Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases.

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts.

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.

Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases.

The contribution of FOXP3-expressing naturally occurring regulatory T (Treg) cells to common polygenic autoimmune diseases remains ambiguous. Here, we characterized genome-wide epigenetic profiles (CpG methylation and histone modifications) of human Treg and conventional T (Tconv) cells in naive and activated states. We found that single-nucleotide polymorphisms (SNPs) associated with common autoimmune diseases were predominantly enriched in CpG demethylated regions (DRs) specifically present in naive Treg cells but much less enriched in activation-induced DRs common in Tconv and Treg cells. Naive Treg cell-specific DRs were largely included in Treg cell-specific super-enhancers and closely associated with transcription and other epigenetic changes in naive and effector Treg cells. Thus, naive Treg cell-specific CpG hypomethylation had a key role in controlling Treg cell-specific gene transcription and epigenetic modification. The results suggest possible contribution of altered function or development of natural Treg cells to the susceptibility to common autoimmune diseases.

HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.

Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.

A sex-biased imbalance between Tfr, Tph, and atypical B cells determines antibody responses in COVID-19 patients.

Sex-biased humoral immune responses to COVID-19 patients have been observed, but the cellular basis for this is not understood. Using single-cell proteomics by mass cytometry, we find disrupted regulation of humoral immunity in COVID-19 patients, with a sex-biased loss of circulating follicular regulatory T cells (cTfr) at a significantly greater rate in male patients. In addition, a male sex-associated cellular network of T-peripheral helper, plasma blasts, proliferating and extrafollicular/atypical CD11c+ memory B cells was strongly positively correlated with neutralizing antibody concentrations and negatively correlated with cTfr frequency. These results suggest that sex-specific differences to the balance of cTfr and a network of extrafollicular antibody production-associated cell types may be a key factor in the altered humoral immune responses between male and female COVID-19 patients.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Genetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association Studies.

BACKGROUND: Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated. METHOD: We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure-associated variants between PA and hypertension with the adjustment of blood pressure. RESULTS: In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk (P<1.0×10-6). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12; P<5.0×10-8), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of WNT2B (odds ratio, 1.50 [95% CI, 1.33-1.69]; P=5.2×10-11). We further identified 1 nearly genome-wide significant locus (8q24, CYP11B2), which presented a significant association in the gene-based test (P=7.2×10-7). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure-associated variants had a higher risk effect for PA than for hypertension. CONCLUSIONS: This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the WNT2B variants reinforces the implication of the Wnt/ß-catenin pathway in the PA pathogenesis.

Genetic architecture of microRNA expression and its link to complex diseases in the Japanese population.

Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10-6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10-5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping.

OBJECTIVE: Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine. METHODS: We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS). RESULTS: Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease. CONCLUSION: Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.

Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology.

The imputation of unmeasured genotypes is essential in human genetic research, particularly in enhancing the power of genome-wide association studies and conducting subsequent fine-mapping. Recently, several deep learning-based genotype imputation methods for genome-wide variants with the capability of learning complex linkage disequilibrium patterns have been developed. Additionally, deep learning-based imputation has been applied to a distinct genomic region known as the major histocompatibility complex, referred to as HLA imputation. Despite their various advantages, the current deep learning-based genotype imputation methods do have certain limitations and have not yet become standard. These limitations include the modest accuracy improvement over statistical and conventional machine learning-based methods. However, their benefits include other aspects, such as their "reference-free" nature, which ensures complete privacy protection, and their higher computational efficiency. Furthermore, the continuing evolution of deep learning technologies is expected to contribute to further improvements in prediction accuracy and usability in the future.

Rigorous evaluation of genetic and epigenetic effects on clinical laboratory measurements using Japanese monozygotic twins.

The investigation of environmental effects on clinical measurements using individual samples is challenging because their genetic and environmental factors are different. However, using monozygotic twins (MZ) makes it possible to investigate the influence of environmental factors as they have the same genetic factors within pairs because the difference in the clinical traits within the MZ mostly reflect the influence of environmental factors. We hypothesized that the within-pair differences in the traits that are strongly affected by genetic factors become larger after genetic risk score (GRS) correction. Using 278 Japanese MZ pairs, we compared the change in within-pair differences in each of the 45 normalized clinical measurements before and after GRS correction, and we also attempted to correct for the effects of genetic factors to identify Cytosine-phosphodiester-Guanine (CpG) sites in DNA sequences with epigenetic effects that are regulated by genetic factors. Five traits were classified into the high heritability group, which was strongly affected by genetic factors. CpG sites could be classified into three groups: regulated only by environmental factors, regulated by environmental factors masked by genetic factors, and regulated only by genetic factors. Our method has the potential to identify trait-related methylation sites that have not yet been discovered.

Genome-wide association study on meningioma risk in Japan: a multicenter prospective study.

PURPOSE: Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility. METHODS: In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan. RESULTS: The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 - 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population. CONCLUSION: This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas.

Prognostic significance of chronic kidney disease and impaired renal function in Japanese patients with COVID-19.

BACKGROUND: Renal impairment is a predictor of coronavirus disease (COVID-19) severity. No studies have compared COVID-19 outcomes in patients with chronic kidney disease (CKD) and patients with impaired renal function without a prior diagnosis of CKD. This study aimed to identify the impact of pre-existing impaired renal function without CKD on COVID-19 outcomes. METHODS: This retrospective study included 3,637 patients with COVID-19 classified into three groups by CKD history and estimated glomerular filtration rate (eGFR) on referral: Group 1 (n = 2,460), normal renal function without a CKD history; Group 2 (n = 905), impaired renal function without a CKD history; and Group 3 (n = 272), history of CKD. We compared the clinical characteristics of these groups and assessed the effect of CKD and impaired renal function on critical outcomes (requirement for respiratory support with high-flow oxygen devices, invasive mechanical ventilation, or extracorporeal membrane oxygen, and death during hospitalization) using multivariable logistic regression. RESULTS: The prevalence of comorbidities (hypertension, diabetes, and cardiovascular disease) and incidence of inflammatory responses (white blood counts, and C-reactive protein, procalcitonin, and D-dimer levels) and complications (bacterial infection and heart failure) were higher in Groups 2 and 3 than that in Group 1. The incidence of critical outcomes was 10.8%, 17.7%, and 26.8% in Groups 1, 2, and 3, respectively. The mortality rate and the rate of requiring IMV support was lowest in Group 1 and highest in Group 3. Compared with Group 1, the risk of critical outcomes was higher in Group 2 (adjusted odds ratio [aOR]: 1.32, 95% confidence interval [CI]: 1.03-1.70, P = 0.030) and Group 3 (aOR: 1.94, 95% CI: 1.36-2.78, P < 0.001). Additionally, the eGFR was significantly associated with critical outcomes in Groups 2 (odds ratio [OR]: 2.89, 95% CI: 1.64-4.98, P < 0.001) and 3 (OR: 1.87, 95% CI: 1.08-3.23, P = 0.025) only. CONCLUSIONS: Clinicians should consider pre-existing CKD and impaired renal function at the time of COVID-19 diagnosis for the management of COVID-19.

Diagnostic accuracy of a novel ultrasound imaging index for knee osteoarthritis: Evaluation of sensitivity, specificity, and predictive values.

PURPOSE: We aimed to develop and validate a new ultrasonography (US) index for the diagnosis of primary medial-type knee osteoarthritis (OA). METHODS: In total, 156 patients (203 limbs) underwent standing knee radiography and the US for suspected knee OA. Total osteophyte height (TOH) and distance between bones (DBB) aided diagnosis. Logistic regression identified optimal cutoff values. Thresholds from logistic regression informed recipient operating characteristic curve (ROC) analysis, balancing sensitivity and specificity. These thresholds were then applied in the differential thermal analysis (DTA) to construct a 2 × 2 table. RESULTS: The TOH-DBB index showed that a DBB of 5.6 mm or less was required to diagnose primary medial-type knee arthropathy. The results in the 2 × 2 table were 41 true-positive (TP), 10 false negative (FN), 22 true-negative (TN), and 7 false positive (FP). A DBB of 5.6 mm or less and TOH of 4.7 mm or more were necessary to diagnose severe deformity. The results in the 2 × 2 table were 10 TP, 4 FN, 23 TN, and 4 FP. CONCLUSION: The TOH-DBB index was confirmed to capture changes in primary medial-type knee OA across various stages.

Advances in genetics toward identifying pathogenic cell states of rheumatoid arthritis.

Rheumatoid arthritis (RA) risk has a large genetic component (~60%) that is still not fully understood. This has hampered the design of effective treatments that could promise lifelong remission. RA is a polygenic disease with 106 known genome-wide significant associated loci and thousands of small effect causal variants. Our current understanding of RA risk has suggested cell-type-specific contexts for causal variants, implicating CD4 + effector memory T cells, as well as monocytes, B cells and stromal fibroblasts. While these cellular states and categories are still mechanistically broad, future studies may identify causal cell subpopulations. These efforts are propelled by advances in single cell profiling. Identification of causal cell subpopulations may accelerate therapeutic intervention to achieve lifelong remission.

PET/CT findings and dose distribution during radiotherapy in T1N0M0-T2N0M0 glottic cancer.

OBJECTIVE: To investigate the positron emission tomography/computed tomography (PET/CT) findings of T1/T2N0M0 glottic cancer (hereafter referred to as T1/T2) and dose distribution in radiotherapy. SUBJECTS AND METHODS: We retrospectively collected data from patients diagnosed with T1/T2N0M0 glottic cancer who received radiotherapy. The extent of fluorine-18-fluorodeoxyglucose (18F-FDG) accumulation in primary tumors, maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), tumor volume of primary tumors on PET/CT were compared. Furthermore, the tumor identified on PET/CT was incorporated into the radiotherapy plans. A dummy plan (radiation field 6x6cm, prescription point facing the vertebral body, maximum dose ≤107%, T1/T2 66Gy/33 fractions) was developed for three-dimensional conformal radiotherapy, and the dose distribution of primary tumors was calculated. RESULTS: Twenty-nine patients (27 men and two women) were included; their mean age was 67.2±15.0 years. Increased 18F-FDG accumulation in primary tumors was observed on PET/CT in 22/29 (78.5%; T1: 14/21 [67%], T2: 8/8 [100%]) patients. The median SUVmax, TLG, and primary tumor volume were significantly different between T1 and T2 (SUVmax, T1: 4.56 vs. T2: 8.43, P=0.035; TLG, T1: 1.01 vs. T2: 3.71 SUVxmL, P<0.01; primary tumor volume, T1: 0.38mL vs. T2: 0.80mL, P=0.01). At a TLG cut-off value of 3.470, the area under the curve was 0.875, sensitivity was 0.875, and specificity was 0.929 for T1-T2 differentiation. In 20 patients with 18F-FDG accumulation, the minimum radiation dose was significantly different between T1 and T2 (66Gy vs. 64Gy, P<0.01) at the same 66Gy prescription. The minimum radiation dose and primary tumor volume show the correlation value (r=-0.516, P=0.02). CONCLUSION: In glottic cancer, T1 and T2 can be differentiated by the extent of 18F-FDG accumulation in primary tumors on PET/CT. The minimum radiation dose rate decreases as volume increases.

Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates.

Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map), which have inverse expression profiles compared with tissue-specific genetically regulated gene expression. Firstly we confirmed the statistical robustness by the application of the null GWAS data and enrichment in the true-positive drug-disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, then we applied the GWAS summary statistics of large-scale European meta-analysis (17 traits; naverage = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds as well as anisomycin in schizophrenia (false discovery rate (FDR)-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development.

Evidence of Polygenic Adaptation in Sardinia at Height-Associated Loci Ascertained from the Biobank Japan.

Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. We utilized height-associated loci from the Biobank Japan (BBJ) dataset to further alleviate concerns of biased ascertainment of GWAS loci and showed that the Sardinians remain significantly shorter than expected under neutrality (∼0.22 standard deviation shorter than Utah residents with ancestry from northern and western Europe [CEU] on the basis of polygenic height scores, p = 3.89 × 10-4). We also found the trajectory of polygenic height scores between the Sardinian and the British populations diverged over at least the last 10,000 years (p = 0.0082), consistent with a signature of polygenic adaptation driven primarily by the Sardinian population. Although the polygenic score-based analysis showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in the UK population by using a haplotype-based statistic, the trait singleton density score (tSDS), driven by the height-increasing alleles (p = 9.1 × 10-4). In summary, by ascertaining height loci in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, the adaptive signature was detected in haplotype-based analysis but not in polygenic score-based analysis.

Genomic repertoires linked with pathogenic potency of arthritogenic Prevotella copri isolated from the gut of patients with rheumatoid arthritis.

OBJECTIVES: Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri (P. copri RA) compared with healthy control-derived P. copri (P. copri HC). METHODS: We obtained 13 P. copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri, we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri-monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC. RESULTS: Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC, but pangenome analysis revealed the high genome plasticity of P. copri. We identified a P. copri RA-specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA-induced more severe arthritis than P. copri HC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA. CONCLUSION: Our findings reveal the genetic diversity of P. copri, and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA. Our study contributes towards elucidation of the complex pathogenesis of RA.