A phenome-wide association study (PheWAS) to identify the health impacts of 4-cresol sulfate in the Nagahama Study.

Gut-microbiota derived metabolites are important regulators of host biology and metabolism. To understand the impacts of the microbial metabolite 4-cresol sulfate (4-CS) on four chronic diseases [type 2 diabetes mellitus, metabolic syndrome (MetS), non-alcoholic fatty liver disease, and chronic kidney disease (CKD)], we conducted association analyses of plasma 4-CS quantified by liquid chromatography coupled to mass spectrometry (LC-MS) in 3641 participants of the Nagahama study. Our results validated the elevation of 4-CS in CKD and identified a reducing trend in MetS. To delineate the holistic effects of 4-CS, we performed a phenome-wide association analysis (PheWAS) with 937 intermediate biological and behavioral traits. We detected associations between 4-CS and 39 phenotypes related to blood pressure regulation, hepatic and renal functions, hematology, sleep quality, intraocular pressure, ion regulation, ketone and fatty acid metabolisms, disease history and dietary habits. Among them, 19 PheWAS significant traits, including fatty acids and 14 blood pressure indices, were correlated with MetS, suggesting that 4-CS is a potential biomarker for MetS. Consistent associations of this gut microbial-derived metabolite on multiple endophenotypes underlying distinct etiopathogenesis support its role in the overall host health, with prospects of probiotic-based therapeutic solutions in chronic diseases.

Alterations of default mode and cingulo-opercular salience network and frontostriatal circuit: A candidate endophenotype of obsessive-compulsive disorder.

Background It is gradually becoming clear that obsessive-compulsive disorder (OCD) patients have aberrant resting-state large-scale intrinsic networks of cingulo-opercular salience (SN), default mode (DMN), and front-parietal network (FPN). However, it remains unknown whether unaffected first-degree relatives of OCD patients have these alterations as a vulnerability marker to the disorder. Methods We performed resting-state functional magnetic resonance imaging (rsfMRI) scans of 47 medication-free OCD patients, 21 unaffected healthy first-degree relatives of OCD patients, and 62 healthy control (HC) participants. We explored differences between the three groups in the functional connectivity from SN (seeds: anterior-insula (AI) and dorsal anterior cingulate cortex (dACC)), DMN (seeds: medial prefrontal cortex (MPFC) and posterior parietal cortex (PCC)), and FPN (seeds: dorsolateral prefrontal cortex (DLPFC)). Results Compared to HC, both OCD patients and first-degree relatives showed significantly greater functional connectivity between AI and PCC and between DLPFC and the thalamus. Compared to first-degree relatives and HC, OCD patients showed reduced functional connectivity between PCC and DLPFC, and this altered functional connectivity was negatively correlated with anxiety and depressive symptom within OCD group. Conclusions OCD patients and unaffected first-degree relatives of OCD patients showed overlapping alterations in resting state functional connectivity between the regions of SN and DMN and between DLPFC and the thalamus. Our results suggested that alterations between large-scale intrinsic networks and within the dorsal cognitive cortico-striato-thalamo-cortical (CSTC) circuit could represent endophenotype markers of OCD.

Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation.

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.

Electrophysiological assessment methodology of sensory processing dysfunction in schizophrenia and dementia of the Alzheimer type.

Schizophrenia and Alzheimer's disease impacts on various sensory processings are extensively reviewed in the present publication. This article describes aspects of a research project whose aim is to delineate the neurobiology that may underlie Social Withdrawal in Alzheimer's disease, Schizophrenia and Major Depression. This is a European-funded IMI 2 project, identified as PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This paper focuses specifically on the selected electrophysiological paradigms chosen based on a comprehensive review of all relevant literature and practical constraints. The choice of the electrophysiological biomarkers were fundamentality based their metrics and capacity to discriminate between populations. The selected electrophysiological paradigms are resting state EEG, auditory mismatch negativity, auditory and visual based oddball paradigms, facial emotion processing ERP's and auditory steady-state response. The primary objective is to study the effect of social withdrawal on various biomarkers and endophenotypes found altered in the target populations. This has never been studied in relationship to social withdrawal, an important component of CNS diseases.

Thalamic Reticular Dysfunction as a Circuit Endophenotype in Neurodevelopmental Disorders.

Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate level of explanatory description that links gene to behavior and as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g., macroscopic rhythms and goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a circuit endophenotype would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome-wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.

Decomposing P300 into correlates of genetic risk and current symptoms in schizophrenia: An inter-trial variability analysis.

BACKGROUND: The P300 event-related potential (ERP) component, which reflects cognitive processing, is a candidate biomarker for schizophrenia. However, the role of P300 in the pathophysiology of schizophrenia remains unclear because averaged P300 amplitudes reflect both genetic predisposition and current clinical status. Thus, we sought to identify which aspects of P300 are associated with genetic risk versus symptomatic status via an inter-trial variability analysis. METHODS: Auditory P300, clinical symptoms, and neurocognitive function assessments were obtained from forty-five patients with schizophrenia, thirty-two subjects at genetic high risk (GHR), thirty-two subjects at clinical high risk (CHR), and fifty-two healthy control (HC) participants. Both conventional averaging and inter-trial variability analyses were conducted for P300, and results were compared across groups using analysis of variance (ANOVA). Pearson's correlation was utilized to determine associations among inter-trial variability for P300, current symptoms and neurocognitive status. RESULTS: Average P300 amplitude was reduced in the GHR, CHR, and schizophrenia groups compared with that in the HC group. P300 inter-trial variability was elevated in the CHR and schizophrenia groups but relatively normal in the GHR and HC groups. Furthermore, P300 inter-trial variability was significantly related to negative symptom severity and neurocognitive performance results in schizophrenia patients. CONCLUSIONS: These results suggest that P300 amplitude is an endophenotype for schizophrenia and that greater inter-trial variability of P300 is associated with more severe negative and cognitive symptoms in schizophrenia patients.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Differences in Neural Correlates of Speech Perception in 3 Month Olds at High and Low Risk for Autism Spectrum Disorder.

In this study, we investigated neural precursors of language acquisition as potential endophenotypes of autism spectrum disorder (ASD) in 3-month-old infants at high and low familial ASD risk. Infants were imaged using functional near-infrared spectroscopy while they listened to auditory stimuli containing syllable repetitions; their neural responses were analyzed over left and right temporal regions. While female low risk infants showed initial neural activation that decreased over exposure to repetition-based stimuli, potentially indicating a habituation response to repetition in speech, female high risk infants showed no changes in neural activity over exposure. This finding may indicate a potential neural endophenotype of language development or ASD specific to females at risk for the disorder.

Klassifikation, Genetik und Epidemiologie der Glaukome.

Glaucoma is a heterogeneous group of diseases which all share retinal ganglion cell loss leading to a typical optic disc cupping and characteristic visual field defects. Glaucoma is the leading cause of irreversible blindness affecting 8.4 million people. In 2013, 65 million people suffered from glaucoma worldwide and the number will increase to about 112 million in 2040. This review provides an overview about the classification and genetic basics in glaucoma.

Molecular and Digital Biomarker Supported Decision Making in Clinical Studies in Cardiovascular Indications.

Although a large number of pharmaceutical therapies are available to treat cardiovascular diseases like heart failure, in many medical conditions treatment is still not optimal and, therefore, the need for innovative, safe and efficacious drugs is still very high in this indication. Biomarkers are an important tool in the preclinical and clinical drug development process; they allow patient selection for clinical studies as well as therapy monitoring during studies. Biomarker concepts in cardiovascular indications differ very much from those in oncology and are very diverse. The present article gives an overview of the pathomechanisms of heart failure and describes the socioeconomic impact of the disease and the biomarker strategies being applied in the development of new heart failure drugs. The focus lies on protein biomarkers that can be measured in the blood and on functional biomarkers that can be derived from implanted and wearable medical devices.

Ophthalmology issues in schizophrenia.

Schizophrenia is a complex mental disorder associated with not only cognitive dysfunctions, such as memory and attention deficits, but also changes in basic sensory processing. Although most studies on schizophrenia have focused on disturbances in higher-order brain functions associated with the prefrontal cortex or frontal cortex, recent investigations have also reported abnormalities in low-level sensory processes, such as the visual system. At very early stages of the disease, schizophrenia patients frequently describe in detail symptoms of a disturbance in various aspects of visual perception that may lead to worse clinical symptoms and decrease in quality of life. Therefore, the aim of this review is to describe the various studies that have explored the visual issues in schizophrenia.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

The study of psychiatric disease genes and drugs in zebrafish.

Mutations associated with psychiatric disease are being identified, but it remains unclear how the affected genes contribute to disease. Zebrafish is an emerging model to study psychiatric disease genes with a rich repertoire of phenotyping tools. Recent zebrafish research has uncovered potential developmental phenotypes for genes associated with psychiatric disorders, while drug screens have behaviorally characterized small molecules and identified new classes of drugs. Behavioral studies have led to promising models for endophenotypes of psychiatric diseases. While further research is needed to firmly link these models to psychiatric disorders, they are valuable tools for phenotyping genetic mutations and drugs. Recently developed tools in genome editing and in vivo imaging promise additional insights into the processes disrupted by mutations in psychiatric disease genes.

Event-related potential and time-frequency endophenotypes for schizophrenia and psychotic bipolar disorder.

BACKGROUND: The investigators compared event-related potential (ERP) amplitudes and event-related oscillations across a broad frequency range during an auditory oddball task using a comprehensive analysis approach to describe shared and unique neural auditory processing characteristics among healthy subjects (HP), schizophrenia probands (SZ) and their first-degree relatives, and bipolar disorder I with psychosis probands (BDP) and their first-degree relatives. METHODS: This Bipolar-Schizophrenia Network on Intermediate Phenotypes sample consisted of clinically stable SZ (n = 229) and BDP (n = 188), HP (n = 284), first-degree relatives of schizophrenia probands (n = 264), and first-degree relatives of bipolar disorder I with psychosis probands (n = 239). They were administered an auditory oddball task in the electroencephalography environment. Principal components analysis derived data-driven frequency bands evoked power. Spatial principal components analysis reduced ERP and frequency data to component waveforms for each subject. Clusters of time bins with significant group differences on response magnitude were assessed for proband/relative differences from HP and familiality. RESULTS: Nine variables survived a linear discriminant analysis between HP, SZ, and BDP. Of those, two showed evidence (deficit in relatives and familiality) as genetic risk markers more specific to SZ (N1, P3b), one was specific to BDP (P2) and one for psychosis in general (N2). CONCLUSIONS: This study supports for both shared and unique deficits in early sensory and late cognitive processing across psychotic diagnostic groups. Additional ERP and time-frequency component alterations (frontal N2/P2, late high, early, mid, and low frequency) may provide insight into deficits in underlying neural architecture and potential protective/compensatory mechanisms in unaffected relatives.

A combined study of GSK3ß polymorphisms and brain network topological metrics in major depressive disorder.

GSK3ß genotypes may interact with major depressive disorder (MDD) and may have a role in determining regional gray matter volume differences from healthy comparison subjects. However, any associations of GSK3ß genotypes with MDD related to abnormal functional brain activity have yet to be elucidated. In the present study, resting state functional brain networks were constructed by thresholding partial correlation matrices of 90 regions. Differences in the network features of GSK3ß-rs6438552 genotypes were tested, and a 2×2 analysis of variance was performed to identify the main effects of genotypes, disease status, and their interactions in MDD. Compared with CC carriers, T+ carriers with MDD showed increased nodal centralities in many brain regions-mainly the limbic system, thalamus and parts of the parietal, temporal, occipital, and frontal regions. Decreased nodal centralities predominantly occurred in the sensorimotor area and parts of the frontal, occipital, and temporal lobes. Significant interactions between genotypes and disease status were found in the left thalamus, left superior occipital gyrus, and left inferior parietal lobe. Only altered nodal centrality in the left angular gyrus was negatively correlated with scores on the Hamilton Depression Rating Scale. Our results suggest the GSK3ß genotypic effect of rs6438552 and its interaction with disease status may contribute to the altered topological organization of resting state functional brain networks in MDD patients.

[Pathogenesis of anorexia nervosa. Neurobiological risk factors and possible endophenotypes]. / Az anorexia nervosa kóreredetének újabb megközelítése. Neurobiológiai tényezok és lehetséges endofenotípusok a kutatási eredmények tükrében.

Anorexia nervosa is a serious, chronical state of illness which often starts in childhood or adolescence and has serious consequences on the quality of life. This review focuses on the heterogenity of the disease with emphasis on special diagnostic implications in case of childhood onset. Research findings of the last decade showed that genetic and neurobiological vulnerabilities are at least as potent risk factors as psychological, family constellations and sociocultural preferences. The heritability of eating disorders levels those of diseases predominantly influenced by biological factors. The authors give a summary of the most investigated neurobiologic and neurocognitive factors which could be the fundaments of a biological vulnerablilty. To date, no common risk factor could be identified, but some existing adversities can clearly be related to distinct subgroups with the disorder. The concept of endo- and subphenotypes leads to more specific and more efficient methods of therapy in other somatic and psychiatric diseases.

[The endophenotype concept in the neurophysiological studies of schizophrenia].

The endophenotype concept is considered as theoretical basis for the study of pathobiological mechanisms of schizophrenia and for the development of the complex of instrumental diagnostic methods. The contemporary state of the problem and the most significant results of the study of three neurophysiological schizophrenia endophenotypes are presented in the review: P50 auditory evoked potential suppression, prepulse inhibition of the startle reflex and antisaccade task. The current understanding of the underlying neurophysiological and neurochemical mechanisms is described for each measure. The results of the association studies of neurophysiological endophenotypes with the relevant to schizophrenia genes' polymorphisms are laid down. High degree of independence of the considered endophenotypes is demonstrated. Taking into account the data on relatively low specificity of each endophenotype to schizophrenia compared to other mental disturbances the authors pay special attention to the model of multivariate endophenotype as a scientific and diagnostic tool.

P50 sensory gating is a trait marker of the bipolar spectrum.

UNLABELLED: Sensory gating deficit, assessed by a paired auditory stimulus paradigm (P50), has been reported as a stable marker of schizophrenia. The aim of this study was to explore if this neurophysiological disturbance also fulfilled stability criteria in the bipolar disorder (BD) spectrum bipolar, as state independence is one of the main points to be considered as a potential endophenotype of the illness. The P50 evoked potential was studied in 95 healthy controls and 126 bipolar euthymic patients. Euthymia was established according to Van Gorp's criteria. Bipolar I and II subtypes were analyzed separately. The influence of a lifetime history of psychoses was also evaluated in the clinical sample. P50 gating was deficitary in all the subsamples of patients relative to healthy comparison subjects. Bipolar I patients with and without a history of psychosis showed higher P50 ratios than the other subgroups of patients, although these differences were not significant. P50 alterations were mainly due to a deficit in the inhibition of the second wave (test wave or S2) amplitude. CONCLUSIONS: The findings suggest that this inhibitory deficit can be considered characteristic of the illness and that the intensity of the gating abnormality varies according to the severity of BD.

Reversible disruption of pre-pulse inhibition in hypomorphic-inducible and reversible CB1-/- mice.

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout ((-/-)) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1(-/-) mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1(-/-)) only in absence of doxycycline (Dox). In such mice, under Dox(+) or vehicle, as well as in wild-type (WT) and CB1(-/-), two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1(-/-) and IRh-CB1(-/-) showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1(-/-) animals, was on the contrary highly and significantly disrupted only in Dox(+) IRh-CB1(-/-) mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1(-/-) mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1(-/-) mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders.