NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia.

The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ) risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation.

Human-specific evolutionary markers linked to foetal neurodevelopment modulate brain surface area in schizophrenia.

Schizophrenia may represent a trade-off in the evolution of human-specific ontogenetic mechanisms that guide neurodevelopment. Human Accelerated Regions (HARs) are evolutionary markers functioning as neurodevelopmental transcription enhancers that have been associated with brain configuration, neural information processing, and schizophrenia risk. Here, we have investigated the influence of HARs' polygenic load on neuroanatomical measures through a case-control approach (128 patients with schizophrenia and 115 controls). To this end, we have calculated the global schizophrenia Polygenic Risk Score (Global PRSSZ) and that specific to HARs (HARs PRSSZ). We have also estimated the polygenic burden restricted to the HARs linked to transcriptional regulatory elements active in the foetal brain (FB-HARs PRSSZ) and the adult brain (AB-HARs PRSSZ). We have explored the main effects of the PRSs and the PRSs x diagnosis interactions on brain regional cortical thickness (CT) and surface area (SA). The results indicate that a higher FB-HARs PRSSZ is associated with patients' lower SA in the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule. While noHARs-derived PRSs show an effect on the risk, our neuroanatomical findings suggest that the human-specific transcriptional regulation during the prenatal period underlies SA variability, highlighting the role of these evolutionary markers in the schizophrenia genomic architecture.

Cannabis Use and Endocannabinoid Receptor Genes: A Pilot Study on Their Interaction on Brain Activity in First-Episode Psychosis.

The role of both cannabis use and genetic background has been shown in the risk for psychosis. However, the effect of the interplay between cannabis and variability at the endocannabinoid receptor genes on the neurobiological underpinnings of psychosis remains inconclusive. Through a case-only design, including patients with a first-episode of psychosis (n = 40) classified as cannabis users (50%) and non-users (50%), we aimed to evaluate the interaction between cannabis use and common genetic variants at the endocannabinoid receptor genes on brain activity. Genetic variability was assessed by genotyping two Single Nucleotide Polymorphisms (SNP) at the cannabinoid receptor type 1 gene (CNR1; rs1049353) and cannabinoid receptor type 2 gene (CNR2; rs2501431). Functional Magnetic Resonance Imaging (fMRI) data were obtained while performing the n-back task. Gene × cannabis interaction models evidenced a combined effect of CNR1 and CNR2 genotypes and cannabis use on brain activity in different brain areas, such as the caudate nucleus, the cingulate cortex and the orbitofrontal cortex. These findings suggest a joint role of cannabis use and cannabinoid receptor genetic background on brain function in first-episode psychosis, possibly through the impact on brain areas relevant to the reward circuit.

A Systematic Review of the Human Accelerated Regions in Schizophrenia and Related Disorders: Where the Evolutionary and Neurodevelopmental Hypotheses Converge.

Schizophrenia is a psychiatric disorder that results from genetic and environmental factors interacting and disrupting neurodevelopmental trajectories. Human Accelerated Regions (HARs) are evolutionarily conserved genomic regions that have accumulated human-specific sequence changes. Thus, studies on the impact of HARs in the context of neurodevelopment, as well as with respect to adult brain phenotypes, have increased considerably in the last few years. Through a systematic approach, we aim to offer a comprehensive review of HARs' role in terms of human brain development, configuration, and cognitive abilities, as well as whether HARs modulate the susceptibility to neurodevelopmental psychiatric disorders such as schizophrenia. First, the evidence in this review highlights HARs' molecular functions in the context of the neurodevelopmental regulatory genetic machinery. Second, brain phenotypic analyses indicate that HAR genes' expression spatially correlates with the regions that suffered human-specific cortical expansion, as well as with the regional interactions for synergistic information processing. Lastly, studies based on candidate HAR genes and the global "HARome" variability describe the involvement of these regions in the genetic background of schizophrenia, but also in other neurodevelopmental psychiatric disorders. Overall, the data considered in this review emphasise the crucial role of HARs in human-specific neurodevelopment processes and encourage future research on this evolutionary marker for a better understanding of the genetic basis of schizophrenia and other neurodevelopmental-related psychiatric disorders. Accordingly, HARs emerge as interesting genomic regions that require further study in order to bridge the neurodevelopmental and evolutionary hypotheses in schizophrenia and other related disorders and phenotypes.

Fingerprints as Predictors of Schizophrenia: A Deep Learning Study.

BACKGROUND AND HYPOTHESIS: The existing developmental bond between fingerprint generation and growth of the central nervous system points to a potential use of fingerprints as risk markers in schizophrenia. However, the high complexity of fingerprints geometrical patterns may require flexible algorithms capable of characterizing such complexity. STUDY DESIGN: Based on an initial sample of scanned fingerprints from 612 patients with a diagnosis of non-affective psychosis and 844 healthy subjects, we have built deep learning classification algorithms based on convolutional neural networks. Previously, the general architecture of the network was chosen from exploratory fittings carried out with an independent fingerprint dataset from the National Institute of Standards and Technology. The network architecture was then applied for building classification algorithms (patients vs controls) based on single fingers and multi-input models. Unbiased estimates of classification accuracy were obtained by applying a 5-fold cross-validation scheme. STUDY RESULTS: The highest level of accuracy from networks based on single fingers was achieved by the right thumb network (weighted validation accuracy = 68%), while the highest accuracy from the multi-input models was attained by the model that simultaneously used images from the left thumb, index and middle fingers (weighted validation accuracy = 70%). CONCLUSION: Although fitted models were based on data from patients with a well established diagnosis, since fingerprints remain lifelong stable after birth, our results imply that fingerprints may be applied as early predictors of psychosis. Specially, if they are used in high prevalence subpopulations such as those of individuals at high risk for psychosis.

NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case-control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180-rs10484320-rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

A functional neuroimaging association study on the interplay between two schizophrenia genome-wide associated genes (CACNA1C and ZNF804A).

The CACNA1C and the ZNF804A genes are among the most relevant schizophrenia GWAS findings. Recent evidence shows that the interaction of these genes with the schizophrenia diagnosis modulates brain functional response to a verbal fluency task. To better understand how these genes might influence the risk for schizophrenia, we aimed to study the interplay between CACNA1C and ZNF804A on working memory brain functional correlates. The analyses included functional and behavioural N-back task data (obtained from an fMRI protocol) and CACNA1C-rs1006737 and ZNF804A-rs1344706 genotypes for 78 healthy subjects and 78 patients with schizophrenia (matched for age, sex and premorbid IQ). We tested the effects of the epistasis between these genes as well as of the three-way interaction (CACNA1C × ZNAF804A × diagnosis) on working memory-associated activity (N-back: 2-back vs 1-back). We detected a significant CACNA1C × ZNAF804A interaction on working memory functional response in regions comprising the ventral caudate medially and within the left hemisphere, the superior and inferior orbitofrontal gyrus, the superior temporal pole and the ventral-anterior insula. The individuals with the GWAS-identified risk genotypes (CACNA1C-AA/AG and ZNF804A-AA) displayed a reduced working memory modulation response. This genotypic combination was also associated with opposite brain activity patterns between patients and controls. While further research will help to comprehend the neurobiological mechanisms of this interaction, our data highlight the role of the epistasis between CACNA1C and ZNF804A in the functional mechanisms underlying the pathophysiology of schizophrenia.

New insights of the role of the KCNH2 gene in schizophrenia: An fMRI case-control study.

The KCNH2 gene, encoding for a subunit of a voltage-gated potassium channel, has been identified as a key element of neuronal excitability and a promising novel therapeutic target for schizophrenia (SZ). Nonetheless, evidence highlighting the role of KCNH2 on cognitive and brain activity phenotypes comes mainly from studies based on healthy controls (HC). Therefore, we aimed to study the role of KCNH2 on the brain functional differences between patients with SZ and HC. The fMRI sample comprised 78 HC and 79 patients with SZ (matched for age, sex and premorbid IQ). We studied the effect of the polymorphism KCNH2-rs3800779 on attention and working memory-related brain activity, evaluated through the N-back task, in regions with detected diagnostic differences (regression model, controlled for age, sex and premorbid IQ, FEAT-FSL). We report a significant diagnosis x KCNH2 interaction on brain activity (1-back vs baseline contrast) at the medial superior prefrontal cortex (Zmax=3.55, p = 0.00861). In this region, patients with SZ carrying the risk genotype (AA) show a deactivation failure, while HC depict the opposite pattern towards deactivation. The brain region with significant diagnosis x KCNH2 interaction has been previously associated with SZ. The results of this study, in which the role of KCNH2 on fMRI response is analysed for the first time in patients, suggest that KCNH2 variability contributes to inefficient brain activity modulation during the N-back task in affected subjects. These data may pave the way to further understand how KCNH2 genetic variability is related to the pathophysiological mechanisms underlying schizophrenia.

Combining fMRI and DISC1 gene haplotypes to understand working memory-related brain activity in schizophrenia.

The DISC1 gene is one of the most relevant susceptibility genes for psychosis. However, the complex genetic landscape of this locus, which includes protective and risk variants in interaction, may have hindered consistent conclusions on how DISC1 contributes to schizophrenia (SZ) liability. Analysis from haplotype approaches and brain-based phenotypes can contribute to understanding DISC1 role in the neurobiology of this disorder. We assessed the brain correlates of DISC1 haplotypes associated with SZ through a functional neuroimaging genetics approach. First, we tested the association of two DISC1 haplotypes, the HEP1 (rs6675281-1000731-rs999710) and the HEP3 (rs151229-rs3738401), with the risk for SZ in a sample of 138 healthy subjects (HS) and 238 patients. This approach allowed the identification of three haplotypes associated with SZ (HEP1-CTG, HEP3-GA and HEP3-AA). Second, we explored whether these haplotypes exerted differential effects on n-back associated brain activity in a subsample of 70 HS compared to 70 patients (diagnosis × haplotype interaction effect). These analyses evidenced that HEP3-GA and HEP3-AA modulated working memory functional response conditional to the health/disease status in the cuneus, precuneus, middle cingulate cortex and the ventrolateral and dorsolateral prefrontal cortices. Our results are the first to show a diagnosis-based effect of DISC1 haplotypes on working memory-related brain activity, emphasising its role in SZ.

Brain imaging of executive function with the computerised multiple elements test.

The Computerised Multiple Elements Test (CMET) is a novel executive task to assess goal management and maintenance suitable for use within the fMRI environment. Unlike classical executive paradigms, it resembles neuropsychological multi-elements tests that capture goal management in a more ecological way, by requiring the participant to switch between four simple games within a specified time period. The present study aims to evaluate an fMRI version of the CMET and examine its brain correlates. Thirty-one healthy participants performed the task during fMRI scanning. During each block, they were required to play four simple games, with the transition between games being made either voluntarily (executive condition) or automatically (control condition). The executive condition was associated with increased activity in fronto-parietal and cingulo-opercular regions, with anterior insula activity linked to better task performance. In an additional analysis, the activated regions showed to form functional networks during resting-state and to overlap the executive fronto-parietal and cingulo-opercular networks identified in resting-state with independently defined seeds. These results show the ability of the CMET to elicit activity in well-known executive networks, becoming a potential tool for the study of executive impairment in neurological and neuropsychiatric populations in a more ecological way than classical paradigms.