychosis: Functional Relevance of a Structural Endophenotype

Background: Structural brain changes and cognitive impairments have been identified as indicators of genetic risk for schizophrenia. However, the pattern of associations between such structural and functional liability markers has been less well investigated. Methods: Magnetic resonance imaging data and cognitive assessments were acquired in 31 patients with psychosis, 32 non-psychotic first-degree relatives and 28 controls. The relationship between cerebral grey matter density and cognitive performance was examined using computational morphometry. Results: Two out of 6 cognitive tests revealed significant associations with grey matter density in regions of the frontal lobe, basal ganglia, thalamus and cerebellum in patients and relatives. In patients, poorer executive functioning was associated with cerebellar grey matter density deficits. In relatives, poorer executive functioning was associated with increased grey matter density in the cerebellum and frontal lobe. In both patients and relatives, strategic retrieval from semantic memory was positively associated with grey matter density in basal ganglia structures. Some additional negative associations in the patients differentiated this group from relatives. Conclusions: The overlap in structure-function relationships in individuals with schizophrenia and those with liability for the disorder may suggest that regional grey matter density alterations functionally alter particular neurocircuits, which could lead to cognitive deficits. The non-overlapping structure-function correlations may reflect disease-related or compensatory mechanisms.

Unaffected Family Members and Schizophrenia Patients Share Brain Structure Patterns: A High-Dimensional Pattern Classification Study

A number of studies have provided evidence for genetic modulation of brain structure in unaffected family members (FM) of schizophrenia patients using conventional volumetric analysis. High-dimensional pattern classification methods have been reported to have the capacity to determine subtle and spatially complex structural patterns that distinguish schizophrenia patients from healthy control subjects using standard magnetic resonance imaging. This study investigates whether such endophenotypic patterns are found in FM via similar image analysis approaches. A high-dimensional pattern classifier was constructed from a group of 69 patients and 79 control subjects, via an analysis that identified a subtle and spatially complex pattern of reduced brain volumes. The constructed classifier was applied to examine brain structure of 30 FM. The classifier indicated that FM had highly overlapping structural profiles with those of patients. Moreover, an orbitofrontal region of relatively increased white matter was found to contribute significantly to the classification, indicating that white matter alterations, along with reductions of gray matter volumes, might be present in patients and unaffected FM. These findings provide evidence that high-dimensional pattern classification can identify complex and subtle structural endophenotypes that are shared by probands and their unaffected FM.

Searching for a structural endophenotype in psychosis using computational morphometry

Structural cerebral abnormalities are frequently observed in schizophrenia. These abnormalities may indicate vulnerability for the disorder, as evidenced by reports of familial clustering of measures identified through region-of-interest analyses using manual outlining procedures. We used computational morphometry to detect structural differences within the entire brain to further examine possible structural endophenotypes. Magnetic resonance imaging scans were obtained in 31 psychotic patients, 32 non-psychotic first-degree relatives of psychotic patients and 27 healthy controls. The images were processed using an automated procedure, yielding global grey matter, white matter, CSF and total brain volume. The relative distribution of grey matter was compared between groups on a clustered-voxel basis. Global grey matter and total brain volume did not differ between the groups. White matter volume was significantly higher and CSF volume significantly lower in relatives compared to both cases and controls. The clustered-voxel based group comparison yielded evidence for significant grey matter deficits in fronto-thalamic-cerebellar regions, in psychotic patients, whereas the most prominent deficits in relatives involved the cerebellum. Patients with psychosis and first-degree healthy relatives of patients with psychosis show cerebellar abnormalities, which may constitute a marker of genetic transmission.