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Objective: Restless legs syndrome (RLS) is a neurological condition that causes uncomfortable sensations in the legs and an irresistible urge to move them, typically during periods of rest. The genetic basis and pathophysiology of RLS are incompletely understood. We sought to identify additional novel genetic risk factors associated with RLS susceptibility. Methods: We performed a whole‐genome sequencing and genome‐wide association meta‐analysis of RLS cases (n = 9,851) and controls (n = 38,957) in 3 population‐based biobanks (All of Us, Canadian Longitudinal Study on Aging, and CARTaGENE). Results: Genome‐wide association analysis identified 9 independent risk loci, of which 8 had been previously reported, and 1 was a novel risk locus (LMX1B, rs35196838, OR 1.14, 95% CI 1.09–1.19, p value = 2.2 × 10−9). Furthermore, a transcriptome‐wide association study also identified GLO1 and a previously unreported gene, ELFN1. A genetic correlation analysis revealed significant common variant overlaps between RLS and neuroticism (rg = 0.40, se = 0.08, p value = 5.4 × 10−7), depression (rg = 0.35, se = 0.06, p value = 2.17 × 10−8), and intelligence (rg = −0.20, se = 0.06, p value = 4.0 × 10−4). Interpretation: Our study expands the understanding of the genetic architecture of RLS, and highlights the contributions of common variants to this prevalent neurological disorder. ANN NEUROL 2024;96:994–1005 [ABSTRACT FROM AUTHOR]

This paper reports findings and observations on using the Social Construction of Technology (SCOT) framework in a questionnaire study of literary translators' self-imaging strategies and attitudes towards technology. The study took advantage of SCOT's methodological flexibility to prioritise literary translators as a social group, hence compensating for the lack of opportunities to voice their interpretations of technology and become an active part in the framework's development and implementation. Ultimately, the use (and adaptation) of SCOT proved useful for the identification, analysis, and discussion of recurrent themes in respondents' narratives about technology and their position in society. In particular, SCOT helped to uncover the gap between how literary translators choose to (re)present themselves in society and how they see technology, and what other social groups might be pivotal for a more comprehensive, socially-relevant analysis. Finally, the paper presents suggestions for the use of SCOT in future research projects concerning the technologisation of the literary translation profession. [ABSTRACT FROM AUTHOR]

The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments. An epigenome-wide association study of dementia with Lewy bodies discovers differentially methylated probes, genomic regions and pathways associated with this disease. [ABSTRACT FROM AUTHOR]

Background: The complex interplay between health, lifestyle and genetics represents a critical area of research for understanding and promoting human well-being. Importantly, genetics plays a key role in determining individual susceptibility to disease and response to lifestyle. The aim of the present study was to identify genetic factors related to the metabolic/inflammatory profile of adolescents providing new insights into the individual predisposition to the different effects of the substances from the environment. Methods: Association analysis of genetic variants and biochemical parameters was performed in a total of 77 healthy adolescents recruited in the context of the DIMENU study. Results: Polymorphisms of 3-hydroxy-3-methylglutaril coenzyme A reductase (HMGCR; rs142563098), C-reactive protein gene (CRP; rs1417938, rs1130864), cholesteryl ester transfer protein (CETP; rs5030708), interleukin (IL)—10 (IL-10; rs3024509) genes were significantly associated (p < 0.05) with various serum metabolic parameters. Of particular interest were also the correlations between the HMGCRpolymorphism (rs3846663) and tumor necrosis factor (TNF)-α levels, as well Fatty-acid desaturase (FADS) polymorphism (rs7481842) and IL-10 level opening a new link between lipidic metabolism genes and inflammation. Conclusion: In this study, we highlighted associations between single nucleotide polymorphisms (SNPs) and serum levels of metabolic and inflammatory parameters in healthy young individuals, suggesting the importance of genetic profiling in the prevention and management of chronic disease. [ABSTRACT FROM AUTHOR]

Adiponectin is the major adipocytes‐secreted protein involved in obesity‐related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα‐positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα‐coactivator. Here, we showed that adiponectin‐mediated ERα transactivation enhances E‐cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E‐cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E‐cadherin expression in ERα‐positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E‐cadherin gene promoter by ERα/LKB1‐complex. The impact of E‐cadherin on ERα‐positive breast cancer cell proliferation comes from the evidence that in the presence of E‐cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E‐cadherin connects cell polarity and growth, we investigated if the adiponectin‐enhanced E‐cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin‐treated MCF‐7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF‐7 cells revealed an enhanced E‐cadherin‐mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF‐7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin‐treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E‐cadherin expression, alters cell polarity and stimulates ERα‐positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden. [ABSTRACT FROM AUTHOR]

TDP-43 intracellular aggregates are a pathogenic sign of most amyotrophic lateral sclerosis (ALS) cases. Familial ALS, brought on by TARDBP gene mutations, emphasizes the relevance of this altered protein in pathophysiology. Growing evidence suggests a role for dysregulated microRNA (miRNA) in ALS disease. Furthermore, several studies showed that miRNAs are highly stable in various biological fluids (CSF, blood, plasma, and serum), and they are expressed differentially by comparing ALS patients and controls. In 2011, our research group discovered a rare mutation in a TARDBP gene (G376D) in a large ALS Apulian family with affected members exhibiting a rapidly progressing disease. To identify potential non-invasive biomarkers of preclinical and clinical progression in the TARDBP-ALS family, we assessed the expression levels of plasma microRNAs in affected patients (n = 7) and asymptomatic mutation carriers (n = 7) compared with healthy controls (n = 13). Applying qPCR, we investigate 10 miRNAs that bind TDP-43 in vitro during their biogenesis or in their mature form, and the other nine are known to be deregulated in the disease. We highlight the potential of miR-132-5p, miR-132-3p, miR-124-3p, and miR-133a-3p expression levels in plasma as biomarkers of preclinical progression for G376D-TARDBP-associated ALS. Our research strongly supports the potential of plasma miRNAs as biomarkers for performing predictive diagnostics and identifying new therapeutic targets. [ABSTRACT FROM AUTHOR]

The "omics revolution" has totally changed the scientific research approach and is contributing to the development of personalized therapies. In motor neuron diseases (MNDs), a set of complex, multifactorial, late-onset and chronic neurodegenerative diseases, the use of multi-omics approaches in clinical trials is providing new opportunities to stratify patients and develop target therapies. To show how omics science is gaining momentum in MNDs, in this work, we review the interventional clinical trials for MNDs based on the application of omics sciences. We analyze a total of 62 clinical trials listed in the ClinicalTrials database where different omics approaches have been applied in an initial phase, for diagnosis or patient selection, or in subsequent stages to cluster subjects, identify molecular signatures or evaluate drugs security or efficacy. The rise of omics sciences in clinical experimentation of MNDs is leading to an upheaval in their diagnosis and therapy that will require significant investments and means to ensure the correct and rapid evolution of personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Plasma lipid profile and anthropometric variables are known to be under strong genetic control and the identification of genetic variants associated with bioclinical parameters is of considerable public health importance. In this study, a young cohort of healthy individuals was genotyped for genes related to health and pathological conditions, to analyze the association of single nucleotide polymorphisms (SNPs) with different bioclinical parameters, adherence to the Mediterranean Diet (MD) and physical activity, studying the role of lifestyle and body composition parameters on biochemical metabolic profile. Methods: Association analysis of single variants in the genes of lipoprotein lipase (LPL), fibronectin type III domain containing protein 5 (FNDC5), and peroxisome proliferator-activated receptor-gamma (PPARγ) and haplotype analyses were performed. Results: Multiple (n = 14) common variants in the three genes demonstrated a significant effect on plasma lipoprotein-lipid levels and/or on biochemical parameters in our sample. Specifically, SNPs were related to lipid metabolism (rs3866471, rs4922115, rs11570892, rs248, rs316, rs1059507, rs1801282) or glycemic profile (rs3208305) or anthropometric parameters (rs3480, rs726344, rs1570569) for a total of 26 significant associations (P < 0.01 and/or P < 0.05) and two haplotypes, for the first time, were strongly associated with lipid and body composition parameters. Interestingly, we identified twenty-four new variants not previously described in the literature and a novel significant association between rs80143795 and body composition. Conclusions: In this study we confirm the association between these SNPs on lipid metabolism and body parameters also in a young cohort, indicating the important role of these genetic factors as determinants of health. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria. [ABSTRACT FROM AUTHOR]

Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer's disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments. [ABSTRACT FROM AUTHOR]

Parallel and massive sequencing of total RNA samples derived from different samples are possible thanks to the use of NGS (Next Generation Sequencing) technologies. This allowed characterizing the transcriptomic profile of both cell and tissue populations, increasing the knowledge of the molecular pathological processes of complex diseases, such as neurodegenerative diseases (NDs). Among the NDs, Amyotrophic Lateral Sclerosis (ALS) is caused by the progressive loss of motor neurons (MNs), and, to date, the diagnosis is often made by exclusion because there is no specific symptomatologic picture. For this reason, it is important to search for biomarkers that are clinically useful for carrying out a fast and accurate diagnosis of ALS. Thanks to various studies, it has been possible to propose several molecular mechanisms associated with the disease, some of which include the action of non-coding RNA, including circRNAs, miRNAs, and lncRNAs which will be discussed in the present review. The evidence analyzed in this review highlights the importance of conducting studies to better characterize the different ncRNAs in the disease to use them as possible diagnostic, prognostic, and/or predictive biomarkers of ALS and other NDs. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) showed several processes and risk factors in common with neurodegenerative disorders (NDDs). The present work explored the existence of genetic determinants associated with AMD, which may provide insightful clues concerning its relationship with NDDs and their possible application into the clinical practice. In this study, 400 AMD patients were subjected to the genotyping analysis of 120 genetic variants by OpenArray technology. As the reference group, 503 samples representative of the European general population were utilized. Statistical analysis revealed the association of 23 single-nucleotide polymorphisms (SNPs) with AMD risk. The analysis of epistatic effects revealed that ARMS2, IL6, APOE , and IL2RA could contribute to AMD and neurodegenerative processes by synergistic modulation of the expression of disease-relevant genes. In addition, the bioinformatic analysis of the associated miRNA variants highlighted miR-196a, miR-6796, miR-6499, miR-6810, miR-499, and miR-7854 as potential candidates for counteracting AMD and neurodegenerative processes. Finally, this work highlighted the existence of shared disease mechanisms (oxidative stress, immune-inflammatory response, mitochondrial dysfunction, axonal guidance pathway, and synaptogenesis) between AMD and NDDs and described the associated SNPs as candidate biomarkers for developing novel strategies for early diagnosis, monitoring, and treatment of such disorders in a progressive aging population. [ABSTRACT FROM AUTHOR]