Endophenotype Of Schizophrenia Research Articles

The Relationship between Mismatch Negativity and the COMTVal108/158Met Genotype in Schizophrenia

Mismatch negativity (MMN) is a component of auditory event-related potentials that reflects automatic change detection in the brain, showing qualities of endophenotypes in schizophrenia. MMN deficiency is one of the robust findings in patients, and it reflects both cognitive and functional decline. Catechol-o-methyltransferase (COMT) is a key enzyme involved in regulating dopamine transmission within the prefrontal cortex. A preliminary study suggested that the COMTVal108/158Met genotype (rs4680) is related to cognitive function in schizophrenia. Both the COMTVal108/158Met genotype and MMN are related to cognitive function, but no studies have reported on the relationship between MMN and the COMTVal108/158Met genotype in schizophrenia. This study therefore examined the relationship between COMTVal108/158Met genotype and MMN. The duration of MMN was measured, and the COMTVal108/158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 49 Japanese schizophrenia patients (Val/Val, n = 21; Met carriers, n = 28). Amplitude and latency of MMN were compared between Val/Val and Met carriers.

Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity

Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.

Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice.

As part of the βγ-superfamily, βB2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three βB2-mutant lines Crybb2O377, Crybb2Philly, and Crybb2Aey2 included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.

The Relationship between Cytokines and Verbal Memory in Individuals with Schizophrenia and Their Unaffected Siblings

Background: Verbal memory impairment may be considered an endophenotype in schizophrenia (SZ), also affecting the siblings of SZ subjects. Furthermore, the immune-inflammatory system response has an important modulatory effect on brain processes, especially on memory circuits. Objective: Investigating the relationship between TNF-α and IL-6 and memory performance in patients with SZ, their unaffected siblings (SB) and healthy controls (HC). Methods: 35 subjects with SZ, 36 SB, and 47 HC underwent a neurocognitive assessment for verbal memory by means of the revised Hopkins Verbal Learning Test (HVLT-R) in addition to serum cytokines analyses. Results: SZ patients performed worse in HVLT-R than SB and HC, but SB and HC were not different. Regarding the biomarker levels, we found significant results of TNF-α for both groups. However, we did not find differences between groups after multiple-comparisons analysis. There were no significant correlations between episodic verbal memory, TNF-α, and IL-6. Conclusion: The results are compatible with the hypothesis that deficits in verbal memory of individuals with SZ could be secondary to inadequate functioning of cognitive processing areas, such as proactive cognitive control.

Disrupted asymmetry of inter- and intra-hemispheric functional connectivity in patients with drug-naive, first-episode schizophrenia and their unaffected siblings.

BackgroundLack of normal asymmetry in the brain has been reported in patients with schizophrenia. However, it remains unclear whether disrupted asymmetry originates from inter-hemispheric functional connectivity (FC) and/or intra-hemispheric FC in this patient population.MethodsForty-four patients with drug-naive, first-episode schizophrenia, 42 unaffected siblings, and 44 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The parameter of asymmetry (PAS) and support vector machine (SVM) were used to analyze the data. Patients were treated with olanzapine for 8 weeks.FindingsCompared with healthy controls, patients showed lower PAS scores in the left middle temporal gyrus (MTG)/inferior temporal gyrus (ITG), left posterior cingulate cortex (PCC)/precuneus and left angular gyrus, and higher PAS scores in the left precentral gyrus/postcentral gyrus. Unaffected siblings also showed lower PAS scores in the left MTG/ITG and left PCC/precuneus relative to healthy controls. Further, SVM analysis showed that a combination of the PAS scores in these two clusters in patients at baseline was able to predict clinical response after 8 weeks of olanzapine treatment with 77.27% sensitivity, 72.73% specificity, and 75.00% accuracy.InterpretationThe present study suggests disrupted asymmetry of inter- and intra-hemispheric FC in drug-naive, first-episode schizophrenia; in addition, a reduced asymmetry of inter-hemispheric FC in the left MTG/ITG and left PCC/precuneus may serve as an endophenotype for schizophrenia, and may have clinical utility to predict response to olanzapine treatment.FundThe National Key R&D Program of China and the National Natural Science Foundation of China.

Characterization of neurological soft signs in a Brazilian sample of stable patients with schizophrenia.

Neurological soft signs (NSS) have been considered one of the target features and a potential endophenotype for schizophrenia. The present study aimed to characterize NSS in a sample of patients with chronic schizophrenia and to compare them with healthy control individuals. In this study, we evaluated the presence of NSS in a sample of stable patients (n = 24) diagnosed with schizophrenia according to DSM-IV criteria, recruited at the Schizophrenia Outpatient Clinic of Instituto Raul Soares, Belo Horizonte, state of Minas Gerais, southeastern Brazil. Assessment was made with the Brief Motor Scale (BMS), and extrapyramidal symptoms (EPS) were evaluated with the Simpson-Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS). A control group (n = 21) was also submitted to the same battery of tests. We observed a significant difference in relation to BMS and SAS scores (p < 0.0001), revealing that individuals with schizophrenia present more NSS and EPS than healthy ones. BMS total scores correlated positively with SAS scores (r = 0.495, p = 0.014), but not with AIMS scores, indicating that NSS could be influenced by the intensity of EPS. Nevertheless, we observed that this relationship remained only for motor coordination tasks (r = 0.550, p = 0.005), while motor sequencing tasks were not influenced by EPS (r = 0.313, p = 0.136). The results suggest that NSS are more frequent in patients with schizophrenia and that motor sequencing tasks could be more specific to the syndrome.

Slow Binocular Rivalry as a Potential Endophenotype of Schizophrenia.

Objectives: Binocular rivalry is a typical example of bistable perception that arises when two monocular images are simultaneously presented to each eye. Binocular rivalry is a heritable perceptual cognitive function that is impaired in patients with schizophrenia (SZ). Despite its potential suitability as a visual endophenotype, binocular rivalry has hardly been studied in the unaffected siblings of schizophrenia (SIB). There is also little research about whether binocular rivalry is a potential visual endophenotype between SZ and SIB.Methods: In our cross-sectional study, we included 40 SZ and their unaffected SIBs, as well as 40 age- and sex-matched healthy controls (HC). All subjects underwent the binocular rivalry test, the Positive and Negative Syndrome Scale (PANSS) and a battery of cognitive neuropsychological assessments evaluating attention, memory and executive function domains.Results: Our results demonstrate that the switching rate in SZ was significantly slower than in HC (p < 0.001), and compared to the SIB, the mean alternation rates were significantly different (p < 0.01). Moreover, there was a significant difference in mean switching rate between the SIB and the HC (p < 0.001). There was no significant correlation between the alternation rate of binocular rivalry and these cognitive tasks and the PANSS scores.Conclusion: The present study shows that SZ and SIB both exhibit changes in binocular rivalry, with SIB exhibiting intermediate performance compared with that of SZ and the HC. This supports the claim that the switching rate for SZ differs from that of SIB and suggests that binocular rivalry may qualify as a visual endophenotype for SZ.

Genetic risk factors for schizophrenia associate with sleep spindle activity in healthy adolescents.

Schizophrenia has been associated with disturbed sleep, even before the onset of the disorder, and also in non-schizophrenic first-order relatives. This may point to an underlying genetic influence. Here we examine whether weighted polygenic risk scores (PRS) for schizophrenia are associated with sleep spindle activity in healthy adolescents. Our sample comes from a community-based cohort of 157 non-schizophrenic adolescents (57% girls) having both genetic data and an overnight sleep EEG measurement available. Based on a recent genome-wide association study, we calculated PRS for schizophrenia across the whole genome. We also calculated PRS for the CACNA1l gene region, which has been associated with both schizophrenia and sleep spindle formation. We performed an overnight sleep EEG at the homes of the participants. Stage two sleep spindles were detected using an automated algorithm. Sleep spindle amplitude, duration, intensity and density were measured separately for central and frontal derivations and for fast (13-16Hz) and slow (10-13Hz) spindles. PRS for schizophrenia was associated with higher fast spindle amplitude (p=0.04), density (p=0.006) and intensity (p=0.04) at the central derivation, and PRS in the CACNA1l region associated with higher slow spindle amplitude (p=0.01), duration (p=0.03) and intensity (p=0.002) at the central derivation. A positive association between genetic variants for schizophrenia and sleep spindle activity among healthy adolescents supports a view that sleep spindles and schizophrenia share similar genetic pathways. This study suggests that altered sleep spindle activity might serve as an endophenotype of schizophrenia.

Modelling reaction time distribution of fast decision tasks in schizophrenia: Evidence for novel candidate endophenotypes

Increased reaction time (RT) and variability of RT in fast decision tasks is observed in patients with schizophrenia and their first degree relatives. This study used modelling of the RT distribution with the aim of identifying novel candidate endophenotypes for schizophrenia. 20 patients with schizophrenia, 15 siblings of patients and 25 healthy controls performed an oddball task of varying working memory load. Increases in mean and standard deviation (SD) of RT were observed for both patients and siblings compared to controls and they were again independent of working memory load. Ex-Gaussian modelling of the RT distribution confirmed that parameters μ, σ and τ increased significantly in patients and siblings compared to controls. The Drift Diffusion Model was applied on RT distributions. A decrease in the diffusion drift rate (v) modeling the accumulation of evidence for reaching the decision to choose one stimulus over the other, was observed in patients and siblings compared to controls. The mean time of the non-decisional sensorimotor processes (t0) and it's variance (st0) was also increased in patients and siblings compared to controls. In conclusion modeling of the RT distribution revealed novel potential cognitive endophenotypes in the quest of heritable risk factors for schizophrenia.

Genome-wide Association Analysis of Eye Movement Dysfunction in Schizophrenia

Eye movements are considered endophenotypes of schizophrenia. However, the genetic factors underlying eye movement are largely unknown. In this study, we explored the susceptibility loci for four eye movement scores: the scanpath length during the free viewing test (SPL), the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test (HPG), the duration of fixations during the far distractor paradigm of the fixation stability test (DF) and the integrated eye movement score of those three scores (EMS). We found 16 SNPs relevant to the HPG that were located in 3 genomic regions (1q21.3, 7p12.1 and 20q13.12) in the patient group; however, these SNPs were intronic or intergenic SNPs. To determine whether these SNPs occur in functional non-coding regions (i.e., enhancer or promoter regions), we examined the chromatin status on the basis of publicly available epigenomic data from 127 tissues or cell lines. This analysis suggested that the SNPs on 1q21.3 and 20q13.12 are in enhancer or promoter regions. Moreover, we performed an analysis of expression quantitative trait loci (eQTL) in human brain tissues using a public database. Finally, we identified significant eQTL effects for all of the SNPs at 1q21.3 and 20q13.12 in particular brain regions.

The schizophrenia and bipolar twin study in Sweden (STAR)

The schizophrenia and bipolar twin study in Sweden (STAR) is a large nation-wide cohort of monozygotic (MZ) and dizygotic (DZ) same-sex twins with schizophrenia or bipolar disorder and healthy control pairs, extensively characterized with brain imaging, neuropsychological tests, biomarkers, genetic testing, psychiatric symptoms and personality traits. The purpose is to investigate genetic and environmental mechanisms that give rise to schizophrenia and bipolar disorder as well as the intermediate phenotypes. This article describes the design, recruitment, data collection, measures, collected twins' characteristics, diagnostic procedures as well as ongoing and planned analyses. Identification of biomarkers, genetic and epigenetic variation and the development of specific and common endophenotypes for schizophrenia and bipolar disorder are potential gains from this cohort.

Impact of childhood trauma on sensory gating in patients with first-episode schizophrenia

BackgroundChildhood trauma (CT) has been found to contribute to the onset of schizophrenia and auditory sensory gating deficit is a leading endophenotype for schizophrenia. However, the association between the CT and sensory gating in first-episode schizophrenia remains elusive.MethodsFifty-six patients and 49 age and sex-matched healthy controls were assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) for CT and Positive and Negative Syndrome Scale (PANSS) for symptoms severity. Sensory gating was tested using the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS-PPI), and the perceived spatial co-location PPI (PSC-PPI or classical PPI).ResultsComparing with healthy controls, the patients had significantly higher score on sexual abuse (t = 2.729, p < 0.05), lower PSS- PPI, % (ISI = 120 ms and ISI = 60 ms) (t = − 3.089, − 4.196, p < 0.05). Univariate analysis revealed the absence of a significant correlation among CT, PPI paradigms and symptoms. However, multiple linear regression analyses demonstrated the CTQ-SF total was negatively associated with PSS PPI (ISI = 120 ms) (p = 0.018).ConclusionThe current study illustrates that the impact of CT on sensory gating in patients with first-episode schizophrenia, and thus we conclude that CT may be a risk factor to the occurrence of schizophrenia through its impact on sensory gating.

Associations and Heritability of Auditory Encoding, Gray Matter, and Attention in Schizophrenia.

Auditory encoding abnormalities, gray-matter loss, and cognitive deficits are all candidate schizophrenia (SZ) endophenotypes. This study evaluated associations between and heritability of auditory network attributes (function and structure) and attention in healthy controls (HC), SZ patients, and unaffected relatives (UR). Whole-brain maps of M100 auditory activity from magnetoencephalography recordings, cortical thickness (CT), and a measure of attention were obtained from 70 HC, 69 SZ patients, and 35 UR. Heritability estimates (h2r) were obtained for M100, CT at each group-difference region, and the attention measure. SZ patients had weaker bilateral superior temporal gyrus (STG) M100 responses than HC and a weaker right frontal M100 response than UR. Abnormally large M100 responses in left superior frontal gyrus were observed in UR and SZ patients. SZ patients showed smaller CT in bilateral STG and right frontal regions. Interrelatedness between 3 putative SZ endophenotypes was demonstrated, although in the left STG the M100 and CT function-structure associations observed in HC and UR were absent in SZ patients. Heritability analyses also showed that right frontal M100 and bilateral STG CT measures are significantly heritable. Present findings indicated that the 3 SZ endophenotypes examined are not isolated markers of pathology but instead are connected. The pattern of auditory encoding group differences and the pattern of brain function-structure associations differ as a function of brain region, indicating the need for regional specificity when studying these endophenotypes, and with the presence of left STG function-structure associations in HC and UR but not in SZ perhaps reflecting disease-associated damage to gray matter that disrupts function-structure relationships in SZ.

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.

Disrupted Asymmetry of Inter- and Intra-Hemispheric Functional Connectivity in Patients with Drug-Naive, First-Episode Schizophrenia and Their Unaffected Siblings

Background: Lack of normal asymmetry in the brain has been implicated in schizophrenia. However, it remains unclear whether disrupted asymmetry originates from inter-hemispheric functional connectivity (FC) and/or intra-hemispheric FC in patients with schizophrenia. Methods: Forty-four patients with drug-naive, first-episode schizophrenia, 42 unaffected siblings, and 44 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The parameter of asymmetry (PAS) and support vector machine (SVM) were used to analyze the data. Patients were treated with olanzapine for 8 weeks. Findings: Compared with healthy controls, patients showed lower PAS scores in the left middle temporal gyrus (MTG)/inferior temporal gyrus (ITG), left posterior cingulate cortex (PCC)/precuneus and left angular gyrus, and higher PAS scores in the left precentral gyrus/postcentral gyrus. Unaffected siblings also showed lower PAS scores in the left MTG/ITG and left PCC/precuneus relative to healthy controls. Further, SVM analysis showed that a combination of the PAS scores in these two clusters in patients at baseline was able to predict clinical response after 8 weeks of olanzapine treatment with 77.27% sensitivity, 72.73% specificity, and 75.00% accuracy. Interpretation: The present study suggests disrupted asymmetry of inter- and intra-hemispheric FC in drug-naive, first-episode schizophrenia; in addition, a reduced asymmetry of inter-hemispheric FC in the left MTG/ITG and left PCC/precuneus may serve as an endophenotype for schizophrenia, and may have clinical utility to predict response to olanzapine treatment. Funding: National Key R&D Program of China and National Natural Science Foundation of China. Conflict of Interest: Dr Fan reports receiving research support from the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, the Stanley Medical Research Institute, the Baer Foundation, the Shine Foundation, the Vanguard Group, Janssen, Avanir Pharmaceuticals, Neurocrine, and Alkermes, and reports receiving honoraria for serving on an advisory board for Allergen. Other authors have nothing to disclose. Ethical approval statement: The study was approved by the ethics committees of the Second Affiliated Hospital of Guangxi Medical University. All subjects signed a written informed consent.

Assessment of Neurocognitive Functions in 7-Year-Old Children at Familial High Risk for Schizophrenia or Bipolar Disorder

Children at familial high risk of schizophrenia spectrum disorders (FHR-SZ) or bipolar disorder (FHR-BP) exhibit neurocognitive impairments. Large studies of neurocognition in young children at familial high risk at the same age are important to differentiate the pathophysiology and developmental trajectory of these 2 groups. To characterize neurocognitive functions in 7-year-old children with FHR-SZ or FHR-BP and a control population. This multisite population-based cohort study collected data from January 1, 2013, to January 31, 2016, in the first wave of the Danish High Risk and Resilience Study VIA 7 at 2 university hospital research sites in Copenhagen and Aarhus using Danish registries. Participants (n = 514) included 197 children with FHR-SZ, 118 with FHR-BP, and 199 controls matched with the FHR-SZ group for age, sex, and municipality. Assessors were blinded to risk status. Parents with schizophrenia, bipolar disorder, or neither diagnosis. Neurocognitive functions were measured across 23 tests. Four neurocognitive domains were derived by principal component analysis, including processing speed and working memory, verbal functions, executive and visuospatial functions, and declarative memory and attention. A total of 514 children aged 7 years were included in the analysis (46.3% girls), consisting of 197 children with FHR-SZ (46.2% girls), 118 with FHR-BP (46.6% girls), and 199 controls (46.2% girls). Children with FHR-SZ were significantly impaired compared with controls on processing speed and working memory (Cohen d = 0.50; P < .001), executive and visuospatial functions (Cohen d = 0.28; P = .03), and declarative memory and attention (Cohen d = 0.29; P = .02). Compared with children with FHR-BP, children with FHR-SZ performed significantly poorer in processing speed and working memory (Cohen d = 0.40; P = .002), executive and visuospatial functions (Cohen d = 0.35; P = .008), and declarative memory and attention (Cohen d = 0.31; P = .03). Children with FHR-BP and controls did not differ. Children with FHR-SZ had widespread neurocognitive impairments, supporting the hypothesis of neurocognitive functions as endophenotypes of schizophrenia. The absence of neurocognitive deficits in children with FHR-BP suggests distinct neurodevelopmental manifestations in these familial high-risk groups at this age. Early detection of children with FHR-SZ and cognitive impairments is warranted to investigate associations of neurocognition with transition to psychosis, add to the knowledge of their developmental pathophysiology, and inform early intervention programs.

Higher-order language dysfunctions as a possible neurolinguistic endophenotype for schizophrenia: Evidence from patients and their unaffected first degree relatives.

The purpose of the study was to examine the presence of pragmatic dysfunctions in first episode (FE) subjects and their healthy first degree relatives as a potential endophenotype for schizophrenia. Thirty-four FE patients, 34 parents of the patients (REL) and 32 healthy controls (HC) took part in the study. Pragmatic language functions were evaluated with the Right Hemisphere Language Battery, attention and executive functions were controlled, as well as age and education level. The parents differed from HC but not from their FE offspring with regard to overall level of language and communication and the general knowledge component of language processing. The FE participants differed from HC in comprehension of inferred meaning, emotional prosody, discourse dimensions, overall level of language and communication, language processing with regard to general knowledge and communication competences. The FE participants differed from REL regarding discourse dimensions. Our findings suggest that pragmatic dysfunctions may act as vulnerability markers of schizophrenia; their assessment may help in the diagnosis of early stages of the illness and in understanding its pathophysiology. In future research the adoptive and biological parents of schizophrenia patients should be compared to elucidate which language failures reflect genetic vulnerability and which ones environmental factors.

S209. Genome-Wide Association of Endophenotypes for Schizophrenia From the Consortium On the Genetics of Schizophrenia (COGS) Study

We have previously reported our efforts to characterize the genetic architecture of 12 heritable endophenotypes for schizophrenia in the COGS-1 family sample. Candidate gene association and genome-wide linkage results converge on a single network related to glutamate signaling. We now report genome-wide association results for these endophenotypes in an independent cohort of schizophrenia cases and controls.

T62. COMPARISON OF NEUROCOGNITIVE FUNCTIONS IN FIRST-EPISODE SCHIZOPHRENIA PATIENTS, NON-PSYCHOTIC SIBLINGS, AND INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundNeurocognitive impairment is a core feature of schizophrenia, and has been observed among healthy non-psychotic siblings of schizophrenia patients as well as individuals at clinical high-risk (CHR) for psychosis. Thus far, few studies have directly contrasted neurocognitive performance between non-psychotic siblings and CHR samples. Potential differential patterns of neurocognitive deficits among schizophrenia patients, familial high-risk and CHR samples remain to be clarified. This study aimed to compare neurocognitive functions among first-episode schizophrenia (FES) patients, their non-psychotic siblings, CHR individuals, and healthy controls.MethodsFES patients (n=69, mean age=25.3) and CHR individuals (n=97, mean age=21.1) without family history of psychosis were recruited from a territory-wide specialized early intervention service for psychosis in Hong Kong. A group of non-psychotic siblings of FES patients (n=50, mean age=25.4) and healthy controls (HC) (n=68, mean age=24.5) were also recruited. A standardized battery of neurocognitive tests encompassing working memory, processing speed, executive function, visual memory, verbal learning, and sustained attention was administered. Group differences were examined using analysis of covariance (ACOVA) with Bonferroni correction applied for statistical significance (P<0.008), controlling for age and years of education.ResultsCompared with HC, FES patients exhibited significantly poorer performance across all neurocognitive domains (Hedges g ranged: 0.48–1.73), while CHR individuals demonstrated significantly worse neurocognitive functioning in all domains (Hedges g ranged: 0.53–1.15) but sustained attention. Non-psychotic performed significantly worse than HC in executive function (Hedges g=0.63, p<0.001), visual memory (Hedges g=0.57, p=0.002), verbal learning (Hedges g=0.52, p=0.001), and working memory (Hedges g=0.37, p=0.003). Among four groups, FES patients displayed the most severe neurocognitive impairment. The pattern of neurocognitive dysfunction was similar between CHR and non-psychotic sibling groups, except for processing speed, of which CHR individuals demonstrated greater degree of impairment than siblings in digit symbol coding test (p<0.001).DiscussionOur results indicate a gradient of neurocognitive impairment across FES, CHR and non-psychotic sibling samples, reflecting differential degrees of psychosis liability. Processing speed, as measured by digit symbol coding test, demonstrated the highest discriminant utility in discriminating CHR from familial high-risk individuals. Our findings thus confirm the critical role of neurocognitive dysfunction as a reliable risk indicator and an endophenotype for schizophrenia and related psychoses.

S132. A NORMATIVE CHART FOR THE TRAJECTORY OF COGNITIVE FUNCTIONING IN INDIVIDUALS AT HIGH RISK FOR SCHIZOPHRENIA: LONGITUDINAL FINDINGS FROM THE INTERNATIONAL BRAIN AND BEHAVIOR CONSORTIUM ON 22Q11.2 DELETION SYNDROME

BackgroundIn schizophrenia, a decline in cognitive functioning often precedes the onset of the first psychotic episode by many years. We have previously shown this to be the case for individuals with 22q11.2 deletion syndrome (22q11DS), a genetic variant associated with a 20–25% risk of developing schizophrenia. We also observed that, regardless of the subsequent development of psychosis, individuals with 22q11DS show, on average a modest decline in IQ between 8 and 24 years and that in those who develop a psychotic disorder this decline follows a steeper trajectory. The tendency for a modest cognitive decline may represent a cognitive phenotype that is specific to 22q11DS, and possibly, an endophenotype for schizophrenia in this population. In order to assess this, we constructed a normative chart for cognitive development over time in individuals with 22q11DS.MethodsWe made use of the International Brain and Behavior Consortium on 22q11DS (IBBC) database that includes cross-sectional and longitudinal cognitive data from 1871 individuals with 22q11DS (mean age 15.7, SD 7.4, years; n = 330 (17.6%) with schizophrenia). All IQ measurements were obtained by qualified personnel using Wechsler tests, including WPPSI, WISC and WAIS, depending on the participants’ ages. We used all available IQ data points obtained in the age range 6 - 40 years to construct normative charts for Full Scale IQ (FSIQ), Verbal IQ (VIQ) and Performance IQ (PIQ), after a comprehensive quality control procedure to ensure reliable and comparable IQ data across all international sites. We used a polynomial regression model, similar to what is used in standardized international growth charts for height and weight, to create the normative chart.ResultsThe 4th order polynomial regression provided a good fit for the IQ data from our sample, allowing for the observed larger variability in very young age groups. On average, between the ages of 6 and 40 years, the 22q11DS population showed a gradual, modest decline in FSIQ, VIQ and PIQ. Consistent with our previous results, individuals who went on to develop schizophrenia showed a steeper decline, representing a deviation from their expected trajectory, than those who had no documented psychotic illness.DiscussionThis study is, to our knowledge, the first to demonstrate that a normative chart for cognitive development through to adulthood can be reliably constructed for a genetically selected high-risk population. This normative chart can be readily applied both in clinical care and in research and may serve as an example for constructing similar normative charts in other high-risk groups and/or genetic disorders.