Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we ...conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n
= 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study ...(GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10
). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association ...between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.
Polygenic risk scores suffer reduced accuracy in non-European populations, exacerbating health disparities. We propose PolyPred, a method that improves cross-population polygenic risk scores by ...combining two predictors: a new predictor that leverages functionally informed fine-mapping to estimate causal effects (instead of tagging effects), addressing linkage disequilibrium differences, and BOLT-LMM, a published predictor. When a large training sample is available in the non-European target population, we propose PolyPred
, which further incorporates the non-European training data. We applied PolyPred to 49 diseases/traits in four UK Biobank populations using UK Biobank British training data, and observed relative improvements versus BOLT-LMM ranging from +7% in south Asians to +32% in Africans, consistent with simulations. We applied PolyPred
to 23 diseases/traits in UK Biobank east Asians using both UK Biobank British and Biobank Japan training data, and observed improvements of +24% versus BOLT-LMM and +12% versus PolyPred. Summary statistics-based analogs of PolyPred and PolyPred
attained similar improvements.
The global population is concentrating unprecedentedly into urban areas, raising concerns on global sustainability and human well-being. There also exists a niche trend of migration from urban to ...rural areas particularly in countries with post-industrial economies. This paper investigated values of migration expressed by the migrants arrived in Hokuto City, a Japanese rural municipality experiencing pervasive population decline but is also a popular destination for migrants from urban areas. Statistical analyses of 868 responses to a Hokuto City's migrant survey between April 2017 and January 2019 identified their common values of migration, i.e., nature, housing and food. In addition to these common values, households with different demographic characteristics had different priorities: employment for singles in ages between 16 and 29; favorable environment for raising children for married couples in their 30s and 40s; not specific or ‘lifestyle’ for migrants in 50s; and staying with or near family for retirees over 60 years. Knowledge of heterogeneity in migrants and of their values, as described herein, will enable targeted policies and public services concerning migration. Widespread acceptance of teleworking after experiencing the COVID-19 pandemic might offer people of working age, particularly in their 20s and younger, a wider range of options of places to work and live, and thus is likely to influence future urban-rural population flow. A more detailed analysis of the region's natural attributes which are central to the values of migration to rural areas, such as Hokuto City, will be useful to inform regional land use planning that is salient to the values of migrants.
•The natural environment, comfortable housing and food are important and common values for the migrants to Hokuto City.•Households of different traits had different priorities of some value types that were decisive in their migration decision.•Migrants in 20s or less prioritized job, implying that now widespread teleworking potentially influences migration decision.•More detailed analyses of the nature-related values can help landscape management that is salient to the values of migrants.
Background
Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. ...This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes.
Methods
One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m
2
b.i.d.) on days 1–14 and intravenous cisplatin (60 mg/m
2
) and docetaxel (50–60 mg/m
2
) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery.
Results
Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0–88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (
P
= 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS.
Conclusions
DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.
Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a ...triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine’s Clinical Data Warehouse (2004–2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change −1.00 ± 0.23 mmol/L, P < 0.001) or serotonin‐noradrenaline reuptake inhibitor (SNRI; −1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within‐class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004–2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58–5.45) and SNRIs (5.66, 4.38–7.31), but not for mirtazapine (1.08, 0.74–1.58), fluvoxamine (1.48, 0.94–2.32), and milnacipran (0.85, 0.45–1.62). Finally, pharmacoepidemiological–pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = −0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.
Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to ...recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10
) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.
Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in Asian ...populations. To identify novel genetic loci associated with resistant hypertension in the Japanese population, we conducted a genome-wide association study with 2705 resistant hypertension cases and 21,296 mild hypertension controls, all from BioBank Japan. We identified one novel susceptibility candidate locus, rs1442386 on chromosome 18p11.3 (DLGAP1), achieving genome-wide significance (odds ratio (95% CI) = 0.85 (0.81-0.90), P = 3.75 × 10
) and 18 loci showing suggestive association, including rs62525059 of 8q24.3 (CYP11B2) and rs3774427 of 3p21.1 (CACNA1D). We further detected biological processes associated with resistant hypertension, including chemical synaptic transmission, regulation of transmembrane transport, neuron development and neurological system processes, highlighting the importance of the nervous system. This study provides insights into the etiology of resistant hypertension in the Japanese population.
Abstract
Multidot single-electron devices (SEDs) can enable new types of computing technologies, such as those that are reconfigurable and reservoir-computing. A self-assembled metal nanodot array ...film that is attached to multiple gates is a candidate for use in such SEDs for achieving high functionality. However, the single-electron properties of such a film have not yet been investigated in conjunction with optimally controlled multiple gates because of the structural complexity of incorporating many nanodots. In this study, Fe nanodot-array-based double-gate SEDs were fabricated by vacuum deposition, and their single-electron properties (modulated by the top- and bottom-gate voltages;
V
T
and
V
B
, respectively) were investigated. The phase of the Coulomb blockade oscillation systematically shifted with
V
T
, indicating that the charge state of the single dot was controlled by both the gate voltages despite the metallic random multidot structure. This result demonstrates that the Coulomb blockade oscillation (originating from the dot in the multidot array) can be modulated by the two gates. The top and bottom gates affected the electronic state of the dot unevenly owing to the geometrical effect caused by the following: (1) vertically asymmetric dot shape and (2) variation of the dot size (including the surrounding dots). This is a characteristic feature of a nanodot array that uses self-assembled metal dots; for example, prepared by vacuum deposition. Such variations derived from a randomly distributed nanodot array will be useful in enhancing the functionality of multidot devices.
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