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Genomics of Brain Disorders 4.0
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Genomics of Brain Disorders 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 15011

Special Issue Editor

Prof. Dr. Ramón Cacabelos

E-Mail Website
Guest Editor
Euroespes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Corunna, Spain
Interests: pharmacogenomics; pharmacoepigenetics; genomics of brain disorders; neuroepigenetics; CNS drug development; neurodegenerative disorders; Alzheimer’s disease; Parkinson’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

This Special Issue is the continuation of our 2021 Special Issue, "Genomics of Brain Disorders 3.0" (https://www.mdpi.com/journal/ijms/special_issues/genomics_brain3).

Brain disorders represent the third major problem of health and disability in developed countries after cardiovascular disorders and cancer. From a global health perspective, important issues to be addressed with regard to neuropsychiatric disorders (NPDs) are: (i) disease burden (DALYs: disability-adjusted life years; YLDs: years lived with disability; YLLs: years of life lost); (ii) the costs (direct, indirect) of disease; (iii) disease pathogenesis; (iv) the identification of presymptomatic biomarkers; (v) novel targets for drug development; and (vi) personalized treatments with pharmacogenetic procedures for optimizing drug efficacy and safety. NPDs contribute approximately 10% of the global burden of disease. About 30% of all YLDs are assigned to NPDs, especially depression, alcohol use disorders, schizophrenia, bipolar disorder, and dementia. NPDs are the leading cause of disease burden, responsible for 7.4% of global DALYs and 22.9% of global YLDs. Within NPDs, mental disorders account for 56.7% DALYs, followed by neurological disorders (28.6%) and substance use disorder (14.7%).

The global cost of NPDs is projected to be about US$6 trillion by 2030. An estimated eight million deaths annually are attributed to mental disorders. Approximately 127 million Europeans suffer brain disorders. The total annual cost of brain disorders in Europe is about €386 billion, with €135 billion in direct medical expenditures, €179 billion in indirect costs, and €72 billion in direct non-medical costs. Mental disorders represent €240 billion (62% of the total cost, excluding dementia), followed by neurological diseases (€84 billion, 22%).

The primary cause of most brain disorders is poorly understood. In NPDs there is a convergence of multiple genomic defects distributed across the human genome with epigenetic phenomena and environmental risk factors leading to the phenotypic expression of the disease. In children, neurodevelopmental disorders are determinant for abnormal brain maturation and early mental derailment. In age-related neurodegenerative disorders, a common feature is the presence of intracellular and/or extracellular deposits of abnormally processed proteins that represent prototypical hallmarks probably contributing to premature neuronal death. A better characterization of the genomic background of mental and neurological disorders is necessary for elucidating disease-specific pathogenesis, as well as the identification of accurate biomarkers, and the implementation of novel treatments addressing pathogenic, mechanistic, metabolic, transporter and pleiotropic genes, and their products, associated with specific NPDs.

Prof. Dr. Ramón Cacabelos
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (6 papers)

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Editorial

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5 pages, 200 KiB  
Editorial
Genomics of Brain Disorders 4.0
by Ramón Cacabelos
Int. J. Mol. Sci. 2024, 25(7), 3667; https://doi.org/10.3390/ijms25073667 - 25 Mar 2024
Viewed by 376
Abstract
Several historic, scientific events have occurred in the decade 2013–2023, in particular the COVID-19 pandemic. This massive pathogenic threat, which has affected the world’s population, has had a devastating effect on scientific production worldwide. [...] Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)

Research

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52 pages, 1211 KiB  
Article
Molecular Landscape of Tourette’s Disorder
by Joanna Widomska, Ward De Witte, Jan K. Buitelaar, Jeffrey C. Glennon and Geert Poelmans
Int. J. Mol. Sci. 2023, 24(2), 1428; https://doi.org/10.3390/ijms24021428 - 11 Jan 2023
Viewed by 3551
Abstract
Tourette’s disorder (TD) is a highly heritable childhood-onset neurodevelopmental disorder and is caused by a complex interplay of multiple genetic and environmental factors. Yet, the molecular mechanisms underlying the disorder remain largely elusive. In this study, we used the available omics data to [...] Read more.
Tourette’s disorder (TD) is a highly heritable childhood-onset neurodevelopmental disorder and is caused by a complex interplay of multiple genetic and environmental factors. Yet, the molecular mechanisms underlying the disorder remain largely elusive. In this study, we used the available omics data to compile a list of TD candidate genes, and we subsequently conducted tissue/cell type specificity and functional enrichment analyses of this list. Using genomic data, we also investigated genetic sharing between TD and blood and cerebrospinal fluid (CSF) metabolite levels. Lastly, we built a molecular landscape of TD through integrating the results from these analyses with an extensive literature search to identify the interactions between the TD candidate genes/proteins and metabolites. We found evidence for an enriched expression of the TD candidate genes in four brain regions and the pituitary. The functional enrichment analyses implicated two pathways (‘cAMP-mediated signaling’ and ‘Endocannabinoid Neuronal Synapse Pathway’) and multiple biological functions related to brain development and synaptic transmission in TD etiology. Furthermore, we found genetic sharing between TD and the blood and CSF levels of 39 metabolites. The landscape of TD not only provides insights into the (altered) molecular processes that underlie the disease but, through the identification of potential drug targets (such as FLT3, NAALAD2, CX3CL1-CX3CR1, OPRM1, and HRH2), it also yields clues for developing novel TD treatments. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)
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15 pages, 3157 KiB  
Article
An Integrative Analysis of Identified Schizophrenia-Associated Brain Cell Types and Gene Expression Changes
by Wenxiang Cai, Weichen Song, Zhe Liu, Dhruba Tara Maharjan, Jisheng Liang and Guan Ning Lin
Int. J. Mol. Sci. 2022, 23(19), 11581; https://doi.org/10.3390/ijms231911581 - 30 Sep 2022
Cited by 1 | Viewed by 1972
Abstract
Schizophrenia (SCZ) is a severe mental disorder that may result in hallucinations, delusions, and extremely disordered thinking. How each cell type in the brain contributes to SCZ occurrence is still unclear. Here, we leveraged the human dorsolateral prefrontal cortex bulk RNA-seq data, then [...] Read more.
Schizophrenia (SCZ) is a severe mental disorder that may result in hallucinations, delusions, and extremely disordered thinking. How each cell type in the brain contributes to SCZ occurrence is still unclear. Here, we leveraged the human dorsolateral prefrontal cortex bulk RNA-seq data, then used the RNA-seq deconvolution algorithm CIBERSORTx to generate SCZ brain single-cell RNA-seq data for a comprehensive analysis to understand SCZ-associated brain cell types and gene expression changes. Firstly, we observed that the proportions of brain cell types in SCZ differed from normal samples. Among these cell types, astrocyte, pericyte, and PAX6 cells were found to have a higher proportion in SCZ patients (astrocyte: SCZ = 0.163, control = 0.145, P.adj = 4.9 × 10−4, effect size = 0.478; pericyte: SCZ = 0.057, control = 0.066, P.adj = 1.1 × 10−4, effect size = 0.519; PAX6: SCZ = 0.014, control = 0.011, P.adj = 0.014, effect size = 0.377), while the L5/6_IT_CAR3 cells and LAMP5 cells are the exact opposite (L5/6_IT_Car3: SCZ = 0.102, control = 0.108, P.adj = 0.016, effect size = 0.369; LAMP5: SCZ = 0.057, control = 0.066, P.adj = 2.2 × 10−6, effect size = 0.617). Next, we investigated gene expression in cell types and functional pathways in SCZ. We observed chemical synaptic transmission dysregulation in two types of GABAergic neurons (PVALB and LAMP5), and immune reaction involvement in GABAergic neurons (SST) and non-neuronal cell types (endothelial and oligodendrocyte). Furthermore, we observed that some differential expression genes from bulk RNA-seq displayed cell-type-specific abnormalities in the expression of molecules in SCZ. Finally, the cell types with the SCZ-related transcriptomic changes could be considered to belong to the same module since we observed two major similar coordinated transcriptomic changes across these cell types. Together, our results offer novel insights into cellular heterogeneity and the molecular mechanisms underlying SCZ. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)
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16 pages, 11357 KiB  
Article
Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis
by Julia Horjus, Tineke van Mourik-Banda, Marco A. P. Heerings, Marina Hakobjan, Ward De Witte, Dorothea J. Heersema, Anne J. Jansen, Eva M. M. Strijbis, Brigit A. de Jong, Astrid E. J. Slettenaar, Esther M. P. E. Zeinstra, Erwin L. J. Hoogervorst, Barbara Franke, Wiebe Kruijer, Peter J. Jongen, Leo J. Visser and Geert Poelmans
Int. J. Mol. Sci. 2022, 23(19), 11461; https://doi.org/10.3390/ijms231911461 - 28 Sep 2022
Cited by 3 | Viewed by 2557
Abstract
Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic [...] Read more.
Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)
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18 pages, 2916 KiB  
Article
Agomelatine Changed the Expression and Methylation Status of Inflammatory Genes in Blood and Brain Structures of Male Wistar Rats after Chronic Mild Stress Procedure
by Katarzyna Bialek, Piotr Czarny, Paulina Wigner, Ewelina Synowiec, Lukasz Kolodziej, Michal Bijak, Janusz Szemraj, Mariusz Papp and Tomasz Sliwinski
Int. J. Mol. Sci. 2022, 23(16), 8983; https://doi.org/10.3390/ijms23168983 - 11 Aug 2022
Cited by 1 | Viewed by 1802
Abstract
The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores [...] Read more.
The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores whether the chronic mild stress (CMS) procedure and agomelatine treatment induce changes in TGFA, TGFB, IRF1, PTGS2 and IKBKB expression and methylation status in peripheral blood mononuclear cells (PBMCs) and in the brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or agomelatine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our findings confirm that both CMS and antidepressant agomelatine treatment influenced the expression level and methylation status of the promoter region of investigated genes in PBMCs and the brain. What is more, the present study showed that response to either stress stimuli or agomelatine differed between brain structures. Concluding, our results indicate that TGFA, TGFB, PTGS2, IRF1 and IKBKB could be associated with depression and its treatment. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)
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Review

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51 pages, 20239 KiB  
Review
Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology
by Kao-Jung Chang, Hsin-Yu Wu, Aliaksandr A. Yarmishyn, Cheng-Yi Li, Yu-Jer Hsiao, Yi-Chun Chi, Tzu-Chen Lo, He-Jhen Dai, Yi-Chiang Yang, Ding-Hao Liu, De-Kuang Hwang, Shih-Jen Chen, Chih-Chien Hsu and Chung-Lan Kao
Int. J. Mol. Sci. 2022, 23(17), 9707; https://doi.org/10.3390/ijms23179707 - 26 Aug 2022
Cited by 3 | Viewed by 3974
Abstract
Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization [...] Read more.
Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet–Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus–Merzbacher disease), transcriptional deregulation diseases (Mowat–Wilson disease, Pitt–Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 4.0)
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