The construction of cross-population polygenic risk scores using transfer learning.

As most existing genome-wide association studies (GWASs) were conducted in European-ancestry cohorts, and as the existing polygenic risk score (PRS) models have limited transferability across ancestry groups, PRS research on non-European-ancestry groups needs to make efficient use of available data until we attain large sample sizes across all ancestry groups. Here we propose a PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PRS model from an ancestry group with large sample GWASs to the dataset of target ancestry. In our application of constructing PRS for seven quantitative and two dichotomous traits for 10,285 individuals of South Asian ancestry and 8,168 individuals of African ancestry in UK Biobank, TL-PRS using PRS-CS as a baseline method obtained 25% average relative improvement for South Asian samples and 29% for African samples compared to the standard PRS-CS method in terms of predicted R2. Our approach increases the transferability of PRSs across ancestries and thereby helps reduce existing inequities in genetics research.

Genome-Wide Association Study with Three Control Cohorts of Japanese Patients with Esotropia and Exotropia of Comitant Strabismus and Idiopathic Superior Oblique Muscle Palsy.

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10-8, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10-6. In comparison with BBJ (180K), RARB (retinoic acid receptor-ß) was detected as a candidate at a significant level of p < 5 × 10-8 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.

[National survey of municipalities examining the introduction of Honnintsuchiseido and its effect on the issuance of resident record copies for academic research].

Objectives　This study examines the dissemination of Honnintsuchiseido (a system of providing notifications to citizens that a municipality issued a copy of resident record to a third party) in Japan and its effect on the use of copies of resident record for academic research.Methods　In February and March 2015, a telephone survey was conducted in 1,741 municipalities (including special wards) in Japan. The survey examined the implementation of Honnintsuchiseido and standards for issuing copies of resident record for academic research in the municipalities. Further, we analyzed the implementation of Honnintsuchiseido and the results of requests for issuing copies of resident record for the Biobank Japan (BBJ) project.Results　The results found that 28.9% of the municipalities had already introduced Honnintsuchiseido. Approximately 85% of the municipalities responded that their each official judged the issuance of copies of resident record for academic research based on a handbook of paperwork for the Basic Resident Registration. Further, approximately 14% responded that they had common definite standards in their officials for judging the issuance of copies of resident record for academic research. One of the main reasons for the refusal to issue copies of resident record in the BBJ project was that the consent form of the project did not specify the use of the resident record. In addition, some municipalities refused because the standards for judgments were revised with the implementation of Honnintsuchiseido. However, there was no significant association between the introduction of Honnintsuchiseido and the refusal to issue copies of resident record for the BBJ project.Conclusions　Some municipalities refused to issue copies of resident record because the standards were revised with the implementation of Honnintsuchiseido. Further, many municipalities did not have any common specific criteria for judging the issuance of copies of resident record for academic purposes. Therefore, specific standards should be formulated to clarify the type of research having public interest, which will support the judgment of municipalities regarding the issuance of copies of resident record for academic research.

Clinical and histopathological characteristics of patients with prostate cancer in the BioBank Japan project.

BACKGROUND: Prostate cancer is the sixth leading cause of cancer-related deaths in Japan. We aimed to elucidate the clinical and histopathological characteristics of patients with prostate cancer in the BioBank Japan (BBJ) project. METHODS: Four thousand, seven hundred and ninety-three patients diagnosed with prostate cancer in the BBJ project were included. Clinical and histopathological data, including causes of death, were analyzed. Relative survival (RS) rates of prostate cancer were calculated. RESULTS: Four thousand, one hundred and seventy-one prostate cancer patients with available histological data had adenocarcinoma. The mean age of the patients was 72.5 years. The proportion of patients who were non-smokers, non-drinkers, had a normal body mass index, did not exercise, had a normal prostate-specific antigen level, and had a family history of prostate cancer were 30.7%, 28.0%, 66.6%, 58.1%, 67.6%, and 6.5%, respectively. The proportion of patients with Stage II, III, and IV disease were 24.4%, 7.3%, and 4.4%, respectively. After limiting to patients with a time from the initial diagnosis of prostate cancer to entry into the study cohort of ≤90 days (n = 869), the 5- and 10-year RS rates were 96.3% and 100.5%, respectively, although we were unable to consider management strategies due to a plenty of data missing. CONCLUSIONS: We provide an overview of patients with prostate cancer in the BBJ project. Our findings, coupled with those from various high throughput "omics" technologies, will contribute to the implementation of prevention interventions and medical management of prostate cancer patients.

Cross-sectional analysis of BioBank Japan clinical data: A large cohort of 200,000 patients with 47 common diseases.

BACKGROUND: To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012. METHODS: We analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development. RESULTS: Distribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset. CONCLUSIONS: Cross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine.

Overview of BioBank Japan follow-up data in 32 diseases.

BACKGROUND: We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data. METHODS: A total of 141,612 participants were included. The survival data were last updated in 2014. Kaplan-Meier survival analysis was performed after categorizing subjects according to sex, age group, and disease status. Relative survival rates were estimated using a survival-rate table of the Japanese general population. RESULTS: Of 141,612 subjects (56.48% male) with 1,087,434 person-years and a 97.0% follow-up rate, 35,482 patients died during follow-up. Mean age at enrollment was 64.24 years for male subjects and 63.98 years for female subjects. The 5-year and 10-year relative survival rates for all subjects were 0.944 and 0.911, respectively, with a median follow-up duration of 8.40 years. Patients with pancreatic cancer had the least favorable prognosis (10-year relative survival: 0.184) and patients with dyslipidemia had the most favorable prognosis (1.013). The most common cause of death was malignant neoplasms. A number of subjects died from diseases other than their registered disease(s). CONCLUSIONS: This is the first report to perform follow-up survival analysis across various common diseases. Further studies should use detailed clinical and genomic information to identify predictors of mortality in patients with common diseases, contributing to the implementation of personalized medicine.

Overview of the BioBank Japan Project: Study design and profile.

BACKGROUND: The BioBank Japan (BBJ) Project was launched in 2003 with the aim of providing evidence for the implementation of personalized medicine by constructing a large, patient-based biobank (BBJ). This report describes the study design and profile of BBJ participants who were registered during the first 5-year period of the project. METHODS: The BBJ is a registry of patients diagnosed with any of 47 target common diseases. Patients were enrolled at 12 cooperative medical institutes all over Japan from June 2003 to March 2008. Clinical information was collected annually via interviews and medical record reviews until 2013. We collected DNA from all participants at baseline and collected annual serum samples until 2013. In addition, we followed patients who reported a history of 32 of the 47 target diseases to collect survival data, including cause of death. RESULTS: During the 5-year period, 200,000 participants were registered in the study. The total number of cases was 291,274 at baseline. Baseline data for 199,982 participants (53.1% male) were available for analysis. The average age at entry was 62.7 years for men and 61.5 years for women. Follow-up surveys were performed for participants with any of 32 diseases, and survival time data for 141,612 participants were available for analysis. CONCLUSIONS: The BBJ Project has constructed the infrastructure for genomic research for various common diseases. This clinical information, coupled with genomic data, will provide important clues for the implementation of personalized medicine.

A putative causality of vitamin D in common diseases: A mendelian randomization study.

Backgrounds: Vitamin D is considered as a nutrient protecting individuals against an array of diseases based on observational studies. Such a protective effect, however, has not been demonstrated by randomized controlled trials. This study aims to explore a putative causal role of vitamin D in common diseases through a two-sample Mendelian randomization (MR) framework. Methods: Circulating vitamin D was predicted by 41 genetic variants discovered in European populations. Common diseases were verified through two ways, using information from Japanese patients of Biobank Japan and using information from European patients of FinnGen project. We additionally validated the results by replacing vitamin D-associated instrumental variables (IVs) of European population with that of an independent Japanese population and of an independent Indian population. Inverse-variance weighted method was used as the primary analytical approach while a series of MR methods including MR-Egger regression, weighted median, maximum likelihood, MR-PRESSO and multivariate MR were adopted to guarantee MR model assumptions and to detect horizontal pleiotropy. Results: Genetically predicted vitamin D was significantly associated with an increased risk of Graves' disease (OR = 1.71, 95%CI: 1.25-2.33, P = 0.001) and cataract (OR = 1.14, 95%CI: 1.03-1.28, P = 0.016); while with a decreased risk of esophageal cancer (OR = 0.66, 95%CI: 0.46-0.93, P = 0.019). This significant causal link between vitamin D and cataract was validated replacing IVs identified in the European population with those from Japanese population. No notable associations of vitamin D with other diseases were observed. Conclusions: Our findings indicate a potential causal role of vitamin D in common diseases, which needs further validation.

Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias: genetics in inguinal hernias.

BACKGROUND: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. METHODS: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. FINDINGS: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. INTERPRETATION: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia. FUNDING: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).

Association of Genetic Polymorphisms With Hepatitis C Virus-related Liver Cirrhosis in Japan.

BACKGROUND/AIM: Hepatitis C virus (HCV) infection is an important health problem in the direct-acting antivirals-era. HCV causes life-threatening diseases, such as cirrhosis and hepatocellular carcinoma. Our aim was to examine whether certain single-nucleotide polymorphisms (SNPs) are associated with the prevalence of HCV infections progressing to cirrhosis in the Japanese population by a genome-wide association study-based approach. MATERIALS AND METHODS: We used DNA extracted from blood specimens of Japanese subjects with the establishment of the BioBank Japan project. RESULTS: We observed statistically significant differences in the frequency of 4 SNPs (rs1989972, rs2293766, rs1877033 and rs4805439) between anti-HCV-positive cirrhotic patients and controls. CONCLUSION: Four SNPs are associated with susceptibility to cirrhosis among HCV-infected Japanese subjects, while further studies with cohorts other than those sourced from BioBank Japan, must be conducted.