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

Naito T., Okada Y.. Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology. Journal of Human Genetics , (2024); https://doi.org/10.1038/s10038-023-01213-6.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

Genome Wide Association Study of Age at Menarche in the Japanese Population

Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10−7 and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population

Direct effect of cadmium on citrate uptake by isolated ratrenal brush border membrane vesicles

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Long-Term Bonding Performance of One-Bottle vs. Two-Bottle Bonding Agents to Lithium Disilicate Ceramics

The aim of this study was to compare the long-term bonding performance to lithium disilicate (LDS) ceramic between one-bottle and two-bottle bonding agents. Bonding performance was investigated under these LDS pretreatment conditions: with hydrofluoric acid (HF) only, without HF, with a two-bottle bonding agent (Tokuyama Universal Bond II) only. Shear bond strengths between LDS and nine resin cements (both self-adhesive and conventional adhesive types) were measured at three time periods: after one-day water storage (Base), and after 5000 and 20,000 thermocycles (TC 5k and TC 20k respectively). Difference in degradation between one- and two-bottle bonding agents containing the silane coupling agent was compared by high-performance liquid chromatography. With HF pretreatment, bond strengths were not significantly different among the three time periods for each resin cement. Without HF, ESTECEM II and Super-Bond Universal showed significantly higher values than others at TC 5k and TC 20k when treated with the recommended bonding agents, especially at TC 20k. Difference in degradation between one- and two-bottle bonding agents containing the silane coupling agent was compared by high-performance liquid chromatography (HPLC). For both cements, these values at TC 20k were also not significantly different from pretreatment with only Tokuyama Universal Bond II. For LDS, long-term bond durability could be maintained by pretreatment with Tokuyama Universal Bond II instead of the hazardous HF

Blood DNA virome associates with autoimmune diseases and COVID-19

A list of all authors and their affiliations appears at the end of the paper.Sasa Noah, Kojima Shohei, Koide Rie, et al. Blood DNA virome associates with autoimmune diseases and COVID-19. Nature Genetics 11, 197 (2025); https://doi.org/10.1038/s41588-024-02022-z.Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases

Genome Wide Association Study of Age at Menarche in the Japanese Population

Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P-value of 5.49×10−7 and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population.</p

Variants at HLA-A , HLA-C , and HLA-DQB1 Confer Risk of Psoriasis Vulgaris in Japanese

Psoriasis vulgaris (PsV) is an autoimmune disease of skin and joints with heterogeneity in epidemiologic and genetic landscapes of global populations. We conducted an initial genome-wide association study and a replication study of PsV in the Japanese population (606 PsV cases and 2,052 controls). We identified significant associations of the single nucleotide polymorphisms with PsV risk at TNFAIP3-interacting protein 1and the major histocompatibility complex region (P = 3.7 × 10−10 and 6.6 × 10−15, respectively). By updating the HLA imputation reference panel of Japanese (n = 908) to expand HLA gene coverage, we fine-mapped the HLA variants associated with PsV risk. Although we confirmed the PsV risk of HLA-C*06:02 (odds ratio = 6.36, P = 0.0015), its impact was relatively small compared with those in other populations due to rare allele frequency in Japanese (0.4% in controls). Alternatively, HLA-A*02:07, which corresponds to the cysteine residue at HLA-A amino acid position 99 (HLA-A Cys99), demonstrated the most significant association with PsV (odds ratio = 4.61, P = 1.2 × 10–10). In addition to HLA-A*02:07 and HLA-C*06:02, stepwise conditional analysis identified an independent PsV risk of HLA-DQβ1 Asp57 (odds ratio = 2.19, P = 1.9 × 10–6). Our PsV genome-wide association study in Japanese highlighted the genetic architecture of PsV, including the identification of HLA risk variants

Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer

Sasa N., Kishikawa T., Mori M., et al. Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer. Nature Communications 16, 1052 (2025); https://doi.org/10.1038/s41467-025-56150-z.Integration of human papillomavirus (HPV) into the host genome drives HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC). Whole-genome sequencing of 51 tumors revealed intratumor heterogeneity of HPV integration, with 44% of breakpoints subclonal, and a biased distribution of integration breakpoints across the HPV genome. Four HPV physical states were identified, with at least 49% of tumors progressing without integration. HPV integration was associated with APOBEC-induced broad genomic instability and focal genomic instability, including structural variants at integration sites. HPV+ HNSCCs exhibited almost no smoking-induced mutational signatures. Heterozygous loss of ataxia-telangiectasia mutated (ATM) was observed in 67% of tumors, with its downregulation confirmed by single-cell RNA sequencing and immunohistochemistry, suggesting ATM haploinsufficiency contributes to carcinogenesis. PI3K activation was the major oncogenic mutation, with JAK-STAT activation in tumors with clonal integration and NF-kappa B activation in those without. These findings provide valuable insights into HPV integration in HPV+ HNSCC

Machine learning reveals heterogeneous associations between environmental factors and cardiometabolic diseases across polygenic risk scores

ポリジェニックリスクスコア×機械学習で紐解く生活習慣病の遺伝的リスクと予防効果との関係. 京都大学プレスリリース. 2024-10-04.Background: Although polygenic risk scores (PRSs) are expected to be helpful in precision medicine, it remains unclear whether high-PRS groups are more likely to benefit from preventive interventions for diseases. Recent methodological advancements enable us to predict treatment effects at the individual level. Methods: We employed causal forest to explore the relationship between PRSs and individual risk of diseases associated with certain environmental factors. Following simulations illustrating its performance, we applied our approach to investigate the individual risk of cardiometabolic diseases, including coronary artery diseases (CAD) and type 2 diabetes (T2D), associated with obesity and smoking among individuals from UK Biobank (UKB; n = 369, 942) and BioBank Japan (BBJ; n = 149, 421). Results: Here we find the heterogeneous association of obesity and smoking with diseases across PRS values, complicated by the multi-dimensional combination of individual characteristics such as age and sex. The highest positive correlations of PRSs and the exposure-related disease risks are observed between obesity and T2D in UKB and between smoking and CAD in BBJ (Spearman’s ρ = 0.61 and 0.32, respectively). However, most relationships are weak or negative, suggesting that high-PRS groups will not necessarily benefit most from environmental factor prevention. Conclusions: Our study highlights the importance of individual-level prediction of disease risks associated with target exposure in precision medicine

Loci associated with N-glycosylation of human IgG are not associated with rheumatoid arthritis: a Mendelian randomisation study

Objectives: A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity. Methods: SNPs showing association with IgG N-glycosylation were analysed for association with RA susceptibility in 14 361 RA cases and 43 923 controls. Five SNPs were tested for association with response to anti-tumour necrosis factor (TNF) therapy in 1081 RA patient samples and for association with radiological disease severity in 342 patients. Results: Only one SNP (rs9296009) associated with N-glycosylation showed an association (p=6.92×10–266) with RA susceptibility, although this was due to linkage disequilibrium with causal human leukocyte antigen (HLA) variants. Four regions of the genome harboured SNPs associated with both traits (shared loci); although statistical analysis indicated that the associations observed for the two traits are independent. No SNPs showed association with response to anti-TNF therapy. One SNP rs12342831 was modestly associated with Larsen score (p=0.05). Conclusions: In a large, well-powered cohort of RA patients, we show SNPs driving levels of N-glycosylation have no association with RA susceptibility, indicating colocalisation of associated SNPs are not necessarily indicative of a shared genetic background or a role for glycosylation in disease susceptibility