Prioritizing susceptibility genes for the prognosis of male-pattern baldness with transcriptome-wide association study.

BACKGROUND: Male-pattern baldness (MPB) is the most common cause of hair loss in men. It can be categorized into three types: type 2 (T2), type 3 (T3), and type 4 (T4), with type 1 (T1) being considered normal. Although various MPB-associated genetic variants have been suggested, a comprehensive study for linking these variants to gene expression regulation has not been performed to the best of our knowledge. RESULTS: In this study, we prioritized MPB-related tissue panels using tissue-specific enrichment analysis and utilized single-tissue panels from genotype-tissue expression version 8, as well as cross-tissue panels from context-specific genetics. Through a transcriptome-wide association study and colocalization analysis, we identified 52, 75, and 144 MPB associations for T2, T3, and T4, respectively. To assess the causality of MPB genes, we performed a conditional and joint analysis, which revealed 10, 11, and 54 putative causality genes for T2, T3, and T4, respectively. Finally, we conducted drug repositioning and identified potential drug candidates that are connected to MPB-associated genes. CONCLUSIONS: Overall, through an integrative analysis of gene expression and genotype data, we have identified robust MPB susceptibility genes that may help uncover the underlying molecular mechanisms and the novel drug candidates that may alleviate MPB.

A Transcriptome-Wide Analysis of Psoriasis: Identifying the Potential Causal Genes and Drug Candidates.

Psoriasis is a chronic inflammatory skin disease characterized by cutaneous eruptions and pruritus. Because the genetic backgrounds of psoriasis are only partially revealed, an integrative and rigorous study is necessary. We conducted a transcriptome-wide association study (TWAS) with the new Genotype-Tissue Expression version 8 reference panels, including some tissue and multi-tissue panels that were not used previously. We performed tissue-specific heritability analyses on genome-wide association study data to prioritize the tissue panels for TWAS analysis. TWAS and colocalization (COLOC) analyses were performed with eight tissues from the single-tissue panels and the multi-tissue panels of context-specific genetics (CONTENT) to increase tissue specificity and statistical power. From TWAS, we identified the significant associations of 101 genes in the single-tissue panels and 64 genes in the multi-tissue panels, of which 26 genes were replicated in the COLOC. Functional annotation and network analyses identified that the genes were associated with psoriasis and/or immune responses. We also suggested drug candidates that interact with jointly significant genes through a conditional and joint analysis. Together, our findings may contribute to revealing the underlying genetic mechanisms and provide new insights into treatments for psoriasis.

Identification of Mucilaginibacter conchicola sp. nov., Mucilaginibacter achroorhodeus sp. nov. and Mucilaginibacter pallidiroseus sp. nov. and emended description of the genus Mucilaginibacter.

Three chitinolytic, Gram-negative, light pink, capsule-forming, rod-shaped bacterial strains with gliding motion (MYSH2T, MJ1aT and dk17T) were isolated from seashells, soil and foxtail, respectively. Phylogenetic analysis of the 16S rRNA gene sequences and concatenated alignment of 92 core genes indicated that strains MYSH2T, MJ1aT and dk17T were novel species of the genus Mucilaginibacter and exhibited a high 16S rRNA sequence similarity (i.e. more than 97.2 %) among each other. These novel strains contained summed feature 3 (C16:1 ω7c and/or C16:1 ω6), iso-C15:0 and MK-7 as the predominant fatty acids and menaquinone. According to the CAZys coding gene of KAAS, MYSH2T and MJ1aT were interpreted as strains containing both GH18 and 19 family coding genes, except for dk17T, which shows only GH19 family genes. These strains likely degrade chitin to chitobiose or directly to N-acetyl-d-glucosamine, which may enhance their chitinolytic capacity, thus making these stains potentially useful for industrial chitin degradation. Based on distinct morphological, physiological, chemotaxonomic and phylogenetic differences from their closest phylogenetic neighbours, we propose that strains MYSH2T, MJ1aT and dk17T represent three novel species in the genus Mucilaginibacter, for which the names Mucilaginibacter conchicola sp. nov. (=KACC 19716T=JCM 32787T), Mucilaginibacter achroorhodeus sp. nov. (=KACC 19906T=NBRC 113667T) and Mucilaginibacter pallidiroseus sp. nov. (=KACC 19907T=NBRC 113666T) are proposed. An emended description of the genus Mucilaginibacter is proposed.

Halomonas antri sp. nov., a carotenoid-producing bacterium isolated from surface seawater.

A Gram-negative, moderately halophilic bacterium, designated as strain Y3S6T, was isolated from a surface seawater sample collected from Dongangyoeng cave, Udo-myeon, Jeju-si, Jeju-do, Repulic of Korea. Cells of strain Y3S6T were aerobic, rod-shaped, non-sporulated, yellow, catalase- negative, oxidase-negative and motile with one polar flagellum. Growth of strain Y3S6T occurred at 15-40 °C (optimum: 25-30 °C), at pH 6.0-9.0 (optimum: pH 7.0) and in the presence of 0-13% NaCl (optimum: 1-6 %, w/v). The novel strain was able to produce carotenoids. Its chemotaxonomic and morphological characteristics were consistent with those of members of the genus Halomonas. Phylogenetic analysis of the 16S rRNA gene sequence revealed that strain Y3S6T formed a clade with Halomonas pellis L5T (98.97 %) and Halomonas saliphila LCB169T(98.90%). The average nucleotide identity and digital DNA-DNA hybridization values of strain Y3S6T with the most closely related strains for which whole genomes are publicly available were 82.3-85.2% and 62.8-66.1 %, respectively. The major fatty acids in strain Y3S6T were C16 : 0, C19 : 0 cyclo ω8c and summed feature 8 (composed of C18 : 1 ω7c and/or C18 : 1 ω6c), and the predominant quinone was Q-9. Its polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified phosphoglycolipid, one unidentified phosphoaminoglycolipid and one unidentified phospholipid. The genomic DNA G+C content based on the draft genome sequence was 64.2 mol%. The results of physiological and biochemical tests and 16S rRNA sequence analysis clearly revealed that strain Y3S6T represents a novel species in the genus Halomonas, for which the name Halomonas antri sp. nov. has been proposed. The type strain is Y3S6T (=KACC 21536T=NBRC 114315=TBRC 15164T).

ClinVar: improvements to accessing data.

ClinVar is a freely available, public archive of human genetic variants and interpretations of their relationships to diseases and other conditions, maintained at the National Institutes of Health (NIH). Submitted interpretations of variants are aggregated and made available on the ClinVar website (https://www.ncbi.nlm.nih.gov/clinvar/), and as downloadable files via FTP and through programmatic tools such as NCBI's E-utilities. The default view on the ClinVar website, the Variation page, was recently redesigned. The new layout includes several new sections that make it easier to find submitted data as well as summary data such as all diseases and citations reported for the variant. The new design also better represents more complex data such as haplotypes and genotypes, as well as variants that are in ClinVar as part of a haplotype or genotype but have no interpretation for the single variant. ClinVar's variant-centric XML had its production release in April 2019. The ClinVar website and E-utilities both have been updated to support the VCV (variation in ClinVar) accession numbers found in the variant-centric XML file. ClinVar's search engine has been fine-tuned for improved retrieval of search results.

Nocardioides donggukensis sp. nov. and Hyunsoonleella aquatilis sp. nov., isolated from Jeongbang Waterfall on Jeju Island.

Two bacterial strains, designated MJB4T and SJ7T, were isolated from water samples collected from Jeongbang Falls on Jeju Island, Republic of Korea. Phylogenetic analysis of 16S rRNA gene sequences indicated that the two strains belonged to the genera Nocardioides and Hyunsoonleella, owing to their high similarities to Nocardioides jensenii DSM 29641T (97.5 %) and Hyunsoonleella rubra FA042 T (96.3 %), respectively. These values are much lower than the gold standard for bacterial species (98.7 %). The average nucleotide identity values between strains MJB4T, SJ7T and the reference strains, Nocardioides jensenii DSM 29641T, Nocardioides daejeonensis MJ31T and Hyunsoonleella flava T58T were 77.2, 75.9 and 75.4 %, respectively. Strains MJB4T and SJ7T and the type strains of the species involved in system incidence have average nucleotide identity and average amino acid threshold values of 60.1-82.6 % for the species boundary (95-96 %), which confirms that strains MJB4T and SJ7T represent two new species of genus Nocardioides and Hyunsoonleella, respectively. Based on phylogenetic and phenotypic data, strains MJB4T and SJ7T are considered to represent novel species of the genus Nocardioides and Hyunsoonleella, respectively, for which the names Nocardioides donggukensis sp. nov. (type strain MJB4T=KACC 21724T=NBRC 114402T) and Hyunsoonleella aquatilis sp. nov., (type strain SJ7T=KACC 21715T=NBRC 114486T) have been proposed.

An Integrative Transcriptomic Analysis of Systemic Juvenile Idiopathic Arthritis for Identifying Potential Genetic Markers and Drug Candidates.

Systemic juvenile idiopathic arthritis (sJIA) is a rare subtype of juvenile idiopathic arthritis, whose clinical features are systemic fever and rash accompanied by painful joints and inflammation. Even though sJIA has been reported to be an autoinflammatory disorder, its exact pathogenesis remains unclear. In this study, we integrated a meta-analysis with a weighted gene co-expression network analysis (WGCNA) using 5 microarray datasets and an RNA sequencing dataset to understand the interconnection of susceptibility genes for sJIA. Using the integrative analysis, we identified a robust sJIA signature that consisted of 2 co-expressed gene sets comprising 103 up-regulated genes and 25 down-regulated genes in sJIA patients compared with healthy controls. Among the 128 sJIA signature genes, we identified an up-regulated cluster of 11 genes and a down-regulated cluster of 4 genes, which may play key roles in the pathogenesis of sJIA. We then detected 10 bioactive molecules targeting the significant gene clusters as potential novel drug candidates for sJIA using an in silico drug repositioning analysis. These findings suggest that the gene clusters may be potential genetic markers of sJIA and 10 drug candidates can contribute to the development of new therapeutic options for sJIA.

A Deep Learning Approach with Data Augmentation to Predict Novel Spider Neurotoxic Peptides.

As major components of spider venoms, neurotoxic peptides exhibit structural diversity, target specificity, and have great pharmaceutical potential. Deep learning may be an alternative to the laborious and time-consuming methods for identifying these peptides. However, the major hurdle in developing a deep learning model is the limited data on neurotoxic peptides. Here, we present a peptide data augmentation method that improves the recognition of neurotoxic peptides via a convolutional neural network model. The neurotoxic peptides were augmented with the known neurotoxic peptides from UniProt database, and the models were trained using a training set with or without the generated sequences to verify the augmented data. The model trained with the augmented dataset outperformed the one with the unaugmented dataset, achieving accuracy of 0.9953, precision of 0.9922, recall of 0.9984, and F1 score of 0.9953 in simulation dataset. From the set of all RNA transcripts of Callobius koreanus spider, we discovered neurotoxic peptides via the model, resulting in 275 putative peptides of which 252 novel sequences and only 23 sequences showing homology with the known peptides by Basic Local Alignment Search Tool. Among these 275 peptides, four were selected and shown to have neuromodulatory effects on the human neuroblastoma cell line SH-SY5Y. The augmentation method presented here may be applied to the identification of other functional peptides from biological resources with insufficient data.

Adhaeribacter rhizoryzae sp. nov., a fibrillar matrix-producing bacterium isolated from the rhizosphere of rice plant.

A novel fibrillar matrix-producing, rod-shaped, red-orange, asporogenous, aerobic bacterium, designated DK36T, was isolated from roots of a rice plant in the Ilsan region near Dongguk University, South Korea. Cells of strain DK36T were Gram-stain-negative and motile by means of gliding. The temperature and pH ranges for growth were 7-35 °C (optimum: 30 °C) and pH 5-10 (optimum: pH 7.0). The strain did not require NaCl for growth but tolerated up to 8 % (w/v) NaCl. Phylogenetic anlaysis of the 16S rRNA gene sequence revealed that DK36T formed a monophyletic clade with Adhaeribacter aerophilus 6425 S-25T, Adhaeribacter aerolatus 6515 J-31T and Adhaeribacter swui 17mud1-7T with sequence similarities of 96.3, 95.5 and 95.2%, respectively. The average nucleotide identity and in silico DNA-DNA hybridization values of strain DK36T with the most closely related strains whose whole genomes are publicly available were 72.5-83.6% and 19-28 %, respectively. The strain showed the typical chemotaxonomic characteristics of the genus Adhaeribacter, with the presence of menaquinone MK-7 as the respiratory quinone, and C16 : 1ω5c, iso-C15 : 0 and summed feature 4 (composed of iso-C17 : 1 I/anteiso-C17 : 1 B) as the major fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, one unidentified aminophosphoglycolipid, one unidentified phospholipid, two unidentified aminolipids and five unidentified polar lipids. The genomic DNA G+C content based on the draft genome sequence was 43.4 mol%. The results of physiological and biochemical tests and 16S rRNA gene sequence analysis clearly revealed that strain DK36T represents a novel species of the genus Adhaeribacter, for which the name Adhaeribacter rhizoryzae sp. nov. is proposed. The type strain is DK36T (=KACC 19902T=NBRC 113689T).

Methylobacterium terricola sp. nov., a gamma radiation-resistant bacterium isolated from gamma ray-irradiated soil.

A gamma radiation-resistant and pink-pigmented bacterial strain, designated as 17Sr1-39T, was isolated from a gamma ray-irradiated soil sample collected in the Republic of Korea. Cells were Gram-stain-negative, strictly aerobic, flagellated, asporogenous, rod-shaped and methylotrophic. Results of 16S rRNA gene sequence analysis showed that strain 17Sr1-39T was phylogenetically related to Methylobacterium currus PR1016AT (97.3 %), Methylobacterium aquaticum DSM 16371T (97.2 %), Methylobacterium platani PMB02T (97.0 %), Methylobacterium frigidaeris IER25-16T (96.6 %), Methylobacterium terrae 17Sr1-28T (96.6 %) and Methylobacterium organophilum JCM 2833T (93.4 %). The G+C content calculated based on the genome sequence was 70.4 mol%. The average nucleotide identity and in silico DNA-DNA hybridization values between strain 17Sr1-39T and M. currus, M. aquaticum, M. platani, M. frigidaeris, M. terrae and M. organophilum were 77.3-89.9 and 22-38.2 %, respectively. The predominant fatty acids were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c) and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The predominant quinone was ubiquinone 10 and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Based on the data from phenotypic tests and genotypic differences between strain 17Sr1-39T and its close phylogenetic relatives, strain 17Sr1-39T represented a new species belonging to the genus Methylobacterium, for which the name Methylobacterium terricola sp. nov. (=KACC 52905T=NBRC 112874T) is proposed.

ClinVar: improving access to variant interpretations and supporting evidence.

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant ('provider interpretation') or from groups such as patient registries that primarily provide phenotypic information from patients ('phenotyping only'). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results.

Flavobacterium baculatum sp. nov., a carotenoid and flexirubin-type pigment producing species isolated from flooded paddy field.

A Gram-stain-negative, aerobic, asporogenous, motile by gliding, dull-yellow, long rod-shaped bacterial strain, designated SNL9T, was isolated from a flooded paddy field near Dongguk University, Republic of Korea. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that SNL9T represents a member of the genus Flavobacterium and is most closely related to Flavobacterium ummariense DS-12T (96.2%) and Flavobacterium viscosum YIM 102796T (96.3%). The average nucleotide identity and in silico DNA-DNA hybridization (DDH) values with F. ummariense DS-12T and F. viscosum YIM 102796T were 89.3/39.1 and 87.1/33 %, respectively. The major fatty acids of SNL9T were identified as iso-C15 : 0, summed feature 3 (comprising C16  :  1ω6c and/or C16  :  1ω7c) and summed feature 9 (comprising iso-C17 : 1ω9c and/or 10 methyl C16 : 0). SNL9T contained MK-6 as the major respiratory quinone. The polar lipids were phoshatidylethanolamine, one unidentified aminophosphoglycolipid, three unidentified aminoglycolipids, two unidentified glycolipids and one unidentified phosphoglycolipid. The DNA G+C content was 34.2 mol%. SNL9T produces carotenoid and flexirubin-type pigments. Among them, carotenoids are particularly valuable for the biotechnological and pharmaceutical industries due to their antioxidant activity. Aryl polyenes (APE) pigments were also found in SNL9T which are responsible for yellow pigment in bacteria. They are stored in the bacterial membrane and protect the bacteria from oxidative stress, particularly from reactive oxygen species. In this paper, we describe a novel isolate, SNL9T, which protect itself from the attack of free radicals using specific natural products in the membrane. Because of their anti-oxidation properties, aryl polyenes may also be of interest to the cosmetic industry. On the basis of the results of phenotypic, genotypic and chemotaxonomic analyses, SNL9T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium baculatum sp. nov. is proposed. The type is SNL9T (=KACC 21170T=NBRC 113746T).

Fabrication of Microarrays for the Analysis of Serological Antibody Isotypes against Food Antigens.

Food intolerance is delayed adverse food reactions which follow consumption of specific foods. The underlying mechanisms are not well understood, but food intolerance is often considered as a type 2 hypersensitivity reaction mediated by immunoglobulin G (IgG) antibody. To understand the causes of food intolerance, it is important to investigate sensitization patterns of food-specific IgGs (sIgG) in relation to dietary patterns and physical conditions. Conventional approaches to measure serological IgGs often require large volumes of serum, thus are not suitable for highly multiplexed assays. To overcome this impracticality, we developed a highly sensitive method to screen the sIgGs and other antibody isotypes against 66 antigens with minimal amount of serums. We prepared a microarray by immobilizing food antigens on activated glass slides. Human sera and their dietary information were obtained from 30 subjects. Aliquots (200 nl) of sera were analyzed against 66 food antigens in parallel. sIgG levels were determined and analyzed in relation to subjects' dietary patterns. The levels of antibody isotypes were also examined to understand the relationship between allergy and food intolerance. The developed microarray showed exceptional performances in antibody screening and demonstrated the potential to be used as an automated assay system.

Modelling APOE ɛ3/4 allele-associated sporadic Alzheimer's disease in an induced neuron.

The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) ɛ3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ɛ3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-ß42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE ɛ3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE ɛ3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE ɛ3/4 patient induced neurons reveals a strong interaction between APOE ɛ3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE ɛ3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE ɛ3/4 and another Alzheimer's disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer's disease for therapeutic discovery.

ClinVar: public archive of interpretations of clinically relevant variants.

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.

ClinVar: public archive of relationships among sequence variation and human phenotype.

ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) provides a freely available archive of reports of relationships among medically important variants and phenotypes. ClinVar accessions submissions reporting human variation, interpretations of the relationship of that variation to human health and the evidence supporting each interpretation. The database is tightly coupled with dbSNP and dbVar, which maintain information about the location of variation on human assemblies. ClinVar is also based on the phenotypic descriptions maintained in MedGen (http://www.ncbi.nlm.nih.gov/medgen). Each ClinVar record represents the submitter, the variation and the phenotype, i.e. the unit that is assigned an accession of the format SCV000000000.0. The submitter can update the submission at any time, in which case a new version is assigned. To facilitate evaluation of the medical importance of each variant, ClinVar aggregates submissions with the same variation/phenotype combination, adds value from other NCBI databases, assigns a distinct accession of the format RCV000000000.0 and reports if there are conflicting clinical interpretations. Data in ClinVar are available in multiple formats, including html, download as XML, VCF or tab-delimited subsets. Data from ClinVar are provided as annotation tracks on genomic RefSeqs and are used in tools such as Variation Reporter (http://www.ncbi.nlm.nih.gov/variation/tools/reporter), which reports what is known about variation based on user-supplied locations.

Performance standard-based validation study for local lymph node assay: 5-bromo-2-deoxyuridine-flow cytometry method.

Local lymph node assay: 5-bromo-2-deoxyuridine-flow cytometry method (LLNA: BrdU-FCM) is a modified non-radioisotopic technique with the additional advantages of accommodating multiple endpoints with the introduction of FCM, and refinement and reduction of animal use by using a sophisticated prescreening scheme. Reliability and accuracy of the LLNA: BrdU-FCM was determined according to OECD Test Guideline (TG) No. 429 (Skin Sensitization: Local Lymph Node Assay) performance standards (PS), with the participation of four laboratories. Transferability was demonstrated through successfully producing stimulation index (SI) values for 25% hexyl cinnamic aldehyde (HCA) consistently greater than 3, a predetermined threshold, by all participating laboratories. Within- and between-laboratory reproducibility was shown using HCA and 2,4-dinitrochlorobenzene, in which EC2.7 values (the estimated concentrations eliciting an SI of 2.7, the threshold for LLNA: BrdU-FCM) fell consistently within the acceptance ranges, 0.025-0.1% and 5-20%, respectively. Predictive capacity was tested using the final protocol version 1.3 for the 18 reference chemicals listed in OECD TG 429, of which results showed 84.6% sensitivity, 100% specificity, and 88.9% accuracy compared with the original LLNA. The data presented are considered to meet the performance criteria for the PS, and its predictive capacity was also sufficiently validated.

The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency.

The National Institutes of Health Genetic Testing Registry (GTR; available online at http://www.ncbi.nlm.nih.gov/gtr/) maintains comprehensive information about testing offered worldwide for disorders with a genetic basis. Information is voluntarily submitted by test providers. The database provides details of each test (e.g. its purpose, target populations, methods, what it measures, analytical validity, clinical validity, clinical utility, ordering information) and laboratory (e.g. location, contact information, certifications and licenses). Each test is assigned a stable identifier of the format GTR000000000, which is versioned when the submitter updates information. Data submitted by test providers are integrated with basic information maintained in National Center for Biotechnology Information's databases and presented on the web and through FTP (ftp.ncbi.nih.gov/pub/GTR/_README.html).

Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear. METHODS: To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk. RESULTS: We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks. CONCLUSION: Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.

Elucidating immunological characteristics of the adenoma-carcinoma sequence in colorectal cancer patients in South Korea using a bioinformatics approach.

Colorectal cancer (CRC) is one of the top five most common and life-threatening malignancies worldwide. Most CRC develops from advanced colorectal adenoma (ACA), a precancerous stage, through the adenoma-carcinoma sequence. However, its underlying mechanisms, including how the tumor microenvironment changes, remain elusive. Therefore, we conducted an integrative analysis comparing RNA-seq data collected from 40 ACA patients who visited Dongguk University Ilsan Hospital with normal adjacent colons and tumor samples from 18 CRC patients collected from a public database. Differential expression analysis identified 21 and 79 sequentially up- or down-regulated genes across the continuum, respectively. The functional centrality of the continuum genes was assessed through network analysis, identifying 11 up- and 13 down-regulated hub-genes. Subsequently, we validated the prognostic effects of hub-genes using the Kaplan-Meier survival analysis. To estimate the immunological transition of the adenoma-carcinoma sequence, single-cell deconvolution and immune repertoire analyses were conducted. Significant composition changes for innate immunity cells and decreased plasma B-cells with immunoglobulin diversity were observed, along with distinctive immunoglobulin recombination patterns. Taken together, we believe our findings suggest underlying transcriptional and immunological changes during the adenoma-carcinoma sequence, contributing to the further development of pre-diagnostic markers for CRC.