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Article: Statistical genetics and polygenic risk score for precision medicine.

Konuma, Takahiro / Okada, Yukinori

2021 Volume 41, Issue 1, Page(s) 18

Abstract: The prediction of disease risks is an essential part of personalized medicine, which includes early disease detection, prevention, and intervention. The polygenic risk score (PRS) has become the standard for quantifying genetic liability in predicting ... ...

Abstract	The prediction of disease risks is an essential part of personalized medicine, which includes early disease detection, prevention, and intervention. The polygenic risk score (PRS) has become the standard for quantifying genetic liability in predicting disease risks. PRS utilizes single-nucleotide polymorphisms (SNPs) with genetic risks elucidated by genome-wide association studies (GWASs) and is calculated as weighted sum scores of these SNPs with genetic risks using their effect sizes from GWASs as their weights. The utilities of PRS have been explored in many common diseases, such as cancer, coronary artery disease, obesity, and diabetes, and in various non-disease traits, such as clinical biomarkers. These applications demonstrated that PRS could identify a high-risk subgroup of these diseases as a predictive biomarker and provide information on modifiable risk factors driving health outcomes. On the other hand, there are several limitations to implementing PRSs in clinical practice, such as biased sensitivity for the ethnic background of PRS calculation and geographical differences even in the same population groups. Also, it remains unclear which method is the most suitable for the prediction with high accuracy among numerous PRS methods developed so far. Although further improvements of its comprehensiveness and generalizability will be needed for its clinical implementation in the future, PRS will be a powerful tool for therapeutic interventions and lifestyle recommendations in a wide range of diseases. Thus, it may ultimately improve the health of an entire population in the future.
Language	English
Publishing date	2021-06-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2051471-2
ISSN	1880-9693 ; 0389-4290
ISSN	1880-9693 ; 0389-4290
DOI	10.1186/s41232-021-00172-9
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Article ; Online: Statistical genetics and polygenic risk score for precision medicine

Takahiro Konuma / Yukinori Okada

Inflammation and Regeneration, Vol 41, Iss 1, Pp 1-

2021 Volume 5

Abstract: Abstract The prediction of disease risks is an essential part of personalized medicine, which includes early disease detection, prevention, and intervention. The polygenic risk score (PRS) has become the standard for quantifying genetic liability in ... ...

Abstract	Abstract The prediction of disease risks is an essential part of personalized medicine, which includes early disease detection, prevention, and intervention. The polygenic risk score (PRS) has become the standard for quantifying genetic liability in predicting disease risks. PRS utilizes single-nucleotide polymorphisms (SNPs) with genetic risks elucidated by genome-wide association studies (GWASs) and is calculated as weighted sum scores of these SNPs with genetic risks using their effect sizes from GWASs as their weights. The utilities of PRS have been explored in many common diseases, such as cancer, coronary artery disease, obesity, and diabetes, and in various non-disease traits, such as clinical biomarkers. These applications demonstrated that PRS could identify a high-risk subgroup of these diseases as a predictive biomarker and provide information on modifiable risk factors driving health outcomes. On the other hand, there are several limitations to implementing PRSs in clinical practice, such as biased sensitivity for the ethnic background of PRS calculation and geographical differences even in the same population groups. Also, it remains unclear which method is the most suitable for the prediction with high accuracy among numerous PRS methods developed so far. Although further improvements of its comprehensiveness and generalizability will be needed for its clinical implementation in the future, PRS will be a powerful tool for therapeutic interventions and lifestyle recommendations in a wide range of diseases. Thus, it may ultimately improve the health of an entire population in the future.
Keywords	Statistical genomics ; Genome-wide association study ; Polygenic risk score ; Precision medicine ; Pathology ; RB1-214
Subject code	610
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Shell colour diversification induced by ecological release: A shift in natural selection after a migration event.

Ito, Shun / Hirano, Takahiro / Chiba, Satoshi / Konuma, Junji

Ecology and evolution

2021 Volume 11, Issue 22, Page(s) 15534–15544

Abstract: Ecological release is often attributed to the rapid adaptive diversification of phenotypic traits. However, it is not well understood how natural selection changes its strength and direction through the process of ecological release. Herein, we ... ...

Abstract	Ecological release is often attributed to the rapid adaptive diversification of phenotypic traits. However, it is not well understood how natural selection changes its strength and direction through the process of ecological release. Herein, we demonstrated how shell colour of the Japanese land snail
Language	English
Publishing date	2021-10-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2635675-2
ISSN	2045-7758
ISSN	2045-7758
DOI	10.1002/ece3.8080
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Article ; Online: Integration of genetically regulated gene expression and pharmacological library provides therapeutic drug candidates.

Konuma, Takahiro / Ogawa, Kotaro / Okada, Yukinori

Human molecular genetics

2021 Volume 30, Issue 3-4, Page(s) 294–304

Abstract: Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving ... ...

Abstract	Approaches toward new therapeutics using disease genomics, such as genome-wide association study (GWAS), are anticipated. Here, we developed Trans-Phar [integration of transcriptome-wide association study (TWAS) and pharmacological database], achieving in silico screening of compounds from a large-scale pharmacological database (L1000 Connectivity Map), which have inverse expression profiles compared with tissue-specific genetically regulated gene expression. Firstly we confirmed the statistical robustness by the application of the null GWAS data and enrichment in the true-positive drug-disease relationships by the application of UK-Biobank GWAS summary statistics in broad disease categories, then we applied the GWAS summary statistics of large-scale European meta-analysis (17 traits; naverage = 201 849) and the hospitalized COVID-19 (n = 900 687), which has urgent need for drug development. We detected potential therapeutic compounds as well as anisomycin in schizophrenia (false discovery rate (FDR)-q = 0.056) and verapamil in hospitalized COVID-19 (FDR-q = 0.068) as top-associated compounds. This approach could be effective in disease genomics-driven drug development.
MeSH term(s)	Anisomycin/pharmacology ; COVID-19/drug therapy ; Databases, Genetic ; Databases, Pharmaceutical ; Drug Development/methods ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Genome-Wide Association Study/methods ; Genome-Wide Association Study/statistics & numerical data ; Genomics/methods ; Humans ; Pharmaceutical Preparations ; Schizophrenia/drug therapy ; Software ; Transcriptome/genetics ; Verapamil/pharmacology
Chemical Substances	Pharmaceutical Preparations ; Anisomycin (6C74YM2NGI) ; Verapamil (CJ0O37KU29)
Language	English
Publishing date	2021-02-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab049
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Article ; Online: A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis.

Namba, Shinichi / Konuma, Takahiro / Wu, Kuan-Han / Zhou, Wei / Okada, Yukinori

Cell genomics

2022 Volume 2, Issue 10, Page(s) 100190

Abstract: Genomics-driven drug discovery is indispensable for accelerating the development of novel therapeutic targets. However, the drug discovery framework based on evidence from genome-wide association studies (GWASs) has not been established, especially for ... ...

Abstract	Genomics-driven drug discovery is indispensable for accelerating the development of novel therapeutic targets. However, the drug discovery framework based on evidence from genome-wide association studies (GWASs) has not been established, especially for cross-population GWAS meta-analysis. Here, we introduce a practical guideline for genomics-driven drug discovery for cross-population meta-analysis, as lessons from the Global Biobank Meta-analysis Initiative (GBMI). Our drug discovery framework encompassed three methodologies and was applied to the 13 common diseases targeted by GBMI (
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2022.100190
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Article ; Online: Shell colour diversification induced by ecological release

Shun Ito / Takahiro Hirano / Satoshi Chiba / Junji Konuma

Ecology and Evolution, Vol 11, Iss 22, Pp 15534-

A shift in natural selection after a migration event

2021 Volume 15544

Abstract: Abstract Ecological release is often attributed to the rapid adaptive diversification of phenotypic traits. However, it is not well understood how natural selection changes its strength and direction through the process of ecological release. Herein, we ... ...

Abstract	Abstract Ecological release is often attributed to the rapid adaptive diversification of phenotypic traits. However, it is not well understood how natural selection changes its strength and direction through the process of ecological release. Herein, we demonstrated how shell colour of the Japanese land snail Euhadra peliomphala simodae has diversified via a shift in natural selection due to ecological release after migration from the mainland to an island. This snail's shell colour diversified on the island due to disruptive selection after migration from the mainland. We used trail camera traps to identify the cause of natural selection on both the mainland and the island. We then conducted a mark–recapture experiment while collecting microhabitat use data. In total, we captured and marked around 1,700 snails on the mainland, some of which were preyed upon by an unknown predator. The trail camera traps showed that the predator is the large Japanese field mouse Apodemus speciosus, and the predatory frequency was higher on the mainland than on the island. However, this predation did not correlate with shell colour. Microhabitat use on the island was more extensive than on the mainland, with snails on the island using both ground and arboreal microhabitats. A Bayesian estimation showed that the stabilizing selection on shell colour came from factors other than predation. Our results suggest that the course of natural selection was modified due to ecological release after migration from the mainland, explaining one cause of the phenotypic diversification.
Keywords	colour diversification ; disruptive selection ; ecological release ; land snail ; mammal predator ; mark–recapture ; Ecology ; QH540-549.5
Subject code	910
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

Konuma, Takaaki / Uchida, Naoyuki / Takeda, Wataru / Doki, Noriko / Yoshihara, Satoshi / Nishida, Tetsuya / Kuriyama, Takuro / Tanaka, Masatsugu / Ohigashi, Hiroyuki / Nakamae, Hirohisa / Katayama, Yuta / Ota, Shuichi / Hashii, Yoshiko / Ishimaru, Fumihiko / Fukuda, Takahiro / Ohbiki, Marie / Atsuta, Yoshiko

Vox sanguinis

2024

Abstract: Background and objectives: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the ... ...

Abstract	Background and objectives: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. Materials and methods: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. Results: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. Conclusion: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.
Language	English
Publishing date	2024-02-29
Publishing country	England
Document type	Journal Article
ZDB-ID	80313-3
ISSN	1423-0410 ; 0042-9007
ISSN (online)	1423-0410
ISSN	0042-9007
DOI	10.1111/vox.13610
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Article ; Online: The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

Bone marrow transplantation

2024 Volume 59, Issue 4, Page(s) 541–549

Abstract: This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was ... ...

Abstract	This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.
MeSH term(s)	Adult ; Humans ; Transplantation, Homologous/adverse effects ; Hematopoietic Stem Cell Transplantation/adverse effects ; Leukemia, Myeloid, Acute/complications ; Prognosis ; Recurrence ; Retrospective Studies ; Graft vs Host Disease/etiology ; Transplantation Conditioning/adverse effects
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Journal Article
ZDB-ID	632854-4
ISSN	1476-5365 ; 0268-3369 ; 0951-3078
ISSN (online)	1476-5365
ISSN	0268-3369 ; 0951-3078
DOI	10.1038/s41409-024-02222-5
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Article ; Online: Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation.

Kuwatsuka, Yachiyo / Kasajima, Rika / Yamaguchi, Rui / Uchida, Naoyuki / Konuma, Takaaki / Tanaka, Masatsugu / Shingai, Naoki / Miyakoshi, Shigesaburo / Kozai, Yasuji / Uehara, Yasufumi / Eto, Tetsuya / Toyosaki, Masako / Nishida, Tetsuya / Ishimaru, Fumihiko / Kato, Koji / Fukuda, Takahiro / Imoto, Seiya / Atsuta, Yoshiko / Takahashi, Satoshi

Transplantation and cellular therapy

2024 Volume 30, Issue 4, Page(s) 444.e1–444.e11

Abstract: Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for ... ...

Abstract	Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.
MeSH term(s)	Humans ; Neutrophils ; Cord Blood Stem Cell Transplantation/methods ; Hematopoietic Stem Cell Transplantation ; Machine Learning ; Leukemia, Myeloid, Acute
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2024.02.001
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Article ; Online: Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia.

Jimbo, Koji / Hattori, Ayuna / Koide, Shuhei / Ito, Takahiro / Sasaki, Katsuhiro / Iwai, Kazuhiro / Nannya, Yasuhito / Iwama, Atsushi / Tojo, Arinobu / Konuma, Takaaki

Leukemia

2022 Volume 37, Issue 1, Page(s) 122–133

Abstract: We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional ... ...

Abstract	We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip. Although both Hoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion of Hoipinduced apoptosis in LSCs but not HSCs in vivo. Structure-function analysis revealed that LUBAC ligase activity and the interaction of LUBAC subunits were critical for the propagation of leukemia. Hoip regulated oxidative phosphorylation pathway independently of nuclear factor kappa B pathway in leukemia, but not in normal hematopoietic cells. Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.
MeSH term(s)	Humans ; Animals ; Mice ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; NF-kappa B/metabolism ; Apoptosis ; Leukemia, Myeloid
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; NF-kappa B
Language	English
Publishing date	2022-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01750-7
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