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

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)

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

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

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

Exploring the Role of Social Anhedonia in the Positive and Negative Dimensions of Schizotypy in a Non-Clinical Sample

INTRODUCTION: The present study aimed to investigate the role of social anhedonia, defined as the lack of ability to feel pleasure from interpersonal relationship, in a multidimensional model of schizotypy and to determine the psychometric properties of the Turkish version of Chapman’s Revised Social Anhedonia Scale (SAS) in a non-clinical sample. METHODS: Second-grade students of Ankara University Medical Faculty were recruited (n=266, Mage=20.28). Confirmatory factor analysis was performed to test schizotypy dimensions. The Cronbach’s alpha internal consistency value, test–retest reliability and congruent validity of SAS were calculated. RESULTS: The model in which social anhedonia was allowed to load on both schizotypy dimensions fit the data set better than the model in which social anhedonia was allowed to load on negative dimension alone. The internal consistency assessed with Cronbach’s alpha was .84, test–retest reliability was r=.76 and the congruent validity of SAS was r=.55. CONCLUSION: The results of current study were consistent with those of earlier studies showing that social anhedonia was related to both schizotypy dimensions. Furthermore, the psychometric properties of the Turkish Version of SAS revealed that it is a reliable and valid measurement to assess social anhedonia in a non-clinical population

ARTICLE IN PRESS Fragile X Premutation in Adult Psychiatry: Four Cases and Overview of Clinical Presentation 2

SUMMARY Fragile X carrier status, also named as Fragile X premutation (FraX-PM), is defined by trinucleotide repeat expansions of shorter length compared to those that cause the full syndrome. Its clinical significance has been limited to the risk of further expansion to a full mutation in the offspring of carriers, until it was recently recognized as a clinical syndrome on its own, manifested by unique symptom constellations, as well as a combination of neuropsychiatric signs and symptoms that may be indistinguishable from several commonly seen disorders. The complex heterogeneity of its neuropsychiatric manifestations may render the diagnosis challenging, unless the clinician is familiar with the clinical picture and transmission pattern. We present four cases of FraX-PM, diagnosed in an adult psychiatry setting and confirmed by genetic testing. The aim of this report is to increase familiarity among psychiatric practitioners, since this common condition is seldom included in the current diagnostic practice, which is based on atheoretical definitions