Endophenotype Of Schizophrenia Research Articles

Deviation from expected cognitive ability is a core cognitive feature of schizophrenia related to neurophysiologic, clinical and psychosocial functioning

Cognitive functioning in schizophrenia is characterized by a generalized impairment in current cognitive ability based on traditional population-based norms. However, these norms assume a normal cognitive trajectory and do not directly account for illness-related declines from expected cognitive potential. Indeed, schizophrenia patients exhibit even greater deviation between their observed and expected cognitive functioning based on expanded norms that leverage premorbid variables resistant to illness-related features. The current study further quantified the extent to which illness-related features account for this deviation from expectation and assessed its relationship to neurophysiologic (mismatch negativity, P3a, theta oscillations), clinical, and psychosocial functioning in schizophrenia patients. Expected cognitive ability (PENN-CNB global cognition) in patients (n = 684) was calculated using healthy comparison subject (n = 660) weighted regression based on premorbid variables resistant to illness-related decline (demographics, single-word reading, parental education). The magnitude of any deviation between current (observed) and regression-predicted (expected) cognitive ability was calculated. Results indicated that 24% (n = 164) of the total patient population exhibited significant (≥-1.96 SD) deviation between observed and expected global cognitive ability. Interestingly, 20% of the total patient population (n = 136) had “normal” range cognitive performance when using traditional population-based norms, but also had significant deviation from expected cognitive ability. The magnitude of this deviation was associated with more severe neurophysiologic abnormalities, longer illness duration, higher levels of negative symptoms, and worse psychosocial functioning. Assessment of cognitive deviation is thus a complementary metric for characterizing the severity of illness-related cognitive declines in patients, while also reflecting the expression and severity of key endophenotypes of schizophrenia.

Electrophysiological correlates of visual backward masking in patients with major depressive disorder

Depression and schizophrenia are two psychiatric diseases with high co-morbidity. For this reason, it is important to find sensitive endophenotypes, which may disentangle the two disorders. The Shine-Through paradigm, a visual backward masking task, is a potential endophenotype for schizophrenia. Masking is strongly deteriorated in schizophrenia patients, which is reflected in reduced EEG amplitudes. Here, we tested whether masking deficits and associated EEG changes are also found in patients with major depressive disorder. First, we replicated previous findings showing that depressive patients exhibit, at most, only weak masking deficits. Second, we found that the EEG amplitudes of depressive patients were reduced compared to controls and slightly increased compared to schizophrenia patients. As a secondary analysis, we compared the performance in the masking paradigm with three cognitive tasks, namely: the Wisconsin card sorting test, a verbal fluency test and a degraded continuous performance test. Performance in all but the verbal fluency test could discriminate schizophrenia from depression.

Region-specific insular volumetric decreases in drug-naive, first-episode schizophrenia and their unaffected siblings.

Decreased insular volume may be one of the anatomical alterations caused by schizophrenia. The possibility of region-specific insular volumetric reduction as an endophenotype and/or a possible treatment predictor is a critical issue with great implications for the diagnosis and prognosis of the disease. The sample of the current study comprised 44 drug-naive and first-episode patients, 42 unaffected siblings, and 44 healthy controls. A computational anatomy toolbox (CAT12) was applied to analyze the structural images with a fine-grained, cross-validated brainnetome atlas. Correlation analysis and support vector regression (SVR) were used to determine the relationship between insular deficits and symptomatic severity among patients. The gray matter volume (GMV) values in the left hypergranular insula (G) exhibited the following pattern: patients < siblings < controls. GMV values in the right ventral agranular insula (vIa) and baseline Positive and Negative Syndrome Scale negative symptoms subscale scores among patients showed a positive correlation (r = 0.384, p = .010). Further SVR analysis exhibited a significantly positive correlation between GMV values in the right vIa and negative symptomatic improvement among patients (r = 0.537, p < .001). Results suggested the presence of region-specific insular volumetric decreases in first-episode schizophrenia. Thus, volumetric decrease in left G might be a potential endophenotype for schizophrenia, and GMV values in right vIa might be used to predict negative symptomatic improvement in schizophrenia.

Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study

The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

The association of striatal volume and positive schizotypy in healthy subjects: intelligence as a moderating factor.

Schizotypy, a putative schizophrenia endophenotype, has been associated with brain-structural variations partly overlapping with those in psychotic disorders. Variations in precuneus structure have been repeatedly reported, whereas the involvement of fronto-striatal networks - as in schizophrenia - is less clear. While shared genetic architecture is thought to increase vulnerability to environmental insults, beneficial factors like general intelligence might buffer their effect. To further investigate the role of fronto-striatal networks in schizotypy, we examined the relationship of voxel- and surface-based brain morphometry and a measure of schizotypal traits (Schizotypal Personality Questionnaire, with subscores Cognitive-Perceptual, Interpersonal, Disorganised) in 115 healthy participants [54 female, mean age (s.d.) = 27.57(8.02)]. We tested intelligence (MWT-B) as a potential moderator. We found a positive association of SPQ Cognitive-Perceptual with putamen volume (p = 0.040, FWE peak level-corrected), moderated by intelligence: with increasing IQ, the correlation of SPQ Cognitive-Perceptual and striatal volume decreased (p = 0.022). SPQ Disorganised was positively correlated with precentral volume (p = 0.013, FWE peak level-corrected). In an exploratory analysis (p < 0.001, uncorrected), SPQ total score was positively associated with gyrification in the precuneus and postcentral gyrus, and SPQ Disorganised was negatively associated with gyrification in the inferior frontal gyrus. Our findings support the role of fronto-striatal networks for schizotypal features in healthy individuals, and suggest that these are influenced by buffering factors like intelligence. We conclude that protective factors, like general cognitive capacity, might attenuate the psychosis risk associated with schizotypy. These results endorse the idea of a continuous nature of schizotypy, mirroring similar findings in schizophrenia.

Risk Model Assessment in Early-Onset and Adult-Onset Schizophrenia Using Neurological Soft Signs.

Age at onset is one of the most important clinical features of schizophrenia that could indicate greater genetic loadings. Neurological soft signs (NSS) are considered as a potential endophenotype for schizophrenia. However, the association between NSS and different age-onset schizophrenia still remains unclear. We aimed to compare risk model in patients with early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) with NSS. This study included 262 schizophrenia patients, 177 unaffected first-degree relatives and 243 healthy controls. We estimated the discriminant abilities of NSS models for early-onset schizophrenia (onset age < 20) and adult-onset schizophrenia (onset age ≥ 20) using three data mining methods: artificial neural networks (ANN), decision trees (DT) and logistic regression (LR). We then assessed the magnitude of NSS performance in EOS and AOS families. For the four NSS subscales, the NSS performance were greater in EOS and AOS families compared with healthy individuals. More interestingly, there were significant differences found between patients’ families and control group in the four subscales of NSS. These findings support the potential for neurodevelopmental markers to be used as schizophrenia vulnerability indicators. The NSS models had higher discriminant abilities for EOS than for AOS. NSS were more accurate in distinguishing EOS patients from healthy controls compared to AOS patients. Our results support the neurodevelopmental hypothesis that EOS has poorer performance of NSS than AOS. Hence, poorer NSS performance may be imply trait-related NSS feature in EOS.

Effect of trace amine-associated receptor 1 agonist RO5263397 on sensory gating in mice.

The trace amine-associated receptor 1 (TAAR1) agonist RO5263397 effect on sensory gating in C57BL/6 mice was studied. Sensory gating is a mechanism for dosing and filtering the incoming information, by which the brain regulates the responses to sensory stimuli coming from the environment. Sensory gating deficit is considered to be one of the schizophrenia endophenotypes. TAAR1 agonist at a 1 mg/kg dosage contributed to the sensory gating index (S1-S2) increase. Sensory gating index rose due to the N40 amplitude increase in response to the first stimulus in a pair, whereas the amplitude of the second stimulus remained unchanged. These results suggest that the sensory gating in mice may be modulated through TAAR1-dependent processes, indicating potential contribution of TAAR1 and trace amines in general to the neuropharmacology of cognitive processes.

Evidence of association of the DISC1 interactome gene set with schizophrenia from GWAS

DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further attempts to find genetic association with schizophrenia were inconclusive. Most of the biology of DISC1 was inferred from the functionality of its protein partners. Recently, a gene set constituted by DISC1 and several of its partners has been associated with cognitive performance during development, a well-known schizophrenia endophenotype, by means of burden test of rare disruptive variants. Here, we performed a gene set analysis using common variants from the largest schizophrenia genome-wide association study of the Psychiatric Genomics Consortium to test if this gene set is associated with schizophrenia. The main test was based on the MAGMA software. Several additional tests were performed to analyze the robustness of the main findings. The DISC1 interactome gene set was associated with schizophrenia (P = .0056), confirmed by an additional method (INRICH). This association was robust to removal of the major histocompatibility complex region, different definitions of gene boundaries, or different statistical gene models. Conditional analysis revealed that the association was not solely explained by higher expression in brain. Three genes from the gene set, CLIC1, DST, and PDE4B, were associated with schizophrenia at the gene level. Consideration of other DISC1 interactome gene sets revealed the importance of gene set definition. Therefore, we present the first evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility, reconciling genetic and molecular biology data.

Evidence of shared familial factors influencing neurocognitive endophenotypes in adult- and childhood-onset schizophrenia.

The aggregation of neurocognitive deficits among the non-psychotic first-degree relatives of adult- and childhood-onset schizophrenia patients suggests that there may be a common etiology for these deficits in childhood- and adult-onset illness. However, there is considerable heterogeneity in the presentation of neurobiological abnormalities, and whether there are differences in the extent of familial transmission for specific domains of cognitive function has not been systematically addressed. We employed variance components analysis, as implemented in SOLAR-Eclipse, to evaluate the evidence of familial transmission for empirically derived composite scores representing attention, working memory, verbal learning, verbal retention, and memory for faces. We contrast estimates for adult- and childhood-onset schizophrenia families and matched community control pedigrees, and compare our findings to previous reports based on analogous neurocognitive assessments. We observed varying degrees of familial transmission; attention and working memory yielded comparable, significant estimates for adult-onset and community control pedigrees; verbal learning was significant for childhood-onset and community control pedigrees; and facial memory demonstrated significant familial transmission only for childhood-onset schizophrenia. Model-fitting analyses indicated significant differences in familiality between adult- and childhood-onset schizophrenia for attention, working memory, and verbal learning. By comprehensively assessing a wide range of neurocognitive domains in adult- and childhood-onset schizophrenia families, we provide additional support for specific neurocognitive domains as schizophrenia endophenotypes. Whereas comparable estimates of familial transmission for certain dimensions of cognitive functioning support a shared etiology of adult- and childhood-onset neurocognitive function, observed differences may be taken as preliminary evidence of partially divergent multifactorial architectures.

Neurological soft signs and neurocognitive deficits in remitted patients with schizophrenia, their first-degree unaffected relatives, and healthy controls.

Neurological soft signs (NSS) and neurocognitive deficits (ND) are highly prevalent in schizophrenia, and have been separately proposed as candidate endophenotypes of schizophrenia. However, few relevant studies focus on remitted patients with schizophrenia (RP) and integrate NSS and ND as a composite endophenotype. This study aimed to explore the NSS and ND and examine the comparative relationship between them in RP, their first-degree unaffected relatives (FDR), and healthy controls, furthermore, to seek potential endophenotypes subitems of NSS and ND and create a composite endophenotype. 86 RP, 86 FDR, and 86 healthy controls were included. NSS and ND were independently assessed with Cambridge Neurological Inventory and MATRICSTM Consensus Cognitive Battery. RP had more NSS and ND than FDR in all subitems except disinhibition, information processing speed, working memory, and visual memory. Similarly, FDR presented poorer performance than controls in all subscales except disinhibition, sensory integration, working memory, and visual memory. Six subitems of NSS and ND met the criteria of endophenotype and the three groups were most accurately classified (71.2%) with these subitems working as a composite endophenotype. Moreover, information processing speed, attention, and social cognition were associated with sensory integration in RP and FDR. These findings add evidences that certain subitems of NSS and ND might be the endophenotypes of schizophrenia and integrating these endophenotypes may prove useful in identifying schizophrenia and high-risk individuals. Furthermore, sensory integration and specific cognitive domains covary, hence suggesting an overlap of compromised underlying neural systems.

Trace Amine-Associated Receptor 1 Agonist Modulates Mismatch Negativity-Like Responses in Mice.

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor widely expressed in the mammalian brain, particularly in limbic system and monoaminergic areas. It has proven to be an important modulator of dopaminergic, serotoninergic, and glutamatergic neurotransmission and is considered to be a potential useful target for the pharmacotherapy of neuropsychiatric disorders, including schizophrenia. One of the promising schizophrenia endophenotypes is a deficit in neurocognitive abilities manifested as mismatch negativity (MMN) deficit. This study examines the effect of TAAR1 partial agonist RO5263397 on the MMN-like response in freely moving C57BL/6 mice. Event-related potentials (ERPs) were recorded from awake mice in the oddball paradigm before and after RO5263397 administration. The RO5263397 (but not saline) administration increased the N40 amplitude in response to deviant stimuli. That provided the MMN-like difference at the 36–44 ms interval after the injection. The pitch deviance-elicited changes before the injection and in the control paradigm were established for the P68 component. After TAAR1 agonist administration the P68 amplitude in response both to standard and deviant stimuli was increased. These results suggest that the MMN-like response in mice may be modulated through TAAR1-dependent processes (possibly acting through the direct or indirect glutamate NMDA receptor modulation), indicating the TAAR1 agonists potential antipsychotic and pro-cognitive activity.

Enhanced Global-Brain Functional Connectivity in the Left Superior Frontal Gyrus as a Possible Endophenotype for Schizophrenia.

The notion of dysconnectivity in schizophrenia has been put forward for many years and results in substantial attempts to explore altered functional connectivity (FC) within different networks with inconsistent results. Clinical, demographical, and methodological heterogeneity may contribute to the inconsistency. Forty-four patients with first-episode, drug-naive schizophrenia, 42 unaffected siblings of schizophrenia patients and 44 healthy controls took part in this study. Global-brain FC (GFC) was employed to analyze the imaging data. Compared with healthy controls, patients with schizophrenia and unaffected siblings shared enhanced GFC in the left superior frontal gyrus (SFG). In addition, patients had increased GFC mainly in the thalamo-cortical network, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC)/precuneus, left superior medial prefrontal cortex (MPFC), right angular gyrus, and right SFG/middle frontal gyrus and decreased GFC in the left ITG/cerebellum Crus I. No other altered GFC values were observed in the siblings group relative to the control group. Further ROC analysis showed that increased GFC in the left SFG could separate the patients or the siblings from the controls with acceptable sensitivities. Our findings suggest that increased GFC in the left SFG may serve as a potential endophenotype for schizophrenia.

Differentiation of Schizophrenia by Combining the Spatial EEG Brain Network Patterns of Rest and Task P300.

The P300 is regarded as a psychosis endophenotype of schizophrenia and a putative biomarker of risk for schizophrenia. However, the brain activity (i.e., P300 amplitude) during tasks cannot always provide satisfying discrimination of patients with schizophrenia (SZs) from healthy controls (HCs). Spontaneous activity at rest indices the potential of the brain, such that if the task information can be efficiently processed, it provides a compensatory understanding of the cognitive deficits in SZs. In this paper, based on the resting and P300 task electroencephalogram (EEG) data sets, we constructed functional EEG networks and then extracted the inherent spatial pattern of network (SPN) features for both brain states. Finally, the combined SPN features of the rest and task networks were used to recognize SZs. The findings of this paper revealed that the combined SPN features could achieve the highest accuracy of 90.48%, with the sensitivity of 89.47%, and specificity of 91.30%. These findings consistently implied that the rest and task P300 EEGs could actually provide comprehensive information to reliably classify SZs from HCs, and the SPN is a promising tool for the clinical diagnosis of SZs.

Cognitive deficits in subjects at risk for psychosis, first-episode and chronic schizophrenia patients

Background: Identifying the types and characteristics of cognitive deficits before the onset of schizophrenia and during its subsequent course could improve early detection and contribute to our understanding of the evolution of the core behavioral deficits underlying this disorder. Methods: This study used the Measurement and Treatment Research to Improve Cognition In Schizophrenia (MATRICS) battery to identify cognitive deficits and their progression during the course of schizophrenia from genetic high risk (HRF) subjects, subjects with prodromal symptoms (prodromal), and patients with first episode (FSCZ) and multi-episode (CSCZ) schizophrenia, compared to controls, in a Chinese Han population of 267 subjects. Results: There were statistically significant cognitive deficits which first appeared in prodromal subjects which were also present in FSCZ and CSCZ. There were no statistically significant differences between controls and HRF on any cognitive measure. Deficits in Visual Learning, Speed of Processing, and Overall Cognition were significantly correlated with some symptom measures on PANSS or SIPS. There were no statistically significant differences in cognitive deficits between FSCZ and CSCZ, and on most measures the patients with schizophrenia did not show a progression to more severe cognitive deficits than the prodromal subjects. Conclusions: In this sample of Chinese subjects, prodromal subjects showed significant cognitive deficits which were similar in most domains to those found in patients with schizophrenia. Whether the pattern of cognitive deficits on the MATRICS battery found in prodromal subjects will help predict conversion to diagnosed schizophrenia or other psychotic disorders would help determine how useful this profile of cognitive deficits is as a potential endophenotype for schizophrenia.

Endophenotypes in Schizophrenia: Digging Deeper to Identify Genetic Mechanisms.

Schizophrenia (SZ) is a severe psychotic disorder that is highly heritable and common in the general population. The genetic heterogeneity of SZ is substantial, with contributions from common, rare, and de novo variants, in addition to environmental factors. Large genome-wide association studies have detected many variants that are associated with SZ, yet the pathways by which these variants influence risk remain largely unknown. SZ is also clinically heterogeneous, with patients exhibiting a broad range of deficits and symptom severity that vary over the course of illness and treatment, which has complicated efforts to identify risk variants. However, the underlying brain dysfunction forms a more stable trait marker that quantitative neurocognitive and neurophysiological endophenotypes may be able to objectively measure. These endophenotypes are less likely to be heterogeneous than the disorder and provide a neurobiological context to detect risk variants and underlying pathways among genes associated with SZ diagnosis. Furthermore, many endophenotypes are translational into animal model systems, allowing for direct evaluation of the neural circuit dysfunctions and neurobiological substrates. We review a selection of the most promising SZ endophenotypes, including prepulse inhibition, mismatch negativity, oculomotor antisaccade, letter-number sequencing, and continuous performance tests. We also highlight recent findings from large consortia that suggest the potential role of genes, particularly in the neuregulin and glutamate pathways, in several of these endophenotypes. Although endophenotypes require additional time and effort to assess, the insight into the underlying neurobiology that they provide may ultimately reveal the underlying genetic architecture for SZ and suggest novel treatment targets.

Development of Subtype Selective GABAA Modulators: A Review Article

GABAA receptors are Cl- channels that can be opened by GABA and are the major inhibitory neurotransmitter receptors in the Central Nervous System. A variety of pharmacologically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, general anesthetics and convulsants, produce at least part of their clinically relevant effects by interacting with distinct allosteric binding sites on GABAA receptors. GABAA receptors are involved in anxiety, feeding and drinking behavior, circadian rhythm, cognition, vigilance, and learning and memory. Different subtype mediates different functions. Neurons expressing a1GABAA receptors have been found to mediate sedation, whereas those expressing a2GABAA receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic a5GABAA receptors. In addition, neurons expressing a3GABAA receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drug.

Working Memory and Attention Influence Antisaccade Error Rate in Schizophrenia.

Objectives: Antisaccade error rate has been proposed to be one of the most promising endophenotypes for schizophrenia. Increased error rate in patients has been associated with working memory, attention and other executive function impairments. The relationship between antisaccade error rate and other neuropsychological processes in patients compared to healthy controls has not been explored in depth. This study aimed to replicate the finding of heightened antisaccade error rate in patients and determine which cognitive processes were most strongly associated with antisaccade error rate in both patients and controls. In addition, the study investigated whether different antisaccade task paradigms engage different cognitive processes. Methods: One hundred and ninety-one participants (54 patients with schizophrenia/schizoaffective disorder and 137 controls) completed the antisaccade task, which included both gap and step task parameters. Neuropsychological measures were obtained using the MCCB and the Stroop task. Results: The current study replicated a pronounced antisaccade error rate deficit in patients. In patients, working memory variance was most significantly associated with antisaccade errors made during the step condition, while attentional processes were most associated with errors made during the gap condition. In controls, overall global cognitive performance was most associated with antisaccade rates for both gap and step conditions. Conclusions: The current study demonstrates that in schizophrenia patients, but not controls, elevated antisaccade error rate is associated with attention and working memory, but not with global cognitive impairment or psychopathological processes. Our novel findings demonstrate that the gap and step conditions of the antisaccade task engage different cognitive processes. (JINS, 2019, 25, 174-183).

Genetics of Factor VIII Inhibitor Development in Hemophilia Patients: Novel Statistical Approaches in the PATH Study

Here we apply state-of-the-art statistical genetic approaches toward investigating the genetic architecture of factor VIII (FVIII) inhibitor (FEI) development in Hemophilia A (HA). A total of 442 North American HA patients (237 Whites and 205 Blacks; 88% severely affected) enrolled in the PATH Study were: 1) ImmunoChip genotyped at ~167,000 single nucleotide polymorphisms (SNPs) in genes previously implicated in autoimmune disease risk; 2) Evaluated by DNA sequencing and assays for the recurrent intron (I)1 and I22 inversions to identify their causative F8 mutations; and 3) Tested with the Bethesda assay to determine their FEI status. The ImmunoChip genotypes were used to construct a genetic relationship matrix (GRM), denoted by K, following our previously published method,1 and the F8 sequence data along with results from the I1 and I22 inversion assays were used to construct a shared F8-mutation matrix, denoted by F. We analyzed a dichotomous FEI variable under the statistical genetic threshold/liability model (a probit regression in the fixed effects) in conjunction with a variance components model for the FEI liability phenotypic covariance matrix, denoted by P, to model potentially important random effects. For the latter, we specifically assumed independent additive genetic, F8-mutation, and residual environmental random effects. By the independence assumption, the covariance matrix is then decomposable as a sum of the additive genetic (Va), F8-mutation (Vf), and residual environmental (Ve) variances respectively structured by K, F, and the identity matrix I. The variance component model is given as: P = K*Va + F*Vf + I*Ve. Heritability, denoted by h2, is defined as the ratio of Va to the total phenotypic variance (Vp): h2 = Va / Vp. We can further speak of the total heritability given as: h2t = h2r + h2f + h2snp, where the subscripts t, r, f, and snp respectively denote total, residual additive genetic, F8-mutation-specific, and SNP heritabilities. Using eigenstructure methods,2 we can compute power under a simpler model in which Va and Vf are combined as a single variance component. We computed power to detect genetic association as measured by SNP-specific heritability for a set of 403 SNPs in or near 14 candidate immune response genes previously implicated in FEI risk. To account for multiple hypothesis testing, power was computed at the Bonferroni-adjusted significance level of 0.05/403 = 1.2 × 10-4. Under the simplified model, we computed the statistical power to detect causal SNPs for our sample and study design for the sample FEI prevalences, denoted by Kp, for Whites (22.5%) and Blacks (45%), across a range of total heritabilities, h2t = 15%, 35%, and 55%, where the lattermost total heritability was observed for FEI liability in the current study (Figure 1). It should be noted that because the liability heritability is known to be biased upward, we applied the Dempster-Lerner correction to both the total and SNP-specific heritabilities.3 Close inspection of Figure 1 reveals that varying h2t from 15% to 35% to 55% results in slight decreases in power due to the decreasing ratio of the SNP-specific heritability to the total heritability. However, as seen in all three panels, the more important determinant of power is clearly the FEI prevalence in that the power curve for a Kp of 45% is associated with greater power than the power curve for a Kp of 22.5% across the range of total heritabilities examined. As seen in Figure 1, we have adequate power to detect SNP heritabilities as low as 5% and 6%, respectively, for a Kp of 45% and 22.5%. As noted above, we observed a FEI liability total heritability of 55% consisting of a 47% residual additive genetic heritability (p = 0.019) and 8% F8-mutation specific heritability (p = 0.005). This is the first study to use a GRM based on genotype data and a shared causal F8 mutation matrix to model additive genetic and F8-mutation specific effects.Almeida M, Peralta J, Farook V, …, Blangero J. Pedigree-based random effect tests to screen gene pathways. BMC Proc. 2014; 8(Suppl 1 Genetic Analysis Workshop): S100.Blangero J, Diego VP, Dyer T, …, Göring H. A kernel of truth: statistical advances in polygenic variance component models for complex human pedigrees. Adv Genetics. 2013; 81: 1-31.Glahn D, Williams J, McKay D, …, Blangero J. Discovering schizophrenia endophenotypes in randomly ascertained pedigrees. Biol Psychiatry. 2015; 77(1): 75-83. [Display omitted] DisclosuresChitlur:Baxter, Bayer, Biogen Idec, and Pfizer: Honoraria; Novo Nordisk Inc: Consultancy. Dinh:Haplomics Biotechnology Corporation: Employment, Equity Ownership. Howard:Haplomics Biotechnology Corporation: Equity Ownership, Other: Chief Scientific Officer, Patents & Royalties: Patent applications and provisional patent applications ; CSL Behring: Research Funding.

Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia

Recent transcriptomic, proteomic and metabolomics studies have highlighted an abnormal cerebral glucose and energy metabolism as one of the potential pathophysiological mechanisms of schizophrenia. This raises the possibility that a metabolically-based intervention might have therapeutic value in the management of schizophrenia, a notion supported by our recent results that a low carbohydrate/high-fat therapeutic ketogenic diet (KD) prevented a variety of behavioural abnormalities induced by pharmacological inhibition of NMDA glutamate receptors. Here we asked if the beneficial effects of KD can be generalised to impaired prepulse inhibition of startle (PPI), a translationally validated endophenotype of schizophrenia, in a pharmacological model in mice. Furthermore, we addressed the issue of whether the effect of KD is linked to the calorie-restricted state typical of the initial phase of KD. We fed male C57BL/6 mice a KD for 7 weeks and tested PPI at 3 and 7 weeks, in the presence and absence of a significant digestible energy deficit, respectively. We used an NMDA receptor hypo-function model of schizophrenia induced by acute injection of dizocilpine (MK-801). We found that KD effectively prevented MK-801-induced PPI impairments at both 3 and 7 weeks, irrespective of the presence or absence of digestible energy deficit. Furthermore, there was a lack of correlation between PPI and body weight changes. These results support the efficacy of the therapeutic KD in a translational model of schizophrenia and furthermore provide evidence against the role of calorie restriction in its mechanism of action.

Electrophysiological correlates of visual backward masking in patients with first episode psychosis

Visual backward masking is strongly impaired in patients with schizophrenia. Masking deficits have been proposed as potential endophenotypes of schizophrenia. Masking performance deficits manifest as strongly reduced amplitudes in the electroencephalogram (EEG). In order to fulfill the criteria of an endophenotype, masking deficits should not vary substantially across time and should be present at the first psychotic event. To verify whether these conditions are met for visual backward masking, we tested patients with first episode psychosis (n = 21) in a longitudinal study. Patients were tested with visual backward masking and EEG three times every six months over a period of one year. We found that the EEG amplitudes of patients with first episode psychosis were higher as compared to those of patients with schizophrenia but lower as compared to those of unaffected controls. More interestingly, we found that the EEG amplitudes of patients with first episode psychosis remained stable over the course of one year. Since chronic schizophrenia patients have strongly reduced amplitudes, we speculate that the neural correlates of masking deficits (EEG amplitudes) continue to decrease as the disease progresses.