The interpretation of discrepancies between peer victimization experiences reported by different informants in capturing victimization‐related genetic liability. A commentary on Armitage et al. (2022)

A recent work published in this journal by Armitage et al. reported that wellbeing-related genetic scores (PGS) are associated with self-informed peer victimization questionnaires. In contrast, peer- and teacher-informed measures would capture intelligence and educational attainment PGS better. However, we argue that this dichotomy does not find comprehensive support in the literature; instead, informants other than self and especially peers may provide reports from angles particularly relevant to mental health. For example, peer reports may more objectively capture adverse social reactions evoked by genetic factors (i.e., evocative gene-environment correlations). Thus, we recommend caution in generalizing the conclusion that self-reports capture the association between genetic contribution to mental health and peer victimization better than other-informant measures, as different gene-environment mechanisms may be at play

The harmonium model and its unified system view of psychopathology: a validation study by means of a convolutional neural network

The harmonium model (HM) is a recent conceptualization of the unifying view of psychopathology, namely the idea of a general mechanism underpinning all mental disorders (the p factor). According to HM, psychopathology consists of a low dimensional Phase Space of Meaning (PSM), where each dimension of meaning maps a component of the environmental variability. Accordingly, the lower thenumber of independent dimensions in the PSM, and hence its intrinsic complexity, the more limited the way of interpreting the environment. The current simulation study, based on a Convolutional Neural Network (CNN) framework, aims at validating the HM low-dimensionality hypothesis. CNN-based classifiers were employed to simulate normotypical and pathological cognitive processes. Results revealed that normotypical and pathological CNNs were different in terms of both classification performance and layer activation patterns. Using Principal Component Analysis to characterize the PSM associated with the two algorithms, we found that the performance of the normotypical CNN relies on a larger and more evenly distributed number of components, compared with the pathological one. This finding might be indicative of the fact that psychopathology can be modelled as a low-dimensional, poorly modulable PSM, which means the environment is detected through few components of meaning, preventing complex information patterns from being taken into account

Heritability of amygdala reactivity to angry faces and its replicable association with the schizophrenia risk locus ofmiR-137

Background: Among healthy participants, the interindividual variability of brain response to facial emotions is associated with genetic variation, including common risk variants for schizophrenia, a heritable brain disorder characterized by anomalies in emotion processing. We aimed to identify genetic variants associated with heritable brain activity during processing of facial emotions among healthy participants and to explore the impact of these identified variants among patients with schizophrenia. Methods: We conducted a data-driven stepwise study including samples of healthy twins, unrelated healthy participants and patients with schizophrenia. Participants approached or avoided pictures of faces with negative emotional valence during functional magnetic resonance imaging (fMRI). Results: We investigated 3 samples of healthy participants - including 28 healthy twin pairs, 289 unrelated healthy participants (genome-wide association study [GWAS] discovery sample) and 90 unrelated healthy participants (replication sample) - and 1 sample of 48 patients with schizophrenia. Among healthy twins, we identified the amygdala as the brain region with the highest heritability during processing of angry faces (heritability estimate 0.54, p < 0.001). Subsequent GWAS in both discovery and replication samples of healthy non-twins indicated that amygdala activity was associated with a polymorphism in the miR-137 locus (rs1198575), a micro-RNA strongly involved in risk for schizophrenia. A significant effect in the same direction was found among patients with schizophrenia (p = 0.03). Limitations: The limited sample size available for GWAS analyses may require further replication of results. Conclusion: Our data-driven approach shows preliminary evidence that amygdala activity, as evaluated with our task, is heritable. Our genetic associations preliminarily suggest a role for miR-137 in brain activity during explicit processing of facial emotions among healthy participants and patients with schizophrenia, pointing to the amygdala as a brain region whose activity is related to miR-137

Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling

Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genomewide copy number variation (CNV) analysis with micro- RNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The “NOTCH signaling pathway” was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/ JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR- 34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type

A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing

Background: MiR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-Wide Association Studies implicate miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. Methods: Using RNA-sequencing data from postmortem prefrontal cortex (N=522), we identified a co-expression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in-vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of co-expression prediction and associated them with fMRI activation in healthy volunteers (N1=214; N2=136; N3=2,075; N4=1,800) and with short-term treatment response in patients with schizophrenia (N=427). Results: In 4,652 human subjects, we found that (i) schizophrenia risk genes are co-expressed in a biologically validated set enriched for miR-137 targets, (ii) increased expression of miR-137 target risk genes is mediated by low prefrontal miR-137 expression, (iii) alleles predicting greater gene-set co-expression are associated with greater prefrontal activation during emotion processing in three independent healthy cohorts (N1-2-3), in interaction with age (N4), (iv) these alleles predict less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. Conclusions: The functional translation of miR-137 target gene expression linked with schizophrenia involves emotion processing