Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study

Background First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes. Methods We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS. Results In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group. Conclusions The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Background. A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. Methods. This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. Results. ES-SCZ was associated with the GAF dimensions in patients (symptom: B = 1.53, p-value = 0.001; disability: B = 1.44, p-value = 0.001), siblings (symptom: B = 3.07, p-value < 0.001; disability: B = 2.52, p-value < 0.001), and healthy controls (symptom: B = 1.50, p-value < 0.001; disability: B = 1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group. Conclusions. Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management

Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy‐genetic liability measures suggest gene‐environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS‐SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene‐environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS‐SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early‐life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS‐SCZ at 75% with alternative cut‐points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p <0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p <0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p <0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p <0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p <0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EU-GEI)

White noise speech illusions: A trait-dependent risk marker for psychotic disorder?

Introduction: White noise speech illusions index liability for psychotic disorder in case-control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. Methods: The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control -> sibling -> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. Results: While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls -> siblings -> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02-1.21, p = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79-1.09, p = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher (p interaction = 0.003; ORlow CAPE positive scale 0.96, 95% CI 0.85-1.07; ORhigh CAPE positive scale 1.26, 95% CI 1.09-1.46); cognitive ability was lower (p interaction < 0.001; ORhigh cognitive ability 0.94, 95% CI 0.84-1.05; ORlow cognitive ability 1.43, 95% CI 1.23-1.68); and exposure to childhood adversity was higher (p interaction < 0.001; ORlow adversity 0.92, 95% CI 0.82-1.04; ORhigh adversity 1.31, 95% CI 1.13-1.52). A similar, although less marked, pattern was seen for categorical patient-control and sibling-control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk (p interaction = 0.232). Conclusion: The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker

Examining facial emotion recognition as an intermediate phenotype for psychosis: findings from the EUGEI study

Background Social cognition impairments, such as facial emotion recognition (FER), have been acknowledged since the earliest description of schizophrenia. Here, we tested FER as an intermediate phenotype for psychosis using two approaches that are indicators of genetic risk for schizophrenia: the proxy-genetic risk approach (family design) and the polygenic risk score for schizophrenia (PRS-SCZ). Methods The sample comprised 2039 individuals with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). The Degraded Facial Affect Recognition Task (DFAR) was applied to measure the FER accuracy. Schizotypal traits in siblings and HC were assessed using the Structured Interview for Schizotypy-Revised (SIS-R). The PRS-SCZ was trained using the Psychiatric Genomics Consortium results. Regression models were applied to test the association of DFAR with psychosis risk, SIS-R, and PRS-SCZ. Results The DFAR-total scores were lower in individuals with schizophrenia than in siblings (RR = 0.97 [95% CI 0.97, 0.97]), who scored lower than HC (RR = 0.99 [95% CI 0.99–1.00]). The DFAR-total scores were negatively associated with SIS-R total scores in siblings (B = −2.04 [95% CI −3.72, −0.36]) and HC (B = −2.93 [95% CI −5.50, −0.36]). Different patterns of association were observed for individual emotions. No significant associations were found between DFAR scores and PRS-SCZ. Conclusions Our findings based on a proxy genetic risk approach suggest that FER deficits may represent an intermediate phenotype for schizophrenia. However, a significant association between FER and PRS-SCZ was not found. In the future, genetic mechanisms underlying FER phenotypes should be investigated trans-diagnostically

Clustering schizophrenia genes by their temporal expression patterns aids functional interpretation

Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia

Effects of paliperidone extended release on functioning level and symptoms of patients with recent onset schizophrenia: An open-label, single-arm, flexible-dose, 12-months follow-up study

Background: Response to antipsychotic treatment is better in the early stages of schizophrenia. Aims: The primary objective of this non-randomized, single-arm, multicenter clinical trial was to explore the response to treatment and safety of a flexible dose of paliperidone (mean = 6.42 mg/day) in patients with recent onset schizophrenia (< 3 years after the first episode/hospitalization). Methods: Severity of clinical symptoms was evaluated by the Positive and Negative Syndrome Scale (PANSS), functioning was assessed using the Global Assessment of Functioning (GAF) scale and the Personal and Social Performance Scale (PSP). Results: In a total of 85 patients enrolled, 80 patients were eligible. Total PSP score at baseline (50.2 +/- 11.6) increased at all visits. Total PSP score was 65.4 +/- 12.1 at month 12 (P < 0.001). GAF scores were significantly higher at all visits compared with baseline (P = 0.001). It was 62.4 +/- 12.5 with an increase of 42.9% at month 12 (P < 0.001). PANSS Positive and Negative subscales and General psychopathology subscale scores showed significant reductions beginning with month 3 and were 11.9 +/- 3.8 (29.3%; P < 0.001), 13.7 +/- 5.6 (27.3% P < 0.001) and 27.8 +/- 7.1 (23.2%; P < 0.001) at month 12, respectively. Twelve patients (14.3%) had a serious adverse event. The most common adverse events were insomnia (17.9%), nausea (8.3%), akathisia (4.8%), anxiety (4.8%) and depression (4.8%). Body weight values at the end of the study were significantly higher compared with baseline. Conclusion: The present study demonstrates that flexible dose of paliperidone resulted in a significant improvement in functioning and reduction in symptoms in patients with recent onset schizophrenia

Normal ve major depresyonlu hasta populasyonlarında duygusal çelişki çözümlemenin beyindeki fonksiyonel lokalizasyonu ve etken nöroanatomik morfolojik faktörlerin incelenmesi

TÜBİTAK EEEAG01.06.2012Dünya Sağlık Örgütü’nün açıklamalarına göre depresyon dünya çapında 120 milyondan fazla insanı etkisi altına almış olan ve kimi zaman intiharla sonuçlanabilen, dolayısıyla anlaşılması önem arzeden bir hastalıktır. Depresyon hastalarının bilişsel ve emosyonel fonksiyonlarında (ör: çelişki çözümleme, dikkat, motivasyon, ve amaca yönelik işlevler) pek çok davranışsal, metabolik ve beyin aktivasyonu bozuklukları tespit edilmiştir. Bu bozuklukların önemli bir kısmı, prefrontal bölgedeki pek çok anatomik yapı ile direkt bağlantıları olan anterior-singulat kortekste lokalize olmuş durumdadır. Öte yandan, depresyonlu hastaların beyinleri ile normal beyinler yapısal olarak karşılaştırıldığında, hastaların beyinlerinde gözlenen en önemli farklılıklar, prefrontal korteksin ve limbik sistemin karşılıklı olarak bağlantısı olan bölgelerindeki (ör: amygdala, hippocampus, parahippocampal girus, anterior singulat korteks, orbito-frontal korteks) hacimsel azalmalardır. Bu farklılıklar bilinmekle birlikte, günümüzde morfolojik ve fonksiyonel nörogörüntüleme alanında geliştirilmiş en son teknikleri birarada kullanarak depresyondaki yapısal ve işlevsel sorunları aynı anda ele alan çalışma pek azdır. Projemizde nörogörüntülemedeki en son teknikler kullanılarak ve yeni teknikler geliştirilerek önemli bir işlevsel bozukluk olan duygusal-çelişki çözümlemenin depresyonlu hastaların beynindeki lokalizasyonu ve fonksiyonel sorunların oluşmasında etken olabilecek yapısal faktörler incelenmektedir. MR görüntülerinde anterior-singulat korteksin ve alt-bölgelerinin dokusal karakteristiği, T1, longitudinal relaksasyon zamanı üzerinden araştırılmaktadır. Buradaki bulgular, diğer yapısal özellikler olan hacim ve korteks kalınlığı ile ilişkilendirilmektedir. Diğer taraftan Anterior singulat korteks tarafından üstlenilen duygusal çelişki çözümleme işlevi, kendi geliştirdiğimiz bir bilgisayar testi kullanılarak fMR görüntüleme ile araştırılmaktadır. Sağlıklı ve depresyonlu bireylerdeki beyin aktivitesi haritaları istatistiksel yöntemlerle karşılaştırılmaktadır. Çalışmalarımız sonucunda üç temel bulguya ulaşmak mümkün olmuştur: 1. Sağlıklı bireylerde Anterior singulat kortekstte Dorsal, Rostral ve ventral bölgelerde doku farklılıkları mevcuttur 2. Sağlıklı bireylerde çelişki çözümleme işlevi Dorsal ACC, uyaranın duygusal değerlendirmesi Rostral ve Ventral ACC’de odaklanmıştır. 3. Duygusal Çelişki çözümleme 5 testinde, hasta ve sağlıklı bireyler arasında Rostral ACC, Dorsal ACC ve Orbitofrontal kortekste beyin aktivitesi farklılıkları mevcuttur. Depresyonlu hasta sayısı arttırılabilirse, hacimsel ve korteks kalınlığı gibi yapısal farklılıkları da daha detaylı olarak incelememiz mümkün olacaktır.According to the World Health Organization, depression is a debilitating disease affecting some 120 million people worldwide, sometimes even resulting in suicide. Many behavioral, metabolic and brain activation disorders have been found in the cognitive and emotional functions (ex: conflict resolution, attention, motivation, goal-oriented-behavior) of depressive patients. An important fraction of these dysfunctionalities have been localized in the anterior- cingulate cortex, which is connected to a multitude of anatomical structures in the prefrontal lobe. On the other hand, when the brains of depression patients and healthy controls are compared morphologically, major differences in terms of volumetric reductions are found in the patients' brains, mostly in regions in the prefrontal and limbic systems (such as: amygdala, hippocampus, parahippocampal gyrus, anterior cingulate cortex (ACC), orbito-frontal cortex, which are conjoined reciprocally. Although these differences have been reported for a while now, there are very few depression studies which investigate the structural and functional problems at the same time using the most recent technological developments in neuroimaging. In this project, we are investigating the localization of problems in emotional conflict resultion in the depressive patients' brains, as well as the underlying structural factors using existing state-of-the-art techniques as well as new techniques developed by us. Through the newly intended structural technique, the structural charateristics of the anterior-cingulate cortex will be investigated, based on the T1 longitudinal relaxation times. These findings are being correlated with other structural measurements such as volume and cortical thickness. On another front, we are studying the emotional conflict resolution process localized to the anterior cingulate cortex through a new emotional conflict test that we have developed for administration during fMRI. We then investigate the brain activity maps of the healthy and depressed populations through statistical analysis. At the end of our investigations, we were able to reach three principal findings: 1. In the healthy brains, there exist tissue differences in the Dorsal, Rostral and Ventral compartments of the ACC. 2. The conflict resolution process is centered at the Dorsal ACC of healthy 7 population, while evaluation of the emotional stimuli is localized to the Rostral and ventral Areas of ACC. 3. In the emotional conflict resolution test, helathy and depressed populations show acitivity differences at the Rostral, Dorsal ACC as well as Orbitofrontal Cortex. If we are able to increase the scans for depressed population, we will be able to investigate the volume and cortical differences in more detail