Tohoku Medical Megabank Organization Research Articles

Abstract P539: The Association Between Social Isolation and Metabolic Syndrome in Japanese Adults: The Tohoku Medical Megabank Project

Metabolic syndrome (MetS) and its components are well established as risk factors for cardiovascular disease (CVD). On the other hand, it has also been reported that social isolation is associated with an increased risk of CVD. However, the relationship between social isolation and MetS and its components is not clear. Thus, the purpose of this study is to investigate the association between social isolation and the number of MetS components in Japanese adults. Participants were 28,917 individuals (male/female = 10,226/18,691, age = 59.9±11.6 years) from the Iwate area of the Tohoku Medical Megabank Organization Community-based cohort study (TMM CommCohort study). They had no history of coronary heart disease or stroke. Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS-6). The participants were classified into two groups, the social isolation group and the non-isolation group, based on a cutoff point of 11/12 on the LSNS-6. An assessment of MetS used the criteria defined by the Japanese societies’ committee. The multivariate-adjusted odds ratios (95% confidence intervals) [AORs (95% CIs)] of the social isolation group versus the non-isolation group were calculated using ordered logistic analyses and compared to the number of MetS components. We used gender, age, education, current smoker, current alcohol drinker, total physical activity, current job status, and depression as covariates. AORs (95% CIs) of social isolation against non-isolation were 1.02 (0.95-1.09) for one component of MetS, 1.09 (1.01-1.19) for two components of MetS, and 1.16 (1.06-1.28) for three or more components of MetS, when compared to 0 component of MetS. In conclusion, Japanese adults who experience social isolation might have a greater number of MetS components.

Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project.

In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.

Association of Germline Variants of TCF3 and PAX5 with Pediatric Acute Lymphoblastic Leukemia Development

Background: The development of B-lymphocyte is controlled by the coordinated action of transcription factors networks, such as IKZF1, TCF3, EBF1 or PAX5. It is increasingly recognized that germline variants of those genes which disrupt their function are responsible for inborn errors of humoral immunity. Meanwhile, it is well understood genetic alterations of those molecules are frequently altered in B-lineage acute lymphoblastic leukemia (ALL) and are associated with leukemogenesis. However, those involvements are usually attributed to somatic mutation. Germline variations may also trigger cancer development in some cases. For instance, genome-wide association studies (GWAS) have identified B-cell precursor (BCP-) ALL susceptibility variants within IKZF1. Furthermore, germline variants of IKZF1, TCF3, and PAX5 are reported to be associated with B-ALL development. Therefore, we hypothesize that attenuated function due to germline variation in those genes may predispose to ALL development in Japanese population to some extent. Method: Saliva DNA from 583 pediatric ALL patients in remission registered in Tokyo Children's Cancer Study Group (TCCSG) were analyzed in this study. Targeted sequencing for exons and exon-intron boundaries of IKZF1, TCF3, and PAX5 was performed using next-generation sequencer. Frequency of the detected variant alleles was compared to data from the Exome Aggregation Consortium (ExAC) East Asian Cohort (n=4327), Tohoku Medical Megabank Organization (ToMMo) cohort (n=3554), and the Human Genetic Variation Database (HGVD) cohort (n=1208) by chi-square test or Fisher's exact test. Results: In total, 113 variants (28 nonsynonymous, 19 synonymous, 56 intronic, 8 untranslated regions, and 2 deletions) were detected. We could not detect any nonsynonymous variations, insertion or deletion in IKZF1. On the other hand, we detected 8 rare variations in TCF3 and 7 of them are found to be deleterious by in silico analysis. Among them, 1 variant, TCF3 p.S514L, was significantly more common in ALL patients (0.26% in patients vs 0% in ExAC, 0.01% in ToMMO and 0% in HGVD, p=0.0017, 0.0115 and 0.0343 respectively). In PAX5, we found 6 rare variations and 3 of them are found to be deleterious by in silico analysis, However, we could not identify a statistically significant difference in frequency among these variants between TCCSG and normal cohorts. On the other hand, a patient who harbored heterozygous PAX5 p.V26G, which had been reported as a somatic mutation in B-ALL, was diagnosed with primary antibody deficiency after treatment of B-ALL. He is receiving immunoglobulin replacement therapy without relapse of ALL for 15 years. Discussion: Our study implied TCF3 p.S514L is associated with ALL development. Besides, we identified a case of heterozygous PAX5 p.V26G variant who exhibited antibody deficiency and B-ALL. These findings suggest those rare variants impair the normal B-cell development and may predispose to ALL development. GWAS is effective in evaluating common genetic variants. However, it is hard to identify the genes involved Mendelian inheritance or functionally defective rare variants associated with disease susceptibility. Although it is rare, our study suggests that rare variants of genes involved in B cell development could be associated with ALL susceptibility and immunodeficiency, and we revealed the frequency of functionally defective rare variants in Japanese childhood ALL cohort. Disclosures No relevant conflicts of interest to declare.

BRCA variant classification is improved by Japanese SNP data and correlate with response to PARP inhibition in MH GUIDE

Abstract Background The BRCA1/2 genes have emerged as critical biomarkers, particularly for patients with hereditary breast and ovarian cancer (HBOC). MH BRCA classifies variants based on ACMG guidelines. Clinical interpretation of NGS results by MH GUIDE provides clinicians with treatment recommendations to cancer based on expert curated biomarker knowledge. Methods MH BRCA was compared to the clinical interpretation of three Japanese HBOC studies. Population-frequency (PF) data from the 1000 Genomes Project (1000G) and the Japanese genome cohort of Tohoku Medical Megabank Organization (ToMMo) were analyzed. Based on functional evidence for DNA damage response, we correlated the ACMG index with the predicted response to PARP inhibition by MH GUIDE. Finally, BRCA classifications of 350 patients with breast and/or ovarian cancer sequenced at the Yamanashi Central Hospital (YPCH) were compared to MH BRCA. Results MH BRCA using the integrated ToMMo data revealed 40% increased accuracy in benign classification. The Japanese-cohort in 1000G represents Conclusion We enhanced the performance of MH BRCA for Japanese HBOC patients by integrating data from the ToMMo database. Our collaboration with YPCH revealed that MH BRCA supports a standardized process for assessment of pathogenicity. Contextualizing of MH BRCA classifications with MH GUIDE supports the treatment strategy of PARP inhibition with the benefit on fine-resolution of hypermorphic and hypomorphic BRCA mutations.

A training and education program for genome medical research coordinators in the genome cohort study of the Tohoku Medical Megabank Organization

BackgroundGenome cohort studies are used to analyze interactions between genetic and environmental factors, providing valuable information for personalized healthcare. Large-scale and long-term cohort studies require a number of specially trained personnel, of whom those involved in obtaining informed consent play a vital role, especially during the initial phase of such studies. The Japanese Society of Human Genetics (JSHG) previously established a certification system for genome medical research coordinators (GMRCs) responsible for obtaining written consent via face-to-face explanation. Meanwhile, in the Tohoku Medical Megabank Organization (ToMMo), GMRCs are expected to play important roles not only in obtaining informed consent and conducting various assessments, but also in communicating with participants throughout the long-term follow-up. Based on the JSHG program, we therefore developed a specific education and training program for ToMMo GMRCs consisting of 17 lectures, one practical training session on the informed consent procedure, and written and interview examinations. Re-education workshops aimed at self-improvement are also carried out following certification. In this study, we evaluated the education and training program in terms of overall understanding, usefulness, and satisfaction using an anonymous questionnaire.MethodsAn anonymous questionnaire addressing each aspect of the education and training program (understanding, usefulness, and satisfaction) was distributed among 152 qualified ToMMo GMRCs. Responses were received from 94 participants (61.8%).ResultsThere was a significant association between the level of overall understanding of lectures and medical qualification (nurse or clinical laboratory technologist), but not with age or educational background. The level of understanding and overall usefulness were lower in sessions related to genetics and epidemiology than those dealing with ToMMo practices. In the re-education workshops, GMRCs showed a preference for and hoped to learn more about both background knowledge and research progress in the ToMMo.ConclusionsThe results of our questionnaire suggest that not all ToMMo GMRCs are able to understand everything during the initial education and training program, especially in terms of genomic medicine. Continuous re-education is therefore vital in improving knowledge, skills and motivation, and preparing GMRCs for a specialist role in community-based personalized healthcare.

Abstract 1717: Variants of uncertain significance of the cancer predisposing genes in 3.5 thousand Japanese whole genome sequencing data

Abstract Many of the cancer predisposing genes are known to be associated with juvenile cancer syndromes such as Li Fraumeni syndrome. The responsible variants of the juvenile cancer syndromes are usually very deleterious and show strong biological effects on the gene functions. It is not so easy to estimate the clinical significance of the moderately deleterious variants in those genes that may have clinically significant effects on the hosts’ cancer predisposition and these moderately deleterious (or hypomorphic) variants are now classified as variants of uncertain significance (VUSs). The insight that VUSs may have moderate but clinically significant effects on cancer susceptibility now attracts cancer geneticists. To elucidate the state of VUSs of more than 150 cancer predisposing genes in general population, we functionally annotate the single nucleotide variants (SNVs) in the genes from a 3,552 whole genome sequence dataset (3.5KJPN) obtained from participants in a genome cohort by Tohoku Medical Megabank Organization. Frequency spectrum of the Combined Annotation-Dependent Depletion (CADD) and deleterious annotation of genetic variants using neural networks (DANN) scores of the more than 150 cancer predisposing genes will be discussed. Finally, the association of the CADD and DANN scores with the past and family histories will be analyzed. Citation Format: Jun Yasuda. Variants of uncertain significance of the cancer predisposing genes in 3.5 thousand Japanese whole genome sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1717.

Association between high-sensitivity cardiac troponin T and future cardiovascular incidence in a general Japanese population: results from the Tohoku medical megabank project

Purpose: Elevation of high-sensitivity cardiac troponin T (hs-cTnT) is associated with an increased risk of cardiovascular disease (CVD). This study determined whether hs-cTnT was detectable with N-terminal pro-b-type natriuretic peptide (NT-proBNP) and related to CV risk factors in a general Japanese population.Materials and methods: The Tohoku Medical Megabank Organization pooled individual participant data for a population-based cohort study in the Iwate prefecture (n = 30,193, age = 60.2 ± 11.5 year).Results: Hs-cTnT levels were higher in participants with hypertension, diabetes mellitus than in participants without these conditions (all ps < 0.001). Logistic regression analysis demonstrated that NT-proBNP was strongly associated with elevation of hs-cTnT (OR = 3.35, 95% CI = 2.90–3.89, p < 0.001). The receiver operating characteristic curve analysis showed that hs-cTnT was one of useful biomarker for the differentiation of high risk for CVD (the Suita score ≥ 56) from a general population. Logistic regression analysis demonstrated hs-cTnT levels were related to the CVD high risk group (OR = 2.67, 95% CI = 2.28–3.14, p < 0.001).Conclusions: Hs-cTnT levels are associated with elevation of NT-proBNP and high Suita score, which suggests that elevated hs-cTnT is related to subclinical myocardial damage and indicates CV risk.

Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals.

Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.

Outlier detection for questionnaire data in biobanks.

Biobanks increasingly collect, process and store omics with more conventional epidemiologic information necessitating considerable effort in data cleaning. An efficient outlier detection method that reduces manual labour is highly desirable. We develop an unsupervised machine-learning method for outlier detection, namely kurPCA, that uses principal component analysis combined with kurtosis to ascertain the existence of outliers. In addition, we propose a novel regression adjustment approach to improve detection, namely the regression adjustment for data by systematic missing patterns (RAMP). Application to epidemiological record data in a large-scale biobank (Tohoku Medical Megabank Organization, Japan) shows that a combination of kurPCA and RAMP effectively detects known errors or inconsistent patterns. We confirm through the results of the simulation and the application that our methods showed good performance. The proposed methods are useful for many practical analysis scenarios.

Abstract P031: Plasma Xanthine Oxidoreductase Activity is Associated With Edothelial Dysfucntion and Increased Arterial Stiffness in a General Japanese Population: the Iwate Tohoku Medical Megabank Project

An increase in xanthine oxidoreductase (XOR) activity is related to various diseases such as diabetes, hypertension and obesity has been reported. However, so far the association with XOR activity and pathogenesis of atherosclerosis in a general Japanese population are not known. The purpose of this study is to investigate the association between XOR activity and progression of atherosclerosis including pulse wave velocity (PWV) and flow mediated dilation (FMD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture (n = 810, male / female = 271 / 539, age = 67.6 ± 7.2). Plasma levels of XOR activity in males were marginally higher than in females (89.6 ± 187.0 vs. 64.8 ± 145.8 pmol / h/ mL, p = 0.06). Arterial stiffness by PWV after log10 transformation was significantly higher in quartiles III and IV of XOR compared to quartiles I in females (F =4.768, p &lt; 0.01) (quartiles I vs. III, 3.187 ± 0.088 vs. 3.214 ± 0.081, p &lt; 0.01; quartiles I vs. IV, 3.187 ± 0.088 vs. 3.213 ± 0.080, p &lt; 0.05). Endothelial function as assessed by FMD was significantly lower in quartiles III and IV compared to quartiles I in females (F = 6.074, p &lt; 0.001) (quartiles I vs. III, 6.02 ± 3.19 vs. 4.90 ± 2.66 %, p &lt; 0.01; quartiles I vs. IV, 6.02 ± 3.19 vs. 5.04 ± 2.76 %, p &lt; 0.01). XOR activity was related to progression of atherosclerosis (FMD, OR = 0.930, p = 0.06) and the high risk for CVD in females (Suita Score ≥ 41, OR = 1.92, 95% confidence interval (CI) = 1.04 - 3.54, p &lt; 0.05). XOR activity was no significant association with progression of atherosclerosis and the high risk for CVD in males. The area under the curve (AUC) for XOR activity combined with Suita score was 0.66 (95% CI = 0.52 - 0.77, p &lt; 0.05). In conclusion, XOR activity is associated with endothelial dysfunction and increased arterial stiffness suggesting that elevated XOR activity may relate to progression of atherosclerosis and indicate the CV risk.

128. Detection of predictive makers for preeclampsia using NMR and GC–MS/MS metabolomics

Introduction The Birth and Three Generation Cohort Study was initiated by Tohoku Medical Megabank Organization (ToMMo), Tohoku University, Japan. A total of 73 085 participants, spanning 3 generations and including 22 493 pregnant women, have been recruited as of January 18, 2018. This cohort study was designed to establish methods for personalized early prediction of multifactorial diseases using cutting-edge technology and an integrated biobank, with a focus on genetic and environmental interactions. Objectives Our aim is to discover early predictors of preeclampsia using nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-tandem mass spectrometry (GC–MS/MS) metabolomics to evaluate maternal plasma samples from the first trimester of pregnancy. Methods Plasma samples collected during the first trimester from pregnant women who later developed preeclampsia were obtained from the ToMMo biobank. There were 298 patients who developed preeclampsia, including 45 with early onset and 253 with late onset; these patients were compared with 338 patients with normal pregnancies, randomly selected from the database. We performed NMR and GC–MS/MS to detect circulating metabolites which could be candidates for early predictors of preeclampsia. The present study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of ToMMo. Results Using NMR metabolomics, 36 metabolites were identified and quantified from each plasma sample. A total of 5 early-onset and 8 late-onset metabolites had significantly different values between the case- and control groups. On GC–MS/MS analysis, 155 metabolites were quantified satisfactorily; 15 early-onset and 31 late-onset metabolites had statistically significant differences between groups. Conclusions We identified several candidate predictors using NMR and GC–MS/MS metabolomics in pregnant women who later developed preeclampsia. These results might bring new insights into the establishment of early-prediction formulae, in combination with additional genetic and epidemiologic information.

Abstract 4465: Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data

Abstract Many of the cancer predisposing genes are known to be associated with juvenile cancer syndromes such as Li Fraumeni syndrome. The responsible variants of the juvenile cancer syndromes are usually very deleterious and show strong biological effects on the gene functions. It is not so easy to estimate the clinical significance of the moderately deleterious variants in those genes that may have intermediate effects on the hosts' cancer predisposition and these moderately deleterious (or hypomorphic) variants are now classified as variants of uncertain significance (VUSs). The insight that VUSs may have moderate but clinically significant effects on cancer susceptibility now attracts cancer geneticists. To elucidate the state of VUSs of 135 cancer predisposing genes in general population, we functionally annotate the single nucleotide variants (SNVs) in the genes from a 2049 whole genome sequence high confident dataset (2KJPN-HC) obtained from participants in a genome cohort by Tohoku Medical Megabank Organization. Frequency spectrum of the Combined Annotation-Dependent Depletion (CADD) scores of the 135 genes showed very similar pattern to the whole 2KJPN-HC and a weak negative correlation (r = -0.0579) is observed between allele frequencies and CADD scores for each SNV. Among the variants found in 2KJPN, some of the variants are considered as responsible for hereditary cancer syndromes. We used the CADD and Eigen, other scoring system for estimation of impact of the variants, for the known damaging variants in the BRCA1 and BRCA2 genes to narrow down the candidate VUSs that may have moderate risks for cancer predisposition and found one VUS that is identified as a moderate risk SNP for breast cancer in the other studies. Combination of CADD and Eigen will be useful to narrow down the candidate deleterious SNVs for cancer predisposition. Citation Format: Jun Yasuda, Keita Iida, Kazuki Kumada, Soichi Ogishima, Yusuke Shibuya, Hideki Tokunaga, Nobuo Yaegashi. Variants of uncertain significance of the cancer-predisposing genes in two thousand Japanese whole-genome sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4465.

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Radiobiological Implications of Fukushima Nuclear Accident for Personalized Medical Approach.

On March 11, 2011, a devastating earthquake and subsequent tsunami caused serious damage to areas of the Pacific coast in Fukushima prefecture and prompted fears among the residents about a possible meltdown of the Fukushima Daiichi Nuclear Power Plant reactors. As of 2017, over six years have passed since the Fukushima nuclear crisis and yet the full ramifications of the biological exposures to this accidental release of radioactive substances remain unclear. Furthermore, although several genetic studies have determined that the variation in radiation sensitivity among different individuals is wider than expected, personalized medical approaches for Fukushima victims have seemed to be insufficient. In this commentary, we discuss radiobiological issues arising from low-dose radiation exposure, from the cell-based to the population level. We also introduce the scientific utility of the Integrative Japanese Genome Variation Database (iJGVD), an online database released by the Tohoku Medical Megabank Organization, Tohoku University that covered the whole genome sequences of 2,049 healthy individuals in the northeastern part of Japan in 2016. Here we propose a personalized radiation risk assessment and medical approach, which considers the genetic variation of radiation sensitivity among individuals, for next-step developments in radiological protection.

Monitoring of minimal residual disease in early T‐cell precursor acute lymphoblastic leukaemia by next‐generation sequencing

Monitoring of minimal residual disease in early T‐cell precursor acute lymphoblastic leukaemia by next‐generation sequencing

The Tohoku Medical Megabank Project: Design and Mission.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.

Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals.

The Tohoku Medical Megabank Organization constructed the reference panel (referred to as the 1KJPN panel), which contains >20 million single nucleotide polymorphisms (SNPs), from whole-genome sequence data from 1070 Japanese individuals. The 1KJPN panel contains the largest number of haplotypes of Japanese ancestry to date. Here, from the 1KJPN panel, we designed a novel custom-made SNP array, named the Japonica array, which is suitable for whole-genome imputation of Japanese individuals. The array contains 659 253 SNPs, including tag SNPs for imputation, SNPs of Y chromosome and mitochondria, and SNPs related to previously reported genome-wide association studies and pharmacogenomics. The Japonica array provides better imputation performance for Japanese individuals than the existing commercially available SNP arrays with both the 1KJPN panel and the International 1000 genomes project panel. For common SNPs (minor allele frequency (MAF)>5%), the genomic coverage of the Japonica array (r2>0.8) was 96.9%, that is, almost all common SNPs were covered by this array. Nonetheless, the coverage of low-frequency SNPs (0.5%<MAF⩽5%) of the Japonica array reached 67.2%, which is higher than those of the existing arrays. In addition, we confirmed the high quality genotyping performance of the Japonica array using the 288 samples in 1KJPN; the average call rate 99.7% and the average concordance rate 99.7% to the genotypes obtained from high-throughput sequencer. As demonstrated in this study, the creation of custom-made SNP arrays based on a population-specific reference panel is a practical way to facilitate further association studies through genome-wide genotype imputations.

Ethical challenges for the design and conduct of mega-biobanking from Great East Japan Earthquake victims.

BackgroundAmid continuing social unrest from the Great East Japan Earthquake and subsequent Fukushima nuclear accident of 2011, the Japanese government announced plans for a major biobanking project in the disaster-stricken areas, to be administered by the ‘Tohoku Medical Megabank Organization’ (ToMMo). This project differs from previous biobanking projects in that it 1) was initiated mainly to boost post-disaster recovery and reconstruction; and 2) targets the area’s survivors as its primary subjects. Here, we review the ethics of the ToMMo biobanking project within the wider context of disaster remediation.DiscussionPrivate citizens in the Tohoku region have criticized the project proposal, asking for further review of the ethics of targeting disaster survivors for this study. They claim the project violates the Declaration of Helsinki’s ethical provisions in that (1) government and university researchers initiated it without consulting any Tohoku survivors; (2) survivors already suffering extreme losses may view study involvement as meaningless or even undesirable, yet feel forced to participate in exchange for tenuous promises of future assistance, thus exploiting those most in need.Although the ToMMo has promised certain future social benefits for the target population in exchange for participating in its biobanking research, it is questionable whether such research can address the immediate health needs of the Tohoku disaster survivors in any significant fashion. The ethics of recruiting still-struggling survivors is also questionable.SummaryThis case analysis demonstrates that conducting a post-disaster biobanking project on survivors poses issues concerning potential exploitation and the just distribution of benefits and burdens. Though the ToMMo emphasizes the project’s importance for individual survivors and regional recovery, it is questionable whether such research can justly respond to the survivors’ immediate health needs and whether truly voluntary participation can be ensured in such a crisis. Our society must enhance this nationwide debate and reexamine our priorities for recovery in the disaster-stricken regions. We should evaluate both whether and how this project can truly contribute to the survivors’ quality of life.

Novel genes located in the co-expression networks detected with Transcriptome Tomography

Event Abstract Back to Event Novel genes located in the co-expression networks detected with Transcriptome Tomography Yuko Okamura-Oho1, 2*, Kazuro Shimokawa3, Masaomi Nishimura2, Satoko Takemoto2, Akira Sato4, Teiichi Furuichi4 and Hideo Yokota2 1 Brain Research Network (BReNt), Japan 2 RIKEN, Japan 3 Tohoku Medical Megabank Organization, Tohoku University, Japan 4 Tokyo University of Science, Japan Detection of gene expression-anatomy association is crucial for understanding functions, in particular, of novel coding and non-coding genes. We have invented a framework for comprehensive gene expression density mapping on the whole three dimensional (3D) anatomical context, Transcriptome Tomography (ref.1): here, the methodology is shown in Movie 1. Measured expression densities are usable directly for gene-by-gene correlation analysis of co-expression, and then we have developed a novel bioinformatics framework for comprehensively assessing co-expression patterns that are latent within expression maps (paper in revision). Co-expression search using almost all genes expressed in the adult mouse brain can be done on our website: ViBrism-DB (Figure 1). In this presentation we would focus on previously uncharacterized mouse-specific genes that were co-expressed with genes encoding transcription factors and related molecules. The combinatorial expression of these genes associated with a discrete cell lineage of developmental stages seems to occur in the adult brain and the previously uncharacterized non-coding genes were located in a co-expression network position linking the combinations. This linkage suggests characteristics of these genes that coordinate multiple gene groups and create mouse-specific designs of neurogenesis. Figure 1 Acknowledgements This research was supported by funding from the RIKEN Strategic Programs for R&D (President’s Discretionary Fund) to H.Y., Y.O., K.S., et, al., JSPS KAKENHI Grant Number 25560428 to Y.O. and H.Y., JST Acceleration Utilization of University IP Program to Y.O., RIKEN Neuroinformatics Japan Center to T. F., and JSPS KAKENHI Grant Number 23300137 and 258057 to T. F..