Familial Risk For Schizophrenia Research Articles

Social exclusion as a major outcome domain of psychotic disorders: early predictors, and associations with non-recovery and clinical staging 21years after a first episode of psychosis.

People with psychotic disorders have high levels of social exclusion; however, little is known about its early predictors. We present a long-term observational cohort study aimed at examining early risk factors for later social exclusion. A total of 243 subjects were assessed at their first psychotic episode for early risk factors including sociodemographic variables, familial risk of major mental disorders, perinatal complications, childhood factors, and adolescent factors and re-assessed after a mean follow-up of 21years for 12 social exclusion domains: leisure activities, housing, work, income, neighborhood deprivation, educational attainment, physical and mental health, family and social support, legal competence, and discrimination. The ability of risk factors to predict social exclusion was examined using hierarchical linear regression. Overall social exclusion was independently predicted by low parental socio-economic status, length of follow-up, familial risk of schizophrenia, obstetric complications, neurodevelopmental delay, poor childhood adjustment, childhood adversity, poor adolescent social networks, poor adolescent adjustment, and low premorbid IQ. The model explained 58.2% of the variance in total social exclusion score. Each social exclusion domain was predicted by a different set of variables, which explained between 17.8 and 57.0% of their variance, although low socio-economic status, familial risk of schizophrenia, obstetric complications, childhood adversity, and poor social networks predicted most of the social exclusion domains. Early risk factors strongly predicted later social exclusion. A multifaceted approach to preventing later social exclusion is crucial in people with a first episode of psychosis and early risk factors of social exclusion.

Impaired mnemonic discrimination in children and adolescents at risk for schizophrenia

People with schizophrenia and their high-risk, first-degree relatives report widespread episodic memory impairments that are purportedly due, at least in part, to failures of mnemonic discrimination. Here, we examined the status of mnemonic discrimination in 36 children and adolescents (aged 11–17 years) with and without familial risk for schizophrenia by employing an object-based recognition task called the Mnemonic Similarity Task (MST). The MST assesses the ability to discriminate between studied images and unstudied images that are either perceptually similar to studied images or completely novel. We compared 16 high-risk, unaffected first-degree relatives of people with schizophrenia, bipolar disorder, and/or schizoaffective disorder to 20 low-risk, control participants. High-risk participants showed worse mnemonic discrimination than low-risk participants, with no difference in recognition memory or perceptual discrimination. Our findings demonstrate that mnemonic discrimination deficits previously observed in people with schizophrenia are also present in their young, high-risk, first-degree relatives.

Epigenetic age deacceleration in youth at familial risk for schizophrenia and bipolar disorder

Epigenetic modifications occur sequentially during the lifespan, but their pace can be altered by external stimuli. The onset of schizophrenia and bipolar disorder is critically modulated by stressors that may alter the epigenetic pattern, a putative signature marker of exposure to environmental risk factors. In this study, we estimated the age-related epigenetic modifications to assess the differences between young individuals at familial high risk (FHR) and controls and their association with environmental stressors. The sample included 117 individuals (6–17 years) at FHR (45%) and a control group (55%). Blood and saliva samples were used estimate the epigenetic age with six epigenetic clocks through methylation data. Environmental risk was measured with obstetric complications, socioeconomic statuses and recent stressful life events data. Epigenetic age was correlated with chronological age. FHR individuals showed epigenetic age deacceleration of Horvath and Hannum epigenetic clocks compared to controls. No effect of the environmental risk factors on the epigenetic age acceleration could be detected. Epigenetic age acceleration adjusted by cell counts showed that the FHR group was deaccelerated also with the PedBE epigenetic clock. Epigenetic age asynchronicities were found in the young at high risk, suggesting that offspring of affected parents follow a slower pace of biological aging than the control group. It still remains unclear which environmental stressors orchestrate the changes in the methylation pattern. Further studies are needed to better characterize the molecular impact of environmental stressors before illness onset, which could be critical in the development of tools for personalized psychiatry.

Is motor function a potential therapeutic target in individuals at risk of psychosis?

The Article by Birgitte Klee Burton and colleagues1 in The Lancet Psychiatry investigated the development of motor skills in a large sample of children with a familial risk of schizophrenia or bipolar disorder at age 8 years and again at age 12 years, and compared their performance with that of a group of children with no familial risk of either schizophrenia or bipolar disorder. The authors showed that children of parents with one of these diagnoses had more than two times higher odds of having definite motor problems, and that for children of parents with a diagnosis of schizophrenia these problems remained stable across time.

The Strengths and Difficulties Questionnaire Is of Clinical Significance Regarding Emotional and Behavioral Problems in 7-Year-Old Children With Familial Risk of Schizophrenia or Bipolar Disorder and Population-Based Controls the Danish High Risk and Resilience Study-VIA 7; A Population-Based Cohort Study.

BackgroundChildren born to parents with severe mental illness are at increased risk of mental and behavioral difficulties during childhood. We aimed to investigate the occurrence of clinically significant behavioral difficulties in 7-year-old children of parents diagnosed with schizophrenia or bipolar disorder as well as in control children by using the Strengths and Difficulties Questionnaire (SDQ). Further, we aimed to determine if the SDQ could function as a screening instrument for clinically relevant behavioral problems of children at high risk of these severe mental illnesses.MethodsBy means of the Danish National Registers, we established a cohort of 522 7-year old children stratified by familial high risk for schizophrenia spectrum disorder (N = 202), bipolar disorder (N =120), and controls (N = 200). The child's primary caregiver completed the SDQ parent version and the Child Behavior Checklist (CBCL) while the schoolteacher completed the SDQ teacher version and the CBCL teacher equivalent; the Teachers Report Form (TRF). Finally, global functioning was assessed with the Children's Global Assessment Scale (CGAS).ResultsChildren with familial high risk of schizophrenia spectrum disorder or bipolar disorder have a significantly increased risk (OR = 3.8 and 2.3) of suffering clinically significant behavioral difficulties at age 7-years according to SDQ parent ratings. The SDQ discriminates with moderate to high sensitivity and high specificity between familial high-risk children with and without a psychiatric diagnosis and has overall compelling discriminatory abilities in line with the more time consuming CBCL/TRF.Conclusions Familial high-risk children have more behavioral difficulties and more frequently at a level indicative of mental illness compared to control children as measured by the SDQ. The SDQ works well as a screening instrument for clinically relevant behavioral problems in high-risk children.

Sex differences across developmental domains among children with a familial risk of severe mental disorders.

Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls. Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment. FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls. Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

Exploring protective and risk factors in the home environment in high-risk families \u2013 results from the Danish High Risk and Resilience Study\u2014VIA 7

BackgroundExposure to inadequate home environment may put the healthy development of familial high-risk children at risk. This study aimed to investigate associations between risk factors and an adequate home environment of children having a parent diagnosed with schizophrenia or bipolar disorder.MethodsFrom a cohort of 522 children, data from 463 7-year-old children was included. Of these 172 children had familial risk for schizophrenia, 109 children had familial risk for bipolar disorder, and 190 were population-based controls. As part of a comprehensive battery, all participants were assessed with the Middle Childhood-Home Observation for Measurement of the Environment Inventory (MC-HOME Inventory) measuring the quality of the home environment.ResultsWhen analyzing all families together, we found that having a parent diagnosed with schizophrenia would have a negative impact on the home environment (ß = -1.08; 95% CI (-2.16;-0.01); p = 0.05), while familial risk for bipolar disorder did not show significant predictive value. Being a single caregiver and child having experienced severe life events from ages 4 to 7 showed significant negative impact, while child having a mental illness diagnosis did not. Being a female caregiver, good social functioning of the caregiver, high child IQ and not being a single caregiver were found to predict positive values for the home environment. We found similar results when analyzing caregivers with and without a diagnosis separately.ConclusionsKnowledge of what predicts good home environment should be used to inform development of early interventions for families at risk.

Association Between Early Risk Factors and Level of Functioning at Age Seven in Children at Familial Risk for Schizophrenia Or Bipolar Disorder - the Danish High Risk and Resilience Study VIA 7.

Facing multiple risk factors, relative to single risk factor exposure early in life can have great implications for negative child development. We aim to examine whether the prevalence of early risk factors is higher among children with familial high risk for schizophrenia or bipolar disorder compared to controls. Further, to investigate the association between number of early risk factors and level of functioning at age seven, and whether this possible association is different in children with familial high risk compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study of children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) and controls (N = 200). We conducted a semi-structured anamnestic interview with the child's primary caregiver to assess early risk factors from pregnancy to age four. We used the Children's Global Assessment Scale to measure level of functioning at age seven. 13 out of 17 risk factors were more prevalent in children at familial high risk for schizophrenia and 7 out of 17 risk factors were more prevalent in children at familial high risk for bipolar disorder compared to controls. Level of functioning decreased 2.7 (95% CI, 2.2; 3.3)-points per risk factor, but the association was not significantly different across the three groups (p = 0.09). Our results showed that children at age seven with familial high risk for schizophrenia or bipolar disorder experience a greater number of early risk factors. A higher number of early risk factors were associated with lower level of functioning at age seven. However, the association is not different for children with familial high risk or controls.

Altered Effective Connectivity within an Oculomotor Control Network in Unaffected Relatives of Individuals with Schizophrenia.

The ability to rapidly stop or change a planned action is a critical cognitive process that is impaired in schizophrenia. The current study aimed to examine whether this impairment reflects familial vulnerability to schizophrenia across two experiments comparing unaffected first-degree relatives to healthy controls. First, we examined performance on a saccadic stop-signal task that required rapid inhibition of an eye movement. Then, in a different sample, we investigated behavioral and neural responses (using fMRI) during a stop-signal task variant that required rapid modification of a prepared eye movement. Here, we examined differences between relatives and healthy controls in terms of activation and effective connectivity within an oculomotor control network during task performance. Like individuals with schizophrenia, the unaffected relatives showed behavioral evidence for more inefficient inhibitory processes. Unlike previous findings in individuals with schizophrenia, however, the relatives showed evidence for a compensatory waiting strategy. Behavioral differences were accompanied by more activation among the relatives in task-relevant regions across conditions and group differences in effective connectivity across the task that were modulated differently by the instruction to exert control over a planned saccade. Effective connectivity parameters were related to behavioral measures of inhibition efficiency. The results suggest that individuals at familial risk for schizophrenia were engaging an oculomotor control network differently than controls and in a way that compromises inhibition efficiency.

Cognitive heterogeneity in the offspring of patients with schizophrenia or bipolar disorder: a cluster analysis across family risk

BackgroundNeurocognitive impairment is considered to lie on a continuum of severity across schizophrenia (SZ) and bipolar disorder (BP), possibly reflecting a gradient of neurodevelopmental load. Cluster analyses have identified different levels of impairment across the two disorders, from none to widespread and severe. We for the first time used this approach to examine cognitive function pooling together children and adolescents at familial risk of SZ or BP. Methods220 participants, 49 offspring of individuals with schizophrenia (SZO), 90 offspring of individuals with bipolar disorder (BPO) and 81 offspring of healthy control parents (HC), aged 6 to 17 years, underwent a comprehensive clinical and cognitive assessment. Cognitive measures were used to group SZO and BPO using K-means clustering. Cognitive performance within each of the clusters was compared to that of HC and clinical variables were compared between clusters. ResultsWe identified three cognitive subgroups: a moderate impairment group, a mild impairment group, and a cognitively intact group. Both SZO and BPO were represented in each of the clusters, yet not evenly, with a larger proportion of the SZO in the moderately impaired cluster, but also a subgroup of BPO showing moderate cognitive dysfunction. LimitationsParticipants have yet to reach the age of onset for the examined disorders. ConclusionsThe findings point to a range of neurodevelopmental loadings across youth at familial risk of both SZ and BP. They have therefore important implications for the stratification of cognitive functioning and the possibility to tailor interventions to individual levels of impairment.

Generative network models of altered structural brain connectivity in schizophrenia

Alterations in the structural connectome of schizophrenia patients have been widely characterized, but the mechanisms remain largely unknown. Generative network models have recently been introduced as a tool to test the biological underpinnings of altered brain network formation. We evaluated different generative network models in healthy controls (n=152), schizophrenia patients (n=66), and their unaffected first-degree relatives (n=32), and we identified spatial and topological factors contributing to network formation. We further investigated how these factors relate to cognition and to polygenic risk for schizophrenia. Our data show that among the four tested classes of generative network models, structural brain networks were optimally accounted for by a two-factor model combining spatial constraints and topological neighborhood structure. The same wiring model explained brain network formation across study groups. However, relatives and schizophrenia patients exhibited significantly lower spatial constraints and lower topological facilitation compared to healthy controls. Further exploratory analyses point to potential associations of the model parameter reflecting spatial constraints with the polygenic risk for schizophrenia and cognitive performance. Our results identify spatial constraints and local topological structure as two interrelated mechanisms contributing to regular brain network formation as well as altered connectomes in schizophrenia and healthy individuals at familial risk for schizophrenia. On an exploratory level, our data further point to the potential relevance of spatial constraints for the genetic risk for schizophrenia and general cognitive functioning, thereby encouraging future studies in following up on these observations to gain further insights into the biological basis and behavioral relevance of model parameters.

Brain structural trajectories in youth at familial risk for schizophrenia or bipolar disorder according to development of psychosis spectrum symptoms.

The evaluation of child and adolescent offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) may help understand changes taking place in the brain in individuals at heightened risk for disease during a key developmental period. One hundred twenty-eight individuals (33 SzO and 46 BpO, considered jointly as 'Familial High Risk' (FHR), and 49 controls) aged 6-17years underwent clinical, cognitive and neuroimaging assessment at baseline, 2- and 4-year follow-up. Twenty FHR participants (11 SzO and 9 BpO) developed psychotic spectrum symptoms during follow-up, while 59 FHR participants did not. Magnetic resonance imaging was performed on a 3Tesla scanner; cortical surface reconstruction was applied to measure cortical thickness, surface area and grey matter volume. FHR participants who developed psychotic spectrum symptoms over time showed greater time-related mean cortical thinning than those who did not and than controls. By subgroups, this effect was present in both BpO and SzO in the occipital cortex. At baseline, FHR participants who developed psychotic spectrum symptoms over time had smaller total surface area and grey matter volume than those who did not and than controls. Over time, all FHR participants showed less longitudinal decrease in surface area than controls. In those who developed psychotic spectrum symptoms over time, this effect was driven by BpO, while in those who did not, this was due to SzO, who also showed less grey matter volume reduction. The emergence of psychotic spectrum symptoms in FHR was indexed by smaller cross-sectional surface area and progressive cortical thinning. Relative preservation of surface area over time may signal different processes according to familial risk. These findings lay the foundation for future studies aimed at stratification of FHR youth.

S159. SUBCORTICAL GRAY MATTER VOLUME IS ASSOCIATED WITH SCHIZOPHRENIA AND WITH BOTH ITS FAMILIAL AND CLINICAL RISK

BackgroundPatients with schizophrenia (SCZ) show lower volumetric estimates of gray matter (GM) than healthy controls (HC). Similar results have been reported in healthy siblings of patients (SIB). However, it is unclear whether this phenotype is also present in individuals at clinical high-risk (CHR), characterized by sub-threshold symptoms and loss of functioning. We hypothesized that GM volumetric differences are associated with both familial and clinical risk for schizophreniaMethodsWe processed the T1-weighted MRI scans acquired at 3 Tesla of 544 HC, 63 SIB, 20 CHR and 120 SCZ using CAT12. We used ANCOVA to assess group differences (HC vs. CHR vs. SIB vs. SCZ), with linear and quadratic age, gender and total intracranial volume as nuisance covariates. We assessed the reproducibility of our case/control findings in an independent sample of 127 HC and 36 SCZ. Group differences were tested post hoc through Fisher’s test.ResultsWe found significant group effects in the bilateral thalamus, bilateral hippocampus and anterior cingulate (FWE<0.05). Specifically, SCZ presented the lowest GM volume in these regions compared to the other three groups, with SIB and CHR’s GM estimates intermediate between HC and SCZ (p<0.05). The associations with schizophrenia were replicated in the independent validation sample.DiscussionIndividuals with familial or clinical risk for schizophrenia have lower GM estimates in the same brain regions. These findings, suggest that these structural features are not only associated with familial risk for schizophrenia but that they are also associated with its sub-threshold symptoms.

Brain structure, IQ, and psychopathology in young offspring of patients with schizophrenia or bipolar disorder.

Studying offspring of schizophrenia (SZo) and bipolar disorder patients (BDo) provides important information on the putative neurodevelopmental trajectories underlying development toward severe mental illnesses. We compared intracranial volume (ICV), as a marker for neurodevelopment, and global and local brain measures between SZo or BDo and control offspring (Co) in relation to IQ and psychopathology. T1-weighted magnetic resonance imaging (MRI) brain scans were obtained from 146 participants (8-19 years; 40 SZo, 66 BDo, 40 Co). Linear mixed models were applied to compare ICV, global, and local brain measures between groups. To investigate the effect of ICV, IQ (four subtests Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale-III) or presence of psychopathology these variables were each added to the model. SZo and BDo had significantly lower IQ and more often met criteria for a lifetime psychiatric disorder than Co. ICV was significantly smaller in SZo than in BDo (d = -0.56) and Co (d = -0.59), which was largely independent of IQ (respectively, d = -0.54 and d = -0.35). After ICV correction, the cortex was significantly thinner in SZo than in BDo (d = -0.42) and Co (d = -0.75) and lateral ventricles were larger in BDo than in Co (d = 0.55). Correction for IQ or lifetime psychiatric diagnosis did not change these findings. Despite sharing a lower IQ and a higher prevalence of psychiatric disorders, brain abnormalities in BDo appear less pronounced (but are not absent) than in SZo. Lower ICV in SZo implies that familial risk for schizophrenia has a stronger association with stunted early brain development than familial risk for bipolar disorder.

Multivariate classification of schizophrenia and its familial risk based on load-dependent attentional control brain functional connectivity.

Patients with schizophrenia (SCZ), as well as their unaffected siblings (SIB), show functional connectivity (FC) alterations during performance of tasks involving attention. As compared with SCZ, these alterations are present in SIB to a lesser extent and are more pronounced during high cognitive demand, thus possibly representing one of the pathways in which familial risk is translated into the SCZ phenotype. Our aim is to measure the separability of SCZ and SIB from healthy controls (HC) using attentional control-dependent FC patterns, and to test to which extent these patterns span a continuum of neurofunctional alterations between HC and SCZ. 65 SCZ with 65 age and gender-matched HC and 39 SIB with 39 matched HC underwent the Variable Attentional Control (VAC) task. Load-dependent connectivity matrices were generated according to correct responses in each VAC load. Classification performances of high, intermediate and low VAC load FC on HC-SCZ and HC-SIB cohorts were tested through machine learning techniques within a repeated nested cross-validation framework. HC-SCZ classification models were applied to the HC-SIB cohort, and vice-versa. A high load-related decreased FC pattern discriminated between HC and SCZ with 66.9% accuracy and with 57.7% accuracy between HC and SIB. A high load-related increased FC network separated SIB from HC (69.6% accuracy), but not SCZ from HC (48.5% accuracy). Our findings revealed signatures of attentional FC abnormalities shared by SCZ and SIB individuals. We also found evidence for potential, SIB-specific FC signature, which may point to compensatory neurofunctional mechanisms in persons at familial risk for schizophrenia.

F205. OLFACTORY IDENTIFICATION IN 7-YEAR OLD CHILDREN AT FAMILIAL RISK TO DEVELOP SCHIZOPHRENIA

BackgroundOlfactory dysfunction has repeatedly been observed in individuals diagnosed with schizophrenia. The most stable and consistent finding on the behavioral level is that of smell identification deficits. However, the nature of olfactory identification abnormalities seems to extend to structural abnormalities in the underlying neurobiology of the olfactory system. Furthermore, smell identification deficits are also documented in first-episode patients and non-psychotic first-degree relatives of schizophrenia patients. Family members of schizophrenia patients also show structural abnormalities of the olfactory system, suggesting that these may serve as an endophenotype for the development of schizophrenia.Only a few studies examined the olfactory identification ability in adolescents at-risk for schizophrenia and suggested smell identification deficits as a risk marker for schizophrenia. These studies included adolescents at clinical as well as at genetic risk for schizophrenia. None of these studies focused on children at genetic risk for schizophrenia. Therefore, we investigated the olfactory identification ability in children of parents with schizophrenia in comparison to children of parents without a psychotic disorder. As we are also interested in the specificity of the olfactory impairments to schizophrenia, we included children of parents with bipolar disorder. We hypothesize that children at genetic risk for schizophrenia would have the most severe smell identification deficits and that children of bipolar disorder patients would have less severe deficits than the at-risk for schizophrenia group but more severe than the group of children without a psychotic parent.MethodsParticipants - The olfactory identification ability was assessed in 202 children of schizophrenia patients (‘children at familial risk for schizophrenia’) in relation to that of 200 children of parents without a psychotic disorder (‘controls’). In addition, we also assessed the B-SIT in 120 children of bipolar disorder patients (‘children at familial risk for bipolar disorder’). All children were 7 years of age at the time of assessment and they were part of the Danish High Risk and Resilience Study – VIA7.Brief Smell Identification Test - The Brief Smell Identification Test (B-SIT) contains 12 items that need to be scratched and sniffed. The test has excellent reliability (> 0.80) and demonstrates agreement for abnormal olfaction comparing B-SIT with the San Diego Odor Identification Test (SDOIT). A maximum score of 12 reflects intact olfactory identification functioning. B-SIT has been conducted in patients with neurodegenerative disorders (Parkinson’s disease and Alzheimer’s disease) and can be used for individuals above 5 years of age.Statistics - We will use analysis of covariance (ANCOVA) for analysis of the B-SIT total scores with ‘diagnosis of parent’ as the independent variable and age and sex as covariates for the three groups.ResultsAnalyses will be performed within the next 3 months so can be presented in April 2018.DiscussionConclusion and discussion cannot be drawn at this time.

O12.5. GENETIC AND ENVIRONMENTAL PREDICTORS OF MAIN OUTCOMES IN THE DANISH HIGH RISK AND RESILIENCE STUDY - VIA 7. A STUDY OF 522 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA, BIPOLAR DISORDER OR NEITHER OF THESE DISORDERS

BackgroundStudies of children born to parents with schizophrenia and affective disorders can allow us to study the processes preceding the manifestation of the disease, and thereby provide a possibility for identifying early amendable risk factors such as poor parenting, deviances in cognitive functioning, and early, subtle signs of psychopathology at a point where preventive intervention can be applied.MethodsThe Danish High Risk and Resilience Study - VIA7 is a representative nationwide cohort study of 522 7-year-old children of parents with schizophrenia, bipolar disorder or neither of these disorders recruited during 2013–2015. The sample consists of: 202 children with a parent diagnosed with schizophrenia spectrum psychosis, 120 children with a parent diagnosed with bipolar disorder, and 200 children with neither of the parents treated in mental health services for the above diagnoses.We have collected blood and saliva samples from the children and their parents and polygenic risk scores were calculated. We have thoroughly assessed the home environment with the instrument HOME. We have assessed main outcomes such as psychopathology, PLIKS, neurocognition and social cognition.We will analyse the influence of genetic and environmental exposures and their interaction.ResultsGenerally, the children with a familial risk of schizophrenia had lower neurocognitive, social cognitive and neuromotor functioning, more child psychiatric diagnoses, and more severe symptoms compared to control children. In most comparisons, children of parents with bipolar disorder were not different from controls, but in some tests they performed poorer or had more symptoms compared to than control children.We will present data on genetic and environmental risk factors for these outcomesDiscussionThis is the largest high-risk study ever conducted. It is unique that we have access to detailed phenotyping and extensive information on environmental and genetic risk factors. Studies like this can inform about patogenesis and possibilities for future preventive interventions

Clustering of Schizotypal Features in Unaffected First-Degree Relatives of Schizophrenia Patients.

Meehl conceptualized schizotypy as the phenotypic manifestations of a neural integrative defect resulting from a schizophrenia diathesis. The majority of schizotypy studies recruited subjects from the general population and revealed a multidimensional construct. This 2-phase investigation first examined the clustering of schizotypy in 194 unaffected relatives of schizophrenia patients using the Chapman Psychosis Proneness scales and then directly compared the cognitive profiles of negative schizotypal individuals and positive schizotypal individuals with schizophrenia patients and controls. In the first phase, cluster analysis categorized 194 unaffected relatives of schizophrenia patients into positive schizotypy (n = 33), negative schizotypy (n = 66), mixed schizotypy (n = 27), and low schizotypy (n = 64). Positive schizotypal participants showed more self-report pleasure experiences than negative schizotypal participants, replicating earlier cluster analytic findings. In the second phase, 27 negative schizotypal individuals, 18 positive schizotypal individuals, 19 schizophrenia patients, and 29 controls were recruited. Although the groups were matched in terms of age, gender, and IQ, they differed significantly in cognitive profiles. While schizophrenia patients exhibited the broadest cognitive impairments, negative schizotypal participants exhibited visual memory, working memory, and verbal fluency impairments, and positive schizotypal participants exhibited logical memory, visual memory, working memory, and theory-of-mind impairments. Among people with familial risk of schizophrenia, individuals exhibiting positive rather than negative schizotypal features resembled schizophrenia patients in cognitive profiles. Using the psychometric-familial method to identify schizotypy, our findings support the heterogeneity of schizotypy as well as the potential utility of the positive schizotypy dimension in genetically high-risk individuals to predict the risk of developing schizophrenia.

Weak dorsolateral prefrontal response to social criticism predicts worsened mood and symptoms following social conflict in people at familial risk for schizophrenia.

Understanding the specific mechanisms that explain why people who have relatives with schizophrenia (i.e., people at familial high risk; FHR) are more likely to develop the disorder is crucial for prevention. We investigated a diathesis-stress model of familial risk by testing whether FHR individuals under-recruit brain regions central to emotion regulation when exposed to social conflict, resulting in worse mood and symptoms following conflict. FHR and non-FHR participants listened to critical, neutral, and praising comments in an fMRI scanner before completing 4 weeks of daily-diary records. Compared to non-FHR individuals, FHR individuals under-recruited the bilateral dorsolateral prefrontal cortex (DLPFC)—a region strongly implicated in cognitive emotion regulation—following criticism. Furthermore, within FHR participants, weak DLPFC response to criticism in the laboratory task was associated with elevated negative mood and positive symptoms on days with distressing social conflicts in daily-diary assessments. Results extend diathesis-stress models of schizophrenia by clarifying neural and environmental pathways to dysregulation in FHR individuals.

A thalamo-cortical genetic co-expression network is associated with thalamic functional connectivity linked with familial risk for schizophrenia

IntroductionThe genetic architecture of schizophrenia is based on polygenic trajectories. Indeed, genes converge on molecular co-expression pathways, which may be associated with heritable characteristics of patients and their siblings, called intermediate phenotypes, such as prefrontal anomalies and thalamic dysconnectivity during attentional control [2].ObjectivesHere, we investigated in healthy humans association between co-expression of genes with coordinated thalamo-prefrontal (THA-PFC) expression and functional connectivity during attentional control.MethodsWe used Brainspan dataset to characterize a coordinated THA-PFC expression gene list by correlating post-mortem gene expression in both areas (Kendall's Tau&gt;.76, Bonferroni P &lt; .05). Then, we identified a PFC co-expression network1 and tested all gene sets for THA-PFC and PGC loci [3] enrichments (P &lt; .05). SNPs associated with the first principal component of the resulting enriched gene set were combined in a Polygenic Co-Expression Index (PCI) [1]. We conducted Independent Component Analysis (ICA) on attentional control fMRI data (n = 265) and selected Independent Components (ICs) including the thalamus and being highly correlated with an attentional control network2. Multiple regressions were conducted (predictor: PCI) using a thalamic cluster previously associated with familial risk for schizophrenia [2] as ROI (FWE P &lt; .05).ResultsIn one of the 8 ICs of interest there was a positive effect of PCI on thalamic connectivity strength in a cluster overlapping with our ROI (Z = 4.3).ConclusionDecreased co-expression of genes included in PCI predicts thalamic dysconnectivity during attentional control, suggesting a novel co-regulated molecular pathway potentially implicated in genetic risk for schizophrenia.Disclosure of interestThe authors have not supplied their declaration of competing interest.