Tohoku Medical Megabank Research Articles

299 A genome-wide association study identifies a novel susceptibility locus for total IgE in a Japanese population from Tohoku Medical Megabank cohort study

299 A genome-wide association study identifies a novel susceptibility locus for total IgE in a Japanese population from Tohoku Medical Megabank cohort study

Strategic Methods for Recruiting Grandparents: The Tohoku Medical Megabank Birth and Three-Generation Cohort Study.

Involvement of family members, especially grandparents, in genome epidemiological research is important to investigate both genetic and environmental factors of common diseases. The aim of the present study was to establish strategies to obtain enough number of family recruitment, especially focusing on grandparents, for the Tohoku Medical Megabank Birth and Three-Generation Cohort Study. Our main strategies are summarized below. 1) We standardized informed consent process with reference materials to help people understand the consent form, 2) we created an invitation letter to contact family members, and 3) we recruited family members in several settings. To obtain informed consent, we were careful of explaining clearly the complex reasons as well as drawing people's attention. By the end of March 2017, the number of invitation letters distributed to family members through the pregnant women was 23,806, including 18,702 grandparents. Among the grandparents who received invitation letters, 2,935 (15.7%) responded to us. Furthermore, some grandparents were asked to provide informed consent with other family members by staff at maternal clinics or Community Support Centers, and others directly booked Community Support Centers without responding to the invitation letter. Grandparents joined the study anytime during mother's maternal check-ups or delivery. Overall, 8,054 grandparents participated in our birth cohort study. The setting in which most grandparents were recruited was our own facilities. Importantly, both paternal and maternal grandparents more frequently participated in the study if the father also participated. In conclusion, we are able to recruit not only pregnant women but also fathers and grandparents.

JMorp: Japanese Multi Omics Reference Panel.

We developed jMorp, a new database containing metabolome and proteome data for plasma obtained from >5000 healthy Japanese volunteers from the Tohoku Medical Megabank Cohort Study, which is available at https://jmorp.megabank.tohoku.ac.jp. Metabolome data were measured by proton nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry (LC–MS), while proteome data were obtained by nanoLC–MS. We released the concentration distributions of 37 metabolites identified by NMR, distributions of peak intensities of 257 characterized metabolites by LC–MS, and observed frequencies of 256 abundant proteins. Additionally, correlation networks for the metabolites can be observed using an interactive network viewer. Compared with some existing databases, jMorp has some unique features: (i) Metabolome data were obtained using a single protocol in a single institute, ensuring that measurement biases were significantly minimized; (ii) The database contains large-scale data for healthy volunteers with various health records and genome data and (iii) Correlations between metabolites can be easily observed using the graphical viewer. Metabolites data are becoming important intermediate markers for evaluating the health states of humans, and thus jMorp is an outstanding resource for a wide range of researchers, particularly those in the fields of medical science, applied molecular biology, and biochemistry.

Population-based biobank participants\u2019 preferences for receiving genetic test results

There are ongoing debates on issues relating to returning individual research results (IRRs) and incidental findings (IFs) generated by genetic research in population-based biobanks. To understand how to appropriately return genetic results from biobank studies, we surveyed preferences for returning IRRs and IFs among participants of the Tohoku Medical Megabank Project (TMM). We mailed a questionnaire to individuals enrolled in the TMM cohort study (Group 1; n=1031) and a group of Tohoku region residents (Group 2; n=2314). The respondents were required to be over 20 years of age. Nearly 90% of Group 1 participants and over 80% of Group 2 participants expressed a preference for receiving their genetic test results. Furthermore, over 60% of both groups preferred to receive their genetic results ‘from a genetic specialist.’ A logistic regression analysis revealed that engaging in ‘health-conscious behaviors’ (such as regular physical activity, having a healthy diet, intentionally reducing alcohol intake and/or smoking and so on) was significant, positively associated with preferring to receive their genetic test results (odds ratio=2.397 (Group 1) and 1.897 (Group 2)). Our findings provided useful information and predictors regarding the return of IRRs and IFs in a population-based biobank.

F-treeGC: a questionnaire-based family tree-creation software for genetic counseling and genome cohort studies

BackgroundThe Tohoku Medical Megabank project aims to create a next-generation personalized healthcare system by conducting large-scale genome-cohort studies involving three generations of local residents in the areas affected by the Great East Japan Earthquake. We collected medical and genomic information for developing a biobank to be used for this healthcare system. We designed a questionnaire-based pedigree-creation software program named “f-treeGC,” which enables even less experienced medical practitioners to accurately and rapidly collect family health history and create pedigree charts.Resultsf-treeGC may be run on Adobe AIR. Pedigree charts are created in the following manner: 1) At system startup, the client is prompted to provide required information on the presence or absence of children; f-treeGC is capable of creating a pedigree up to three generations. 2) An interviewer fills out a multiple-choice questionnaire on genealogical information. 3) The information requested includes name, age, gender, general status, infertility status, pregnancy status, fetal status, and physical features or health conditions of individuals over three generations. In addition, information regarding the client and the proband, and birth order information, including multiple gestation, custody, multiple individuals, donor or surrogate, adoption, and consanguinity may be included. 4) f-treeGC shows only marriages between first cousins via the overlay function. 5) f-treeGC automatically creates a pedigree chart, and the chart-creation process is visible for inspection on the screen in real time. 6) The genealogical data may be saved as a file in the original format. The created/modified date and time may be changed as required, and the file may be password-protected and/or saved in read-only format. To enable sorting or searching from the database, the file name automatically contains the terms typed into the entry fields, including physical features or health conditions, by default. 7) Alternatively, family histories are collected using a completed foldable interview paper sheet named “f-sheet”, which is identical to the questionnaire in f-treeGC.ConclusionsWe developed a questionnaire-based family tree-creation software, named f-treeGC, which is fully compliant with international recommendations for standardized human pedigree nomenclature. The present software simplifies the process of collecting family histories and pedigrees, and has a variety of uses, from genome cohort studies or primary care to genetic counseling.

Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design

BackgroundWith the goal of realizing genome-based personalized healthcare, we have developed a biobank that integrates personal health, genome, and omics data along with biospecimens donated by volunteers of 150,000. Such a large-scale of data integration involves obvious risks of privacy violation. The research use of personal genome and health information is a topic of global discussion with regard to the protection of privacy while promoting scientific advancement. The present paper reports on our plans, current attempts, and accomplishments in addressing security problems involved in data sharing to ensure donor privacy while promoting scientific advancement.MethodsBiospecimens and data have been collected in prospective cohort studies with the comprehensive agreement. The sample size of 150,000 participants was required for multiple researches including genome-wide screening of gene by environment interactions, haplotype phasing, and parametric linkage analysis.ResultsWe established the TohokuMedicalMegabank (TMM) data sharing policy: a privacy protection rule that requires physical, personnel, and technological safeguards against privacy violation regarding the use and sharing of data. The proposed policy refers to that of NCBI and that of the Sanger Institute. The proposed policy classifies shared data according to the strength of re-identification risks. Local committees organized by TMM evaluate re-identification risk and assign a security category to a dataset. Every dataset is stored in an assigned segment of a supercomputer in accordance with its security category. A security manager should be designated to handle all security problems at individual data use locations. The proposed policy requires closed networks and IP-VPN remote connections.ConclusionThe mission of the biobank is to distribute biological resources most productively. This mission motivated us to collect biospecimens and health data and simultaneously analyze genome/omics data in-house. The biobank also has the mission of improving the quality and quantity of the contents of the biobank. This motivated us to request users to share the results of their research as feedback to the biobank. The TMM data sharing policy has tackled every security problem originating with the missions. We believe our current implementation to be the best way to protect privacy in data sharing.

Abstract 3573: VariED: an integrated database of variants and gene expression profiles for genetic diseases

Abstract It is now widely believed that low-frequency variants may play an important role in cancers. In addition, low-frequency variants are usually closely related to populations. To identify the disease-associated variants, several projects are now underway to build a reference of genetic variations from different populations. Furthermore, massive tools and databases are available to compare the dynamic gene expression among different organs and predict functional effects of genetic variants. These resources aid to identify genetic roots of cancers in populations easier. Despite the existence of population allele frequency information, gene expression databases and functional effects of protein mutations, a comprehensive platform providing an integrated annotation database in human genetic variants, is still lacking. In the study, we proposed a web-based database to determine potential variations in cancers with collected variant information from current common databases and integrated those data to provide comprehensive analyses. The web-site offers a function to upload a variant call format (VCF) files for variants annotation. Importantly, we integrated population allele frequency information from NHBI GO Exome Sequencing Project (ESP), 1000 Genomes Project and Tohoku Medical Megabank Project to help users figure out the correlation between disease and population. Additionally, we also collected gene expression profiles from The Human Protein Atlas, Expression Atlas and NCBI SRA in different organs of human, mouse, and zebrafish respectively to reflect the relationship between gene expression and genetic variations in a specific organ. Overall, the database aids to predict protein functions in mutations, analyze population allele frequency and gene expression information from provided variants of diseases. In the result, we use three EGFR mutations to display the proposed system. A recent study has reported that Asian patients with non-small cell lung cancer (NSCLC) carrying a higher rate of EGFR mutations than non-Asian patients. These mutations, such as chr7:55241708G>C (G719A), chr7:55249005G>T (S768I) and chr7:55259515T>G (L858R), are found approximately in 30% of Asian (Japanese) patients. In functional prediction results, these sites are exonic and nonsynonymous mutations. The REVEL scores of three EGFR mutations are 0.824, 0.765 and 0.961, and gerp++ scores are 5.5, 5.85 and 5.71, respectively. Both REVEL and gerp++ show high scores for severe damage of protein structure in the mutations. According to the results, researchers can infer that the three mutations are pathogenic variants implying the nucleotide positions with a higher constraint. Citation Format: Li Mei Chiang, Chien Yueh Lee, Liang Chuan Lai, Mong Hsun Tsai, Tzu Pin Lu, Eric Y. Chuang. VariED: an integrated database of variants and gene expression profiles for genetic diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3573. doi:10.1158/1538-7445.AM2017-3573

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.

Progress of Japanese Omics Reference Panels in Iwate Tohoku Medical Megabank Project

Progress of Japanese Omics Reference Panels in Iwate Tohoku Medical Megabank Project

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.

IJGVD: an integrative Japanese genome variation database based on whole-genome sequencing.

The integrative Japanese Genome Variation Database (iJGVD; http://ijgvd.megabank.tohoku.ac.jp/) provides genomic variation data detected by whole-genome sequencing (WGS) of Japanese individuals. Specifically, the database contains variants detected by WGS of 1,070 individuals who participated in a genome cohort study of the Tohoku Medical Megabank Project. In the first release, iJGVD includes >4,300,000 autosomal single nucleotide variants (SNVs) whose minor allele frequencies are >5.0%.

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..

111th Scientific Meeting of the Japanese Society of Internal Medicine: Panel Discussion: Internal medicine creating future health care: 4. Tohoku Medical Megabank Project and future medicine

111th Scientific Meeting of the Japanese Society of Internal Medicine: Panel Discussion: Internal medicine creating future health care: 4. Tohoku Medical Megabank Project and future medicine

Rhinitis, sinusitis and ocular disease – 2102. The activities of allergy pot as a patient group in Japan: developing treatment guidelines

Among the 120 million people living in Japan, it is estimated that approximately half of the population is suffering from some kind of allergy, and that there are about 7 million adults and children who are suffering from asthma alone. “Allergy Pot” is a parent group founded in 2002, with the prospect of “disseminating information for a better understanding of allergy in educational institutions by respecting their situation and working together, to build a basis for a safe educational environment. We started out from making “Going to School ” booklets, to help the schools and classmates have a better understanding of allergy. We planned, produced, and distributed these booklets, and also made it downloadable from our website. Searching through the internet using the key words “allergy patient group” from either Google or Yahoo websites (from 300 results) shows that there are about 40 patient groups related to allergic diseases in Japan. Most of the allergy patient groups in Japan are self-help groups. Allergy Pot is unique in the sense that it is a group that is continuously sending out messages from the standpoint of patients and patient supporters with the vision and policy that “patient groups are social resources, and our goal is to play our role and contribute in society.” We have gained special recognition by the educational institutions, academic society, administration and citizens for: (1)participating in the process of developing treatment guidelines, (2)being involved not only in allergy related meetings, but numerous administrative meetings related to medical policy making, and for (3)working in cooperation with the Tohoku Medical Megabank Organization to support the reconstruction of Eastern Japan after the earthquake. The history and specific activities of our patient group will be introduced, along with how we have been able to build up a cooperative relationship with the medical and governmental fields, and how we were able to have an influence in the medical administration in Japan. We would also like to discuss the role of patient groups and its possibilities in a country such as Japan, where every citizen is insured under the national health insurance system.

Health outcomes, education, healthcare delivery and quality – 3050. A survey of severe allergic symptoms among children in a disaster-hit area: A challenge of Tohoku Medical Megabank Organization

On March 11, 2011, the Tohoku region and some prefectures along the Pacific coast of Japan were hit by the Great East Japan Earthquake. Past experiences of tsunami in other countries also raised concern about the health of the local people after the disaster. To monitor the health status of people living in Miyagi prefecture and to ensure sufficient quality of healthcare for them, Tohoku University has established the Tohoku Medical Megabank Organization (ToMMo). We plan to conduct three cohort studies of schoolchildren, three-generation families and adults. Here, we report the cohort study of schoolchildren. The aim of the schoolchildren cohort study is to grasp the current status of children’s health after the disaster, focusing on allergic diseases, neuropsychiatric disorders and so on as the main outcome measures. Here we introduce the methodology of our research and its progress, focusing on allergic diseases.