The whole transcriptome analysis using FFPE and fresh tissue samples identifies the molecular fingerprint of osteosarcoma.

Osteosarcoma is a form of bone cancer that predominantly impacts osteoblasts, the cells responsible for creating fresh bone tissue. Typical indications include bone pain, inflammation, sensitivity, mobility constraints, and fractures. Utilising imaging techniques such as X-rays, MRI scans, and CT scans can provide insights into the size and location of the tumour. Additionally, a biopsy is employed to confirm the diagnosis. Analysing genes with distinct expression patterns unique to osteosarcoma can be valuable for early detection and the development of effective treatment approaches. In this research, we comprehensively examined the entire transcriptome and pinpointed genes with altered expression profiles specific to osteosarcoma. The study mainly aimed to identify the molecular fingerprint of osteosarcoma. In this study, we processed 90 FFPE samples from PathWest with an almost equal number of osteosarcoma and healthy tissues. RNA was extracted from Paraffin-embedded tissue; RNA was sequenced, the sequencing data was analysed, and gene expression was compared to the healthy samples of the same patients. Differentially expressed genes in osteosarcoma-derived samples were identified, and the functions of those genes were explored. This result was combined with our previous studies based on FFPE and fresh samples to perform a meta-analysis. We identified 1,500 identical differentially expressed genes in PathWest osteosarcoma samples compared to normal tissue samples of the same patients. Meta-analysis with combined fresh tissue samples identified 530 differentially expressed genes. IFITM5, MMP13, PANX3, and MAGEA6 were some of the most overexpressed genes in osteosarcoma samples, while SLC4A1, HBA1, HBB, AQP7 genes were some of the top downregulated genes. Through the meta-analysis, 530 differentially expressed genes were identified to be identical among FFPE (105 FFPE samples) and 36 fresh bone samples. Deconvolution analysis with single-cell RNAseq data confirmed the presence of specific cell clusters in FFPE samples. We propose these 530 DEGs as a molecular fingerprint of osteosarcoma.

Exploring the Complexity of the Human Respiratory Virome through an In Silico Analysis of Shotgun Metagenomic Data Retrieved from Public Repositories.

BACKGROUND: Respiratory viruses significantly impact global morbidity and mortality, causing more disease in humans than any other infectious agent. Beyond pathogens, various viruses and bacteria colonize the respiratory tract without causing disease, potentially influencing respiratory diseases' pathogenesis. Nevertheless, our understanding of respiratory microbiota is limited by technical constraints, predominantly focusing on bacteria and neglecting crucial populations like viruses. Despite recent efforts to improve our understanding of viral diversity in the human body, our knowledge of viral diversity associated with the human respiratory tract remains limited. METHODS: Following a comprehensive search in bibliographic and sequencing data repositories using keyword terms, we retrieved shotgun metagenomic data from public repositories (n = 85). After manual curation, sequencing data files from 43 studies were analyzed using EVEREST (pipEline for Viral assEmbly and chaRactEriSaTion). Complete and high-quality contigs were further assessed for genomic and taxonomic characterization. RESULTS: Viral contigs were obtained from 194 out of the 868 FASTQ files processed through EVEREST. Of the 1842 contigs that were quality assessed, 8% (n = 146) were classified as complete/high-quality genomes. Most of the identified viral contigs were taxonomically classified as bacteriophages, with taxonomic resolution ranging from the superkingdom level down to the species level. Captured contigs were spread across 25 putative families and varied between RNA and DNA viruses, including previously uncharacterized viral genomes. Of note, airway samples also contained virus(es) characteristic of the human gastrointestinal tract, which have not been previously described as part of the lung virome. Additionally, by performing a meta-analysis of the integrated datasets, ecological trends within viral populations linked to human disease states and their biogeographical distribution along the respiratory tract were observed. CONCLUSION: By leveraging publicly available repositories of shotgun metagenomic data, the present study provides new insights into viral genomes associated with specimens from the human respiratory tract across different disease spectra. Further studies are required to validate our findings and evaluate the potential impact of these viral communities on respiratory tract physiology.

Deciphering the role of a SINE-VNTR-Alu retrotransposon polymorphism as a biomarker of Parkinson's disease progression.

SINE-VNTR-Alu (SVA) retrotransposons are transposable elements which represent a source of genetic variation. We previously demonstrated that the presence/absence of a human-specific SVA, termed SVA_67, correlated with the progression of Parkinson's disease (PD). In the present study, we demonstrate that SVA_67 acts as expression quantitative trait loci, thereby exhibiting a strong regulatory effect across the genome using whole genome and transcriptomic data from the Parkinson's progression markers initiative cohort. We further show that SVA_67 is polymorphic for its variable number tandem repeat domain which correlates with both regulatory properties in a luciferase reporter gene assay in vitro and differential expression of multiple genes in vivo. Additionally, this variation's utility as a biomarker is reflected in a correlation with a number of PD progression markers. These experiments highlight the plethora of transcriptomic and phenotypic changes associated with SVA_67 polymorphism which should be considered when investigating the missing heritability of neurodegenerative diseases.

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson's disease.

Introduction: Parkinson's disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson's Progression Markers Initiative (PPMI) cohort. Aims and methods: In the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as DRA and the DRB3/4/5 haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes. Results: Significant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at p<0.05 by the Fisher's exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%). Conclusions: These data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.

Exploring SVA Insertion Polymorphisms in Shaping Differential Gene Expressions in the Central Nervous System.

Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.

Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.

Transcriptional Landscape of Repetitive Elements in Psoriatic Skin from Large Cohort Studies: Relevance to Psoriasis Pathophysiology.

While studies demonstrating the expression of repetitive elements (REs) in psoriatic skin using RNA-seq have been published before, not many studies have focused on the genome-wide expression patterns using larger cohorts. This study investigated the transcriptional landscape of differentially expressed REs in lesional and non-lesional skin from two previously published large datasets. We observed significant differential expression of REs in lesional psoriatic skin as well as the skin of healthy controls. Significant downregulation of several ERVs, HERVs (including HERV-K) and LINEs was observed in lesional psoriatic skin from both datasets. The upregulation of a small subset of HERV-Ks and Alus in lesional psoriatic skin was also reported. An interesting finding from this expression data was the significant upregulation and overlapping of tRNA repetitive elements in lesional and non-lesional psoriatic skin. The data from this study indicate the potential role of REs in the immunopathogenesis of psoriasis. The expression data from the two independent large study cohorts are powerful enough to confidently verify the differential expression of REs in relation to psoriatic skin pathology. Further studies are warranted to understand the functional impact of these repetitive elements in psoriasis pathogenesis, thereby expanding their significance as a potential targeting pathway for the disease treatment of psoriasis and other inflammatory diseases.

Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data.

Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their use in clinical and research settings. We overcame these issues by performing hierarchical clustering on the 5000 most variably expressed autosomal genes from motor cortex expression data of people with sporadic ALS from the KCL BrainBank (N = 112). Three molecular phenotypes linked to ALS pathogenesis were identified: synaptic and neuropeptide signalling, oxidative stress and apoptosis, and neuroinflammation. Cluster validation was achieved by applying linear discriminant analysis models to cases from TargetALS US motor cortex (N = 93), as well as Italian (N = 15) and Dutch (N = 397) blood expression datasets, for which there was a high assignment probability (80-90%) for each molecular subtype. The ALS and motor cortex specificity of the expression signatures were tested by mapping KCL BrainBank controls (N = 59), and occipital cortex (N = 45) and cerebellum (N = 123) samples from TargetALS to each cluster, before constructing case-control and motor cortex-region logistic regression classifiers. We found that the signatures were not only able to distinguish people with ALS from controls (AUC 0.88 ± 0.10), but also reflect the motor cortex-based disease process, as there was perfect discrimination between motor cortex and the other brain regions. Cell types known to be involved in the biological processes of each molecular phenotype were found in higher proportions, reinforcing their biological interpretation. Phenotype analysis revealed distinct cluster-related outcomes in both motor cortex datasets, relating to disease onset and progression-related measures. Our results support the hypothesis that different mechanisms underpin ALS pathogenesis in subgroups of patients and demonstrate potential for the development of personalised treatment approaches. Our method is available for the scientific and clinical community at https://alsgeclustering.er.kcl.ac.uk .

Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and the most common form of motor neurone disease (MND) which is characterized by the damage and death of motor neurons in the brain and spinal cord of affected individuals. Due to the heterogeneity of the disease, a better understanding of the interaction between genetics and biochemistry with the identification of biomarkers is crucial for therapy development. In this study, we used cerebrospinal fluid (CSF) RNA-sequencing data from the New York Genome Center (NYGC) ALS Consortium and analyzed differential gene expression between 47 MND individuals and 29 healthy controls. Pathway analysis showed that the affected genes are enriched in many pathways associated with ALS, including nucleocytoplasmic transport, autophagy, and apoptosis. Moreover, we assessed differential expression on both gene- and transcript-based levels and demonstrate that the expression of previously identified potential biomarkers, including CAPG, CCL3, and MAP2, was significantly higher in MND individuals. Ultimately, this study highlights the transcriptomic composition of CSF which enables insights into changes in the brain in ALS and therefore increases the confidence in the use of CSF for biomarker development.

Genome-Wide Differential Transcription of Long Noncoding RNAs in Psoriatic Skin.

Long noncoding RNAs (lncRNAs) may contribute to the formation of psoriatic lesions. The present study's objective was to identify long lncRNA genes that are differentially expressed in patient samples of psoriasis through computational analysis techniques. By using previously published RNA sequencing data from psoriatic and healthy patients (n = 324), we analysed the differential expression of lncRNAs to determine transcripts of heightened expression. We computationally screened lncRNA transcripts as annotated by GENCODE across the human genome and compared transcription in psoriatic and healthy samples from two separate studies. We observed 54 differentially expressed genes as seen in two independent datasets collected from psoriasis and healthy patients. We also identified the differential expression of LINC01215 and LINC1206 associated with the cell cycle pathway and psoriasis pathogenesis. SH3PXD2A-AS1 was identified as a participant in the STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop. Both the SH3PXD2A-AS1 and CERNA2 genes have already been recognised as part of the IFN-γ signalling pathway regulation. Additionally, EPHA1-AS1, CYP4Z2P and SNHG12 gene upregulation have all been previously linked to inflammatory skin diseases. Differential expression of various lncRNAs affects the pathogenesis of psoriasis. Further characterisation of lncRNAs and their functions are important for developing our understanding of psoriasis.

Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex.

Genomic and transcriptomic studies of expression quantitative trait loci (eQTL) revealed that SINE-VNTR-Alu (SVA) retrotransposon insertion polymorphisms (RIPs) within human genomes markedly affect the co-expression of many coding and noncoding genes by coordinated regulatory processes. This study examined the polymorphic SVA modulation of gene co-expression within the major histocompatibility complex (MHC) genomic region where more than 160 coding genes are involved in innate and adaptive immunity. We characterized the modulation of SVA RIPs utilizing the genomic and transcriptomic sequencing data obtained from whole blood of 1266 individuals in the Parkinson's Progression Markers Initiative (PPMI) cohort that included an analysis of human leukocyte antigen (HLA)-A regulation in a subpopulation of the cohort. The regulatory properties of eight SVAs located within the class I and class II MHC regions were associated with differential co-expression of 71 different genes within and 75 genes outside the MHC region. Some of the same genes were affected by two or more different SVA. Five SVA are annotated in the human genomic reference sequence GRCh38.p14/hg38, whereas the other three were novel insertions within individuals. We also examined and found distinct structural effects (long and short variants and the CT internal variants) for one of the SVA (R_SVA_24) insertions on the differential expression of the HLA-A gene within a subpopulation (550 individuals) of the PPMI cohort. This is the first time that many HLA and non-HLA genes (multilocus expression units) and splicing mechanisms have been shown to be regulated by eight structurally polymorphic SVA within the MHC genomic region by applying precise statistical analysis of RNA data derived from the blood samples of a human cohort population. This study shows that SVA within the MHC region are important regulators or rheostats of gene co-expression that might have potential roles in diversity, health, and disease.

Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia.

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives: To investigate the effects of genetic variants on risk and time to LID. Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1,612 PD patients with and 3,175 without LID. Results: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (HR=1.42, 95% CI=1.09-1.84, p=0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile=1.27, 95% CI=1.03-1.56, p=0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile=1.38, 95% CI=1.07-1.79, p=0.0128; HRfourth_quartile=1.38, 95% CI=1.06-1.78, p=0.0147). Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.

CRISPR deletion of a SINE-VNTR-Alu (SVA_67) retrotransposon demonstrates its ability to differentially modulate gene expression at the MAPT locus.

Background: SINE-VNTR-Alu (SVA) retrotransposons are hominid-specific elements which have been shown to play important roles in processes such as chromatin structure remodelling and regulation of gene expression demonstrating that these repetitive elements exert regulatory functions. We have previously shown that the presence or absence of a specific SVA element, termed SVA_67, was associated with differential expression of several genes at the MAPT locus, a locus associated with Parkinson's Disease (PD) and frontotemporal dementia. However, we were not able to demonstrate that causation of differential gene expression was directed by the SVA due to lack of functional validation. Methods: We performed CRISPR to delete SVA_67 in the HEK293 cell line. Quantification of target gene expression was performed using qPCR to assess the effects on expression in response to the deletion of SVA_67. Differences between CRISPR edit and control cell lines were analysed using two-tailed t-test with a minimum 95% confidence interval to determine statistical significance. Results: In this study, we provide data highlighting the SVA-specific effect on differential gene expression. We demonstrate that the hemizygous deletion of the endogenous SVA_67 in CRISPR edited cell lines was associated with differential expression of several genes at the MAPT locus associated with neurodegenerative diseases including KANSL1, MAPT and LRRC37A. Discussion: This data is consistent with our previous bioinformatic work of differential gene expression analysis using transcriptomic data from the Parkinson's Progression Markers Initiative (PPMI) cohort. As SVAs have regulatory influences on gene expression, and insertion polymorphisms contribute to interpersonal differences in expression patterns, these results highlight the potential contribution of these elements to complex diseases with potentially many genetic components, such as PD.

Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports.

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.

Genomics of Wolfram Syndrome 1 (WFS1).

Wolfram Syndrome (WFS) is a rare, autosomal, recessive neurogenetic disorder that affects many organ systems. It is characterised by diabetes insipidus, diabetes mellites, optic atrophy, and deafness and, therefore, is also known as DIDMOAD. Nearly 15,000-30,000 people are affected by WFS worldwide, and, on average, patients suffering from WFS die at 30 years of age, usually from central respiratory failure caused by massive brain atrophy. The more prevalent of the two kinds of WFS is WFS1, which is a monogenic disease and caused by the loss of the WFS1 gene, whereas WFS2, which is more uncommon, is caused by mutations in the CISD2 gene. Currently, there is no treatment for WFS1 to increase the life expectancy of patients, and the treatments available do not significantly improve their quality of life. Understanding the genetics and the molecular mechanisms of WFS1 is essential to finding a cure. The inability of conventional medications to treat WFS1 points to the need for innovative strategies that must address the fundamental cause: the deletion of the WFS1 gene that leads to the profound ER stress and disturbances in proteostasis. An important approach here is to understand the mechanism of the cell degeneration after the deletion of the WFS1 gene and to describe the differences in these mechanisms for the different tissues. The studies so far have indicated that remarkable clinical heterogeneity is caused by the variable vulnerability caused by WFS1 mutations, and these differences cannot be attributed solely to the positions of mutations in the WFS1 gene. The present review gives a broader overview of the results from genomic studies on the WFS1 mouse model.

Genome-wide association study identifying variants related to performance and injury in high-performance athletes.

A growing body of evidence exists supporting the role that genetic variation plays in athletic performance and injury. This study sought to identify genetic variants associated with performance and lower limb musculoskeletal injury in a high-level athletic cohort. A total of 126 Estonian National Team members (Olympic athletes and participants of International Championships) (104 males, 82.5%) underwent a genome-wide association analysis between 2017 and 2018, to identify single-nucleotide polymorphisms (SNPs) associated with performance and/or injury. The athletic cohort was stratified within each sport based on performance and whether they were a medalist (n = 29) or not (n = 97), whether they sustained an injury (n = 47) or not (n = 79), and the type of injury (patella tendinopathy n = 22, Achilles tendinopathy n = 17, hamstring injury n = 3, anterior cruciate ligament rupture n = 6). Three SNPs demonstrated strong genome-wide association with athletic performance (podium/medalist versus not), including DSG1 (rs10502567, OR 14.3) and DSG4 (rs73410248, OR 17.4), while 76 SNPs demonstrated suggestive significance. Overall, 37 SNPs gave genome-wide suggestive association with any type of injury, including PAPPA2 (rs11580456, OR 13.8) and MAS1 (rs220735, rs170219, OR 3.1) which demonstrated positive signal with multiple SNPs. Several genes demonstrated positive association for the specific injury types, including COL22A1 (rs3924862) and PLXNA2 (rs11799530), as well as PAPPA2 (rs11580456), DOK5 (rs73142922), GNG12 (rs28435277), and DAP (rs267959, rs2930047, rs1080440, rs267939). The current study identified genetic variants associated with high-level athletic performance and musculoskeletal injury. Further work is required to permit integration of this and future knowledge into individualized training practices, as well as injury mitigation and rehabilitation programs.

Longitudinal dysregulation of long non-coding RNAs in Parkinson's disease.

Long non-coding RNAs (lncRNAs) have been suggested as potential biomarkers for Parkinson's disease (PD). This study aimed to identify blood-based lncRNA transcripts that are dysregulated in PD over time and could serve as peripheral biomarkers. Using RNA-sequencing data from the Parkinson's Progression Markers Initiative, differential expression between case and control groups at five different time points was detected, and pathway analysis was conducted. Seven transcripts, not previously linked to PD, were consistently dysregulated across all time points, while PD-linked lncRNAs were dysregulated at some but not all time points. Pathway analysis highlighted pathways, known to be affected in PD. This suggested that dysregulated lncRNA transcripts could play a role in PD pathogenesis by affecting well-known PD pathways and highlighted their potential as longitudinal biomarkers for PD. Further studies are needed to validate these findings and explore the potential use of identified lncRNAs as diagnostic and therapeutic targets.

Reference LINE-1 insertion polymorphisms correlate with Parkinson's disease progression and differential transcript expression in the PPMI cohort.

Long interspersed nuclear element-1 (LINE-1/L1) retrotransposons make up 17% of the human genome. They represent one class of transposable elements with the capacity to both mobilize autonomously and in trans via the mobilization of other elements, primarily Alu and SVA elements. Reference LINE-1 elements are, by definition, found in the reference genome, however, due to the polymorphic nature of these elements, variation for presence or absence is present within the population. We used a combination of clinical and transcriptomic data from the Parkinson's Progression Markers Initiative (PPMI) and applied matrix expression quantitative trait loci analysis and linear mixed-effects models involving 114 clinical, biochemical and imaging data from the PPMI cohort to elucidate the role of reference LINE-1 insertion polymorphism on both gene expression genome-wide and progression of Parkinson's disease (PD). We demonstrate that most LINE-1 insertion polymorphisms are capable of regulating gene expression, preferentially in trans, including previously identified PD risk loci. In addition, we show that 70 LINE-1 elements were associated with longitudinal changes of at least one PD progression marker, including ipsilateral count density ratio and UPDRS scores which are indicators of degeneration and severity. In conclusion, this study highlights the effect of the polymorphic nature of LINE-1 retrotransposons on gene regulation and progression of PD which underlines the importance of analyzing transposable elements within complex diseases.

A Genome-Wide Screen for the Exonisation of Reference SINE-VNTR-Alus and Their Expression in CNS Tissues of Individuals with Amyotrophic Lateral Sclerosis.

The hominid-specific retrotransposon SINE-VNTR-Alu (SVA) is a composite element that has contributed to the genetic variation between individuals and influenced genomic structure and function. SVAs are involved in modulating gene expression and splicing patterns, altering mRNA levels and sequences, and have been associated with the development of disease. We evaluated the genome-wide effects of SVAs present in the reference genome on transcript sequence and expression in the CNS of individuals with and without the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). This study identified SVAs in the exons of 179 known transcripts, several of which were expressed in a tissue-specific manner, as well as 92 novel exonisation events occurring in the motor cortex. An analysis of 65 reference genome SVAs polymorphic for their presence/absence in the ALS consortium cohort did not identify any elements that were significantly associated with disease status, age at onset, and survival. However, there were transcripts, such as transferrin and HLA-A, that were differentially expressed between those with or without disease, and expression levels were associated with the genotype of proximal SVAs. This study demonstrates the functional consequences of several SVA elements altering mRNA splicing patterns and expression levels in tissues of the CNS.

Polymorphisms in corticotrophin-releasing hormone-proopiomalanocortin (CRH-POMC) system genes: Neuroimmune contributions to psoriasis disease.

BACKGROUND: Skin is a target organ and source of the corticotropin-releasing hormone-proopiomelanocortin (CRH-POMC) system, operating as a coordinator and executor of responses to stress. Environmental stress exacerbates and triggers inflammatory skin diseases through modifying the cellular components of the immune system supporting the importance of CRH-POMC system in the pathogenesis of psoriasis. The aim of this study was to analyse the association of CRH-POMC polymorphisms with psoriasis and evaluate transcript expression of lesional psoriatic and normal skin in RNA-seq data. METHODS: Samples of 104 patients with psoriasis and 174 healthy controls were genotyped for 42 single nucleotide polymorphisms (SNPs) of CRH-POMC using Applied Biosystems SNPlex™ method. The transcript quantification was performed using Salmon software v1.3.0. RESULTS: This study demonstrated the associations between melanocortin 1 receptor (MC1R) polymorphisms rs2228479, rs3212369, dopachrome tautomerase (DCT) polymorphisms rs7987802, rs2031526, rs9524501 and psoriasis in the Tatar population. Very strong association was evident for the SNP rs7987802 in the DCT gene (pc = 5.95е-006) in psoriasis patients. Additionally, the haplotype analysis provided AT DCT (rs7992630 and rs7987802) and AGA MC1R (rs3212358, 2228479 and 885479) haplotypes significantly associated (pc ˂ 0.05) with psoriasis in the Tatar population, supporting the involvement of DCT and MC1R to the psoriasis susceptibility. Moreover, MC1R-203 and DCT-201 expression levels were decreased in psoriasis lesional skin compared with healthy control skin. CONCLUSIONS: This study is the first to identify genetic variants of the MC1R and DCT genes significantly associated with psoriasis in Tatar population. Our results support potential roles of CRH-POMC system genes and DCT in the pathogenesis of psoriasis.