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Genomics of Brain Disorders 3.0

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 (30 November 2021) | Viewed by 24546

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2019 Special Issue, "Genomics of Brain Disorders 2.0" (https://www.mdpi.com/journal/ijms/special_issues/genomics_brain2).

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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Published Papers (6 papers)

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Research

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16 pages, 946 KiB  
Article
Epigenetic Biomarkers as Diagnostic Tools for Neurodegenerative Disorders
by Olaia Martínez-Iglesias, Vinogran Naidoo, Natalia Cacabelos and Ramón Cacabelos
Int. J. Mol. Sci. 2022, 23(1), 13; https://doi.org/10.3390/ijms23010013 - 21 Dec 2021
Cited by 21 | Viewed by 3162
Abstract
Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. The accumulation of epigenetic alterations over the lifespan may contribute to neurodegeneration. The aim of the present study was [...] Read more.
Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. The accumulation of epigenetic alterations over the lifespan may contribute to neurodegeneration. The aim of the present study was to identify epigenetic biomarkers for improving diagnostic efficacy in patients with neurodegenerative diseases. We analyzed global DNA methylation, chromatin remodeling/histone modifications, sirtuin (SIRT) expression and activity, and the expression of several important neurodegeneration-related genes. DNA methylation, SIRT expression and activity and neuregulin 1 (NRG1), microtubule-associated protein tau (MAPT) and brain-derived neurotrophic factor (BDNF) expression were reduced in buffy coat samples from patients with neurodegenerative disorders. Our data suggest that these epigenetic biomarkers may be useful in clinical practical for the diagnosis, surveillance, and prognosis of disease activity in patients with neurodegenerative diseases. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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Review

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14 pages, 2009 KiB  
Review
Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability
by Loredana Poeta, Michela Malacarne, Agnese Padula, Denise Drongitis, Lucia Verrillo, Maria Brigida Lioi, Andrea M. Chiariello, Simona Bianco, Mario Nicodemi, Maria Piccione, Emanuela Salzano, Domenico Coviello and Maria Giuseppina Miano
Int. J. Mol. Sci. 2022, 23(6), 3084; https://doi.org/10.3390/ijms23063084 - 13 Mar 2022
Cited by 2 | Viewed by 2794
Abstract
The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) [...] Read more.
The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants (CNVs) of the ARX locus found in patients presenting wide-ranging phenotypic variations including ID, speech delay, hypotonia and psychiatric abnormalities. We also report on a further novel Xp21.3 duplication detected in a male patient with moderate ID and carrying a fully duplicated copy of the ARX locus and the ultraconserved enhancers. As consequences of this rearrangement, the patient-derived lymphoblastoid cell line shows abnormal activity of the ARX-KDM5C-SYN1 regulatory axis. Moreover, the three-dimensional (3D) structure of the Arx locus, both in mouse embryonic stem cells and cortical neurons, provides new insight for the functional consequences of ARX duplications. Finally, by comparing the clinical features of the 16 CNVs affecting the ARX locus, we conclude that—depending on the involvement of tissue-specific enhancers—the ARX duplications are ID-associated risk CNVs with variable expressivity and penetrance. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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15 pages, 339 KiB  
Review
Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis
by Orietta Pansarasa, Maria Garofalo, Eveljn Scarian, Francesca Dragoni, Jessica Garau, Rosalinda Di Gerlando, Luca Diamanti, Matteo Bordoni and Stella Gagliardi
Int. J. Mol. Sci. 2022, 23(5), 2580; https://doi.org/10.3390/ijms23052580 - 25 Feb 2022
Cited by 10 | Viewed by 3330
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers can help in understanding ALS pathomechanisms, identification of targets for treatment and development of effective therapies. Peripheral blood mononuclear cells (PBMCs) represent a valid source for biomarkers compared to cerebrospinal fluid, as they are simple to collect, and to plasma, because of the possibility of detecting lower expressed proteins. They are a reliable model for patients’ stratification. This review provides an overview on PBMCs as a potential source of biomarkers in ALS. We focused on altered RNA metabolism (coding/non-coding RNA), including RNA processing, mRNA stabilization, transport and translation regulation. We addressed protein abnormalities (aggregation, misfolding and modifications); specifically, we highlighted that SOD1 appears to be the most characterizing protein in ALS. Finally, we emphasized the correlation between biological parameters and disease phenotypes, as regards prognosis, severity and clinical features. In conclusion, even though further studies are needed to standardize the use of PBMCs as a tool for biomarker investigation, they represent a promising approach in ALS research. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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13 pages, 460 KiB  
Review
The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes
by Monica Diez-Fairen, Pilar Alvarez Jerez, Joos Berghausen and Sara Bandres-Ciga
Int. J. Mol. Sci. 2021, 22(15), 8100; https://doi.org/10.3390/ijms22158100 - 28 Jul 2021
Cited by 3 | Viewed by 3784
Abstract
In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic [...] Read more.
In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic architecture underlying these conditions. These disorders are difficult to accurately diagnose and categorize, thus making genetics research challenging. On one hand, dystonia is an umbrella term linked to clinically heterogeneous forms of disease including dopa-responsive dystonia, myoclonus-dystonia, rapid-onset dystonia-parkinsonism and dystonia-parkinsonism, often viewed as a precursor to Parkinson’s disease. On the other hand, atypical parkinsonism disorders, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration, are rare in nature and represent a wide range of diverse and overlapping phenotypic variabilities, with genetic research limited by sample size availability. The current review summarizes the plethora of available genetic information for these diseases, outlining limits and future directions. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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20 pages, 655 KiB  
Review
Deep Learning with Neuroimaging and Genomics in Alzheimer’s Disease
by Eugene Lin, Chieh-Hsin Lin and Hsien-Yuan Lane
Int. J. Mol. Sci. 2021, 22(15), 7911; https://doi.org/10.3390/ijms22157911 - 24 Jul 2021
Cited by 27 | Viewed by 5899
Abstract
A growing body of evidence currently proposes that deep learning approaches can serve as an essential cornerstone for the diagnosis and prediction of Alzheimer’s disease (AD). In light of the latest advancements in neuroimaging and genomics, numerous deep learning models are being exploited [...] Read more.
A growing body of evidence currently proposes that deep learning approaches can serve as an essential cornerstone for the diagnosis and prediction of Alzheimer’s disease (AD). In light of the latest advancements in neuroimaging and genomics, numerous deep learning models are being exploited to distinguish AD from normal controls and/or to distinguish AD from mild cognitive impairment in recent research studies. In this review, we focus on the latest developments for AD prediction using deep learning techniques in cooperation with the principles of neuroimaging and genomics. First, we narrate various investigations that make use of deep learning algorithms to establish AD prediction using genomics or neuroimaging data. Particularly, we delineate relevant integrative neuroimaging genomics investigations that leverage deep learning methods to forecast AD on the basis of incorporating both neuroimaging and genomics data. Moreover, we outline the limitations as regards to the recent AD investigations of deep learning with neuroimaging and genomics. Finally, we depict a discussion of challenges and directions for future research. The main novelty of this work is that we summarize the major points of these investigations and scrutinize the similarities and differences among these investigations. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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24 pages, 406 KiB  
Review
Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives
by Luca Magistrelli, Marco Ferrari, Alessia Furgiuele, Anna Vera Milner, Elena Contaldi, Cristoforo Comi, Marco Cosentino and Franca Marino
Int. J. Mol. Sci. 2021, 22(7), 3781; https://doi.org/10.3390/ijms22073781 - 6 Apr 2021
Cited by 19 | Viewed by 4223
Abstract
Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
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