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Interpersonal trust shows developmental changes during adolescence. The current study used a longitudinal design to examine the development of trust behavior, the presence of gender differences in these developmental trajectories, and the association between individual differences in these developmental trajectories and perspective-taking abilities. The participants played a trust game with a hypothetical trustworthy partner and a trust game with a hypothetical untrustworthy partner in 3 consecutive years (Mage = 12.55 years, Mage = 13.54 years, and Mage = 14.54 years). Concerning the development of trust behavior, the results showed an age-related increase in initial trust behavior and indicated increasingly adaptive trust behavior with age during untrustworthy interactions, whereas no evidence was found for age-related changes in the adaptation of trust during trustworthy interactions. Gender differences were found for the development of initial trust behavior (with boys showing a stronger increase with age than girls), whereas no support was found for the presence of gender differences in the developmental trajectories of adaptive trust behavior during trustworthy and untrustworthy interactions. Furthermore, no evidence was found for perspective-taking abilities to explain individual differences in the development of initial trust behavior or in the development of adaptive trust behavior during trustworthy and untrustworthy interactions. The results provide evidence that, during adolescence initial trust behavior increased with age, more for boys than for girls, and that both boys and girls showed a stronger adaptive response to the untrustworthy partner but not to the trustworthy partner.

Our social interactions take place within numerous social networks, in which our relationships with others define our position within these networks. In this study, we examined how the centrality of positions within social networks was associated with trust behavior and neural activity in 49 adolescents (Mage = 12.8 years, SDage = 0.4 years). The participants played a trust game with a cartoon animation as a partner, which showed adaptive behavior in response to the participant and was generally untrustworthy. Social network positions were obtained in secondary school classrooms where the participants and their classmates reported on who their friends were. Using social network analysis, a score was calculated that indicated the centrality of everyone's position within the friendship network. The results showed that more central social network positions were associated with higher levels of initial trust behavior, although no evidence was found for a relationship between network position and the adaptation of trust behavior. The results of the functional MRI analyses showed that the centrality of the network positions was positively associated with caudate activity when making trust decisions. Furthermore, the adolescents with more central network positions also showed stronger increases of caudate activity when the partner's return was processed compared to the adolescents with less central network positions. The current study provides initial evidence that social network positions in friendship networks relate to socio-cognitive behavior and neural activity in adolescents.

Adolescence is an important developmental period for both trust behavior and personality maturation, and individual differences in trust decisions may be related to different personality traits. In the current study, a group of adolescents (n = 483, Mage = 13.5, SDage = 0.4) played two counterbalanced conditions of a multi-round trust game. In one condition, the partner displayed trustworthy behavior (the trustworthy condition), while the partner in the other condition played untrustworthy behavior (the untrustworthy condition). Three types of trust behavior were examined: initial trust behavior, the adaptation of trust behavior (trustworthy condition), and the adaptation of trust behavior (untrustworthy condition). Personality was measured using the Brief HEXACO Inventory. We expected the HEXACO personality dimensions of honesty–humility and agreeableness to be positively associated with initial trust behavior, but conscientiousness to be negatively related to initial trust behavior. The examination of the relationship between these dimensions and the adaptation of trust behavior were conducted on an exploratory basis. The investigation of the relationship between the remaining dimensions (emotionality, extraversion, and openness to experience) and the three types of trust behavior were also carried out on an exploratory basis. For each type of trust behavior, a hierarchical multiple regression analysis was undertaken to examine whether the HEXACO personality dimensions were related to trust behavior. Using frequentist analyses, no evidence was found that supported the HEXACO dimensions as significant predictors of the three types of trust behavior. Moreover, additional Bayesian analyses showed evidence that the hypothesized HEXACO dimensions (honesty–humility, agreeableness, and conscientiousness) did not outperform the non-hypothesized HEXACO dimensions (emotionality, extraversion, and openness to experience). The association between personality traits and trust might be less pronounced during adolescence as personality maturates across an individual’s lifespan. Additionally, due to a heightened sensitivity to the environment, contextual cues may affect adolescent decision-making processes, leaving less room for personality-driven behaviors.

During adolescence, social cognition and the brain undergo major developments. Social interactions become more important, and adolescents must learn that not everyone can be trusted equally. Prior knowledge about the trustworthiness of an interaction partner may affect adolescents' expectations about the partner. However, the expectations based on prior knowledge can turn out to be incorrect, causing the need to respond adaptively during the interaction. In the current fMRI study, we investigated the effect of incorrect prior knowledge on adolescent trust behavior and on the neural processes of trust. Thirty-three adolescents (Mage = 17.2 years, SDage = 0.5 years) played two trust games with partners whose behavior was preprogrammed using an algorithm that modeled trustworthy behavior. Prior to the start of both games, participants received information suggesting that the partner in one game was untrustworthy (raising incorrect expectations) and the partner in the other game trustworthy (raising correct expectations). Results indicated that participants adapted their trust behavior following incorrect prior expectations. No evidence for a change in trust behavior was shown when prior expectations were correct. fMRI analyses revealed that when receiving the partner's response, activity in the dorsolateral prefrontal cortex and in the superior parietal gyrus were increased when participants had incorrect expectations about the partner compared to when participants had correct expectations. When making trust decisions, no significant differences in neural activity were found when comparing the two games. This study provides insight into how adolescent trust behavior and neural mechanisms are affected by expectations and provides an increased understanding of the factors that influence adolescent social interactions.

Interpersonal connection is a fundamental human motivation, and the extent to which it is fulfilled is a strong predictor of symptoms of internalizing disorders such as social anxiety and depression, perhaps especially during the “social reorienting” period of adolescence. However, little is known about the contribution to this effect of the individual’s social motivations, which are intensified during adolescence. Furthermore, social goal orientation – an individual’s priorities and intentions in social interactions – is an important predictor of vulnerability to internalizing symptoms. Adolescents spend most of their waking lives in classrooms, bounded social networks with a limited pool of candidates for befriending. This study investigated whether friendships within one’s class protects against internalizing symptoms in part by reducing the desire for more classmate friendships, which may tend to promote maladaptive social goals. Participants were 423 young adolescents (M age = 13.2, sd = 0.52 years; 49.4% girls). As predicted, adolescents’ number of reciprocated classroom friendships had a protective effect on internalizing symptoms which was serially mediated by desire for more such friendships, and social goal orientation. However, only demonstration-avoidance goals significantly predicted internalizing symptoms. Unreciprocated friendship nominations were unexpectedly associated with stronger desire and more social anxiety symptoms. The results suggest that the effect of number of friends is mediated by the individual’s thoughts and feelings about their number of friendships, such that a strong desire for more friendships promotes maladaptive goals, oriented toward social status and consequently less oriented toward the cultivation of interpersonal intimacy with the friends they already have.

Innate lymphoid cells (ILC) are important barrier tissue immune regulators. They play a pivotal role in early non-specific protection against infiltrating pathogens, regulation of epithelial integrity, suppression of pro-inflammatory immune responses and shaping the intestinal microbiota. GATA2 haploinsufficiency causes an immune disorder that is characterized by bone marrow failure and (near) absence of monocytes, dendritic cells, B cells and natural killer (NK) cells. T cells develop normally, albeit at lower numbers. Here, we describe the absence of ILCs and their progenitors in blood and bone marrow of two patients with GATA2 haploinsufficiency and show that all subsets of ILCs appear after allogeneic hematopoietic stem cell transplantation, irrespective of the preparative conditioning regimen. Our data indicate that GATA2 is involved in the development of hematopoietic precursor cells (HPC) towards the ILC lineage.

Past research has linked honor to a higher tendency for retaliation. A common method is to compare groups that are either low or high in honor. While effective, this does not account for within-group variation, nor isolate honor as a distinct construct from alternative differences between groups that might affect the outcome. In the current study we investigated honor as a cultural mindset, using priming methodology in both Dutch participants (who are typically low in honor endorsement) and Dutch-Turkish and Dutch-Moroccan participants (who are typically high in honor endorsement), while controlling for trait endorsement of honor values. To quantify retaliation, we used two social dilemmas: presenting an unequal offer in the Ultimatum Game, and chips being taken in the Justice Game. The results showed that priming honor resulted in an increased willingness to pay for punishment in the Justice Game, but not higher rejection in the Ultimatum Game. This suggests that unfairness by itself is not sufficient to trigger retaliation; rather, a pronounced transgression is required—in this case something being taken what is considered rightfully yours. Furthermore, decision-making in both social dilemmas was not associated with cultural background or honor endorsement. This indicates that an honor mindset needs to be salient to affect decision-making, and can affect behavior over and above the endorsement of honor values.

Epidemiological studies suggest that the association between urbanicity and psychosis might be explained by social deprivation, lack of social capital, cohesion and trust, and being part of a minority group. Besides, urbanicity is also associated with pollution, noise, and lack of green space, which have a negative impact on health outcomes. This chapter reviews the neuroimaging literature on brain function, structure, and connectivity in relation to urbanicity. Research in patients with psychosis has shown associations of urbanicity with brain functioning, rather than structure or connectivity. Neuroimaging research in healthy individuals supports altered social stress processing as a possible explanatory mechanism. Altered reward processing associated with urbanicity supports the possible influence of urbanicity on dopamine disregulation and the pathogenesis of psychosis. Mentalising and sensory gating deficits are discussed as alternative mechanisms that could account for the negative effects of the city on mental health.

Innate Lymphoid Cells (ILCs) control tissue and metabolic homeostasis, but also provide protection from infectious diseases. Strategically located in barrier tissues, ILCs produce effector cytokines in an antigen-independent manner, thereby mounting an appropriate immune response to pathogens at mucosal sites. ILCs are classified into three subsets of helper ILCs, each producing their signature cytokines, and cytotoxic Natural Killer (NK) cells. Their plastic nature allows helper ILC subsets to promptly respond to the changing environment by adapting its function and phenotype. However, when not properly regulated, ILCs can contribute to chronic inflammation, autoimmune disease and cancer. Therefore, it is of importance to identify the essential factors involved in the development and functions of ILCs. In this thesis we describe the methods to isolate ILCs from human mucosal tissues. We identified an essential transcription factor for the development of ILCs by studying the immune cell composition of GATA2-deficient patients. Furthermore, we investigated the full spectrum and the plasticity of human ILCs and NK cells in the tonsil and intestine. Thereby we identified cytotoxic ILCs which are distinct from NK cells and unraveled their developmental requirements. Furthermore, we investigated the ILC composition in the inflamed intestinal tissue of Crohn’s disease patients compared to non-inflamed controls, and observed that particular ILC subsets that express high levels of cytotoxic molecules and type 1 cytokines expanded in inflamed tissues. Our findings contribute to a better understanding of the functions of ILCs and their possible roles in inflammatory diseases of the intestine.

Epidemiological studies suggest that the observed association between urbanicity and psychosis may be explained in part by social deprivation, reduced social capital affecting cohesion and trust, and minority group and ethnic density effects, which in turn may represent aspects of “social defeat.” In addition, urbanicity is also associated with pollution, noise, and lack of green space, which may negatively impact a range of health outcomes. This chapter reviews the neuroimaging literature on brain function, structure, and connectivity in relation to urbanicity. Research in patients with psychosis has mostly shown associations of urbanicity with brain functioning, rather than structure or connectivity. Neuroimaging research in healthy individuals may support altered social stress processing as a possible explanatory mechanism. Altered reward processing associated with urbanicity may provide an explanation for the possible influence of urban environments on dopamine dysregulation and the pathogenesis of psychosis. Mentalizing and sensory gating deficits may also mediate some of the negative effects of the city on mental health. A sustained effort toward exact replication is required to further develop this promising field.

Mucosal-associated invariant T (MAIT) cells are an abundant human T-cell subset with antimicrobial properties. They can respond to bacteria presented via antigen-presenting cells (APCs) such as macrophages, which present bacterially derived ligands from the riboflavin synthesis pathway on MR1. Moreover, MAIT cells are also highly responsive to cytokines which enhance and even substitute for T-cell receptor-mediated signaling. The mechanisms leading to an efficient presentation of bacteria to MAIT cells by APCs have not been fully elucidated. Here, we showed that the monocytic cell line THP-1 and B cells activated MAIT cells differentially in response to Escherichia coli. THP-1 cells were generally more potent in inducing IFNγ and IFNγ/TNF production by MAIT cells. Furthermore, THP-1, but not B, cells produced TNF upon bacterial stimulation, which in turn supported IFNγ production by MAIT cells. Finally, we addressed the role of antibody-dependent opsonization of bacteria in the activation of MAIT cells using in vitro models. We found that opsonization had a substantial impact on downstream MAIT cell activation by monocytes. This was associated with enhanced activation of monocytes and increased TNF release. Importantly, this TNF acted in concert with other cytokines to drive MAIT cell activation. These data indicate both a significant interaction between adaptive and innate immunity in the response to bacteria, and an important role for TNF in MAIT cell triggering.

Background Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait., Genetic prediction of complex traits so far has limited accuracy because of insufficient understanding of the genetic risk. Here, Maier et al. develop an improved method for trait prediction that makes use of genetic correlations between traits and apply it to summary statistics of psychiatric diseases.

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. © 2014 American Medical Association. All rights reserved.

BackgroundSchizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence.MethodIQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls.ResultsAlthough significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R2 = 0.055, p = 2.1 × 10−7) and with IQ in the entire sample (R2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status.ConclusionsOur data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.

Lataster T, Verweij K, Viechtbauer W, GROUP. Effect of illnessexpression and liability on familial associations of clinical andsubclinical psychosis phenotypes.Objective: Given the familial influences on schizophrenia, it may behypothesized that specific symptom domains also cluster withinfamilies, and that this applies to both clinical and subclinical levels ofexpression. This hypothesis was put to the test in a group of patientswith a DSM-IV diagnosis of psychotic disorder together with theirunaffected siblings, and a group of healthy sib-pairs.Method: Subclinical positive, negative and depressive symptoms inrelatives and healthy controls were assessed with the CommunityAssessment of Psychic Experiences (CAPE). Positive and negativeschizotypy in relatives and controls was measured with the StructuredInterview for Schizotypy–Revised. Multilevel linear regression analyseswere conducted to investigate clustering of symptom dimensions withinpatient–relative sib-pairs (N = 811 pairs), healthy sib-pairs of affectedfamilies (N = 136 pairs) and healthy control sib-pairs (N = 58 pairs).Results: Familial clustering of symptoms was found in all three groups.Effect sizes were largest in healthy control sib-pairs, smallest in patient–relative sib-pairs and intermediate in healthy sib-pairs of affectedfamilies.Conclusion: Studies of sibling associations in genetic studies ofpsychometric expression of psychosis liability need to take into accountthe fact that the higher levels of background genetic risk and presenceof diagnosed illness are inversely associated with sibling associations.