Chemical Research in Toxicology最新文献

{"title":"Skeletal stem and progenitor cells in bone physiology, ageing and disease","authors":"Seppe Melis, Dana Trompet, Andrei S. Chagin, Christa Maes","doi":"10.1038/s41574-024-01039-y","DOIUrl":"https://doi.org/10.1038/s41574-024-01039-y","url":null,"abstract":"<p>Skeletal stem cells (SSCs) and related progenitors with osteogenic potential, collectively termed skeletal stem and/or progenitor cells (SSPCs), are crucial for providing osteoblasts for bone formation during homeostatic tissue turnover and fracture repair. Besides mediating normal bone physiology, they also have important roles in various metabolic bone diseases, including osteoporosis. SSPCs are of tremendous interest because they represent prime future targets for osteoanabolic therapies and bone regenerative medicine. Remarkable progress has been made in characterizing various SSC and SSPC populations in postnatal bone. SSPCs exist in the periosteum and within the bone marrow stroma, including subsets localizing around arteriolar and sinusoidal blood vessels; they can display osteogenic, chondrogenic, adipogenic and/or fibroblastic potential, and exert critical haematopoiesis-supportive functions. However, much remains to be clarified. By the current markers, bona fide SSCs are commonly contained within broader SSPC populations characterized by considerable heterogeneity and overlap, whose common versus specific functions in health and disease have not been fully unravelled. Here, we review the present knowledge of the identity, fates and relationships of SSPC populations in the postnatal bone environment, their contributions to bone maintenance, the changes observed upon ageing, and the effect of metabolic diseases such as osteoporosis and diabetes mellitus.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"88 1","pages":""},"PeriodicalIF":40.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes","authors":"Alicia Huerta-Chagoya,&nbsp;Philip Schroeder,&nbsp;Ravi Mandla,&nbsp;Jiang Li,&nbsp;Lowri Morris,&nbsp;Maheak Vora,&nbsp;Ahmed Alkanaq,&nbsp;Dorka Nagy,&nbsp;Lukasz Szczerbinski,&nbsp;Jesper G. S. Madsen,&nbsp;Silvia Bonàs-Guarch,&nbsp;Fanny Mollandin,&nbsp;Joanne B. Cole,&nbsp;Bianca Porneala,&nbsp;Kenneth Westerman,&nbsp;Josephine H. Li,&nbsp;Toni I. Pollin,&nbsp;Jose C. Florez,&nbsp;Anna L. Gloyn,&nbsp;David J. Carey,&nbsp;Inês Cebola,&nbsp;Uyenlinh L. Mirshahi,&nbsp;Alisa K. Manning,&nbsp;Aaron Leong,&nbsp;Miriam Udler,&nbsp;Josep M. Mercader","doi":"10.1038/s41588-024-01947-9","DOIUrl":"10.1038/s41588-024-01947-9","url":null,"abstract":"Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels’ limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10−5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual’s polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes. Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"56 11","pages":"2370-2379"},"PeriodicalIF":31.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01947-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electromagnetic irradiation-assisted synthesis, exfoliation and modification of graphene-based materials for energy storage and sensing applications","authors":"Rajesh Kumar ,&nbsp;Sumanta Sahoo ,&nbsp;Raghvendra Pandey ,&nbsp;Ednan Joanni ,&nbsp;Ram Manohar Yadav","doi":"10.1016/j.mser.2024.100860","DOIUrl":"10.1016/j.mser.2024.100860","url":null,"abstract":"<div><div>Over the past ten years, there has been a significant advance in the use of light-based photonic energy to synthesize and modify carbon materials for a variety of applications. Graphene-based materials, formed from different carbon sources, possess distinctive structures, exceptional electrical conductivity, mechanical strength, and lightweight features. These characteristics have attracted growing attention from researchers working on electrodes for energy and sensing devices fabricated by direct illumination of carbon-rich materials with electromagnetic (EM) radiation. In this context, we present an overview of the most recent advancements in the use of light for synthesis, modification and doping of novel carbon-based materials. We discuss a broad range of photon-induced irradiation techniques, including microwave (MW), infrared (IR), visible/sunlight, ultraviolet (UV), X-ray, γ-ray. These techniques have been applied to enhance the mechanical, electrical, and thermal properties of carbon and carbon-based composite electrodes. Furthermore, this text emphasizes the latest results on the application of these electrodes made from EM photon-based graphene in the fields of energy and sensing research, with the goal of showcasing the current advancements in this rapidly developing area. Finally, we also discuss the present constraints and potential future advancements of EM-based photo induced graphene production and its applications. In the near future, as a result of the ongoing advances in materials and processing technologies, graphene-based composite electrodes are expected to play a significant role in various important fields.</div></div>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"161 ","pages":"Article 100860"},"PeriodicalIF":31.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142417835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic architecture reconciles linkage and association studies of complex traits","authors":"Julia Sidorenko,&nbsp;Baptiste Couvy-Duchesne,&nbsp;Kathryn E. Kemper,&nbsp;Gunn-Helen Moen,&nbsp;Laxmi Bhatta,&nbsp;Bjørn Olav Åsvold,&nbsp;Reedik Mägi,&nbsp;Estonian Biobank Research Team,&nbsp;Alireza Ani,&nbsp;Rujia Wang,&nbsp;Ilja M. Nolte,&nbsp;Lifelines Cohort Study,&nbsp;Scott Gordon,&nbsp;Caroline Hayward,&nbsp;Archie Campbell,&nbsp;Daniel J. Benjamin,&nbsp;David Cesarini,&nbsp;David M. Evans,&nbsp;Michael E. Goddard,&nbsp;Chris S. Haley,&nbsp;David Porteous,&nbsp;Sarah E. Medland,&nbsp;Nicholas G. Martin,&nbsp;Harold Snieder,&nbsp;Andres Metspalu,&nbsp;Kristian Hveem,&nbsp;Ben Brumpton,&nbsp;Peter M. Visscher,&nbsp;Loic Yengo","doi":"10.1038/s41588-024-01940-2","DOIUrl":"10.1038/s41588-024-01940-2","url":null,"abstract":"Linkage studies have successfully mapped loci underlying monogenic disorders, but mostly failed when applied to common diseases. Conversely, genome-wide association studies (GWASs) have identified replicable associations between thousands of SNPs and complex traits, yet capture less than half of the total heritability. In the present study we reconcile these two approaches by showing that linkage signals of height and body mass index (BMI) from 119,000 sibling pairs colocalize with GWAS-identified loci. Concordant with polygenicity, we observed the following: a genome-wide inflation of linkage test statistics; that GWAS results predict linkage signals; and that adjusting phenotypes for polygenic scores reduces linkage signals. Finally, we developed a method using recombination rate-stratified, identity-by-descent sharing between siblings to unbiasedly estimate heritability of height (0.76 ± 0.05) and BMI (0.55 ± 0.07). Our results imply that substantial heritability remains unaccounted for by GWAS-identified loci and this residual genetic variation is polygenic and enriched near these loci. Analyses of height and body mass index in 119,000 sibling pairs show that linkage and genome-wide association signals colocalize. Further analyses suggest that family-based linkage signals are fully consistent with a highly polygenic architecture.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"56 11","pages":"2352-2360"},"PeriodicalIF":31.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox-active molecules for aqueous electrolytes of energy storage devices: A review on fundamental aspects, current progress, and prospects","authors":"Ming Chen ,&nbsp;Ri Chen ,&nbsp;Igor Zhitomirsky ,&nbsp;Guanjie He ,&nbsp;Kaiyuan Shi","doi":"10.1016/j.mser.2024.100865","DOIUrl":"10.1016/j.mser.2024.100865","url":null,"abstract":"<div><div>The increasing demand for aqueous energy storage (AES) solutions with high energy density, enlarged voltage windows, and extended cycling stability has spurred the development of advanced electrolytes. Redox-active molecules hold the promise for formulating aqueous electrolytes with enhanced electrochemical performance. In this review, we provide a comprehensive overview of established and recently reported studies on redox electrolytes for AES devices. Delving into mechanisms at both molecular and micrometer scales, this review covers the fundamental principles governing the electrolytes, encompassing their physicochemical properties, ion solvation behavior, interfacial modulation, and transport mechanisms. We present an overview of the redox properties of various compounds from different families. While irreversible electron/mass transfer processes can facilitate the passivation of solid electrolyte interfaces, particular attention is given to the reversible redox electrolyte in enhancing the energy performance of AES systems. Redox-active molecules are categorized based on their ability to improve the cycling stability of electrodes, increase the voltage windows of electrolytes, and enhance the energy density of cells. High solubility and reversible redox behavior have been achieved via the molecular design. Trade-offs between the shuttling effect and electrolyte modification as well as controversies on molecular solubility are discussed. By examining these aspects, the review aims to stimulate advanced research in redox-active molecules for AES technologies.</div></div>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"161 ","pages":"Article 100865"},"PeriodicalIF":31.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142417935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia","authors":"Andrew Stiff,&nbsp;Maarten Fornerod,&nbsp;Bailee N. Kain,&nbsp;Deedra Nicolet,&nbsp;Benjamin J. Kelly,&nbsp;Katherine E. Miller,&nbsp;Krzysztof Mrózek,&nbsp;Isaiah Boateng,&nbsp;Audrey Bollas,&nbsp;Elizabeth A. R. Garfinkle,&nbsp;Omolegho Momoh,&nbsp;Foluke A. Fasola,&nbsp;Hannah O. Olawumi,&nbsp;Nuria Mencia-Trinchant,&nbsp;Jean F. Kloppers,&nbsp;Anne-Cecilia van Marle,&nbsp;Eileen Hu,&nbsp;Saranga Wijeratne,&nbsp;Gregory Wheeler,&nbsp;Christopher J. Walker,&nbsp;Jill Buss,&nbsp;Adrienne Heyrosa,&nbsp;Helee Desai,&nbsp;Andrea Laganson,&nbsp;Ethan Hamp,&nbsp;Yazan Abu-Shihab,&nbsp;Hasan Abaza,&nbsp;Parker Kronen,&nbsp;Sidharth Sen,&nbsp;Megan E. Johnstone,&nbsp;Kate Quinn,&nbsp;Ben Wronowski,&nbsp;Erin Hertlein,&nbsp;Linde A. Miles,&nbsp;Alice S. Mims,&nbsp;Christopher C. Oakes,&nbsp;James S. Blachly,&nbsp;Karilyn T. Larkin,&nbsp;Bethany Mundy-Bosse,&nbsp;Andrew J. Carroll,&nbsp;Bayard L. Powell,&nbsp;Jonathan E. Kolitz,&nbsp;Richard M. Stone,&nbsp;Cassandra Duarte,&nbsp;Diana Abbott,&nbsp;Maria L. Amaya,&nbsp;Craig T. Jordan,&nbsp;Geoffrey L. Uy,&nbsp;Wendy Stock,&nbsp;Kellie J. Archer,&nbsp;Electra D. Paskett,&nbsp;Monica L. Guzman,&nbsp;Ross L. Levine,&nbsp;Kamal Menghrajani,&nbsp;Debyani Chakravarty,&nbsp;Michael F. Berger,&nbsp;Daniel Bottomly,&nbsp;Shannon K. McWeeney,&nbsp;Jeffrey W. Tyner,&nbsp;John C. Byrd,&nbsp;Nathan Salomonis,&nbsp;H. Leighton Grimes,&nbsp;Elaine R. Mardis,&nbsp;Ann-Kathrin Eisfeld","doi":"10.1038/s41588-024-01929-x","DOIUrl":"10.1038/s41588-024-01929-x","url":null,"abstract":"Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected. Black patients with myelodysplasia-related AML were younger than white patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable analyses of Black patients, NPM1 and NRAS mutations were associated with inferior disease-free and IDH1 and IDH2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and white patients with NPM1 mutations. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic risk stratification changed risk group assignment for one-third of Black patients and improved their outcome prediction. Analysis of exomes and transcriptomes from 100 African American patients with acute myeloid leukemia identifies ancestry-related variation in mutation profiles and survival. Refined risk classification suggests clinical relevance of these ancestry-associated differences.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"56 11","pages":"2434-2446"},"PeriodicalIF":31.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01929-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase separation in intrinsically stretchable electronics: Mechanisms, functions and applications","authors":"Hongbo Fu ,&nbsp;Jian Lv ,&nbsp;Quanpeng Li ,&nbsp;Zhuoqun Li ,&nbsp;Xiaoliang Chen ,&nbsp;Gang He ,&nbsp;Zhimao Yang ,&nbsp;Chuncai Kong ,&nbsp;Fenggang Ren ,&nbsp;Yi Lv ,&nbsp;Jinyou Shao","doi":"10.1016/j.mser.2024.100863","DOIUrl":"10.1016/j.mser.2024.100863","url":null,"abstract":"<div><div>Stretchable electronics made from intrinsically stretchable materials have garnered a great deal of attention for future human-friendly electronic applications due to their exceptional mechanical compatibility with soft tissues. However, intrinsically stretchable materials with homogeneous conductive networks often compromise electrical performance to achieve stretchability. By employing phase separation strategies that rationally separate conductive networks and stretchable matrix, the electrical performance of these electronics can be significantly improved without sacrificing stretchability. Meanwhile, phase separation can also be applied to produce diverse porous microstructures, endowing stretchable electronics with desirable functionalities, such as strain buffering, heightened ion transfer, air permeability, and passive cooling. In this article, we reviewed the recent advancements in stretchable electronics fabricated through phase separation strategies. After delving into the driving mechanisms behind various phase-separation strategies, we showcased representative examples to highlight the versatile functionalities of phase-separated structures in stretchable electronic components and devices. Furthermore, we discussed the current challenges and prospects of utilizing phase separation strategies for next-generation intrinsically stretchable electronics.</div></div>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"161 ","pages":"Article 100863"},"PeriodicalIF":31.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142417833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low 3 volt operation of 2D MoTe2 ferroelectric memory transistors with ultrathin pinhole-free P(VDF-TrFE) crystalline film","authors":"Han Joo Lee ,&nbsp;Yongjae Cho ,&nbsp;Jeehong Park ,&nbsp;Hyunmin Cho ,&nbsp;Hyowon Han ,&nbsp;Cheolmin Park ,&nbsp;Yeonjin Yi ,&nbsp;Tae Kyu An ,&nbsp;Ji Hoon Park ,&nbsp;Seongil Im","doi":"10.1016/j.mser.2024.100859","DOIUrl":"10.1016/j.mser.2024.100859","url":null,"abstract":"<div><div>Organic ferroelectric crystalline polymer, P(VDF-TrFE) has attracted broad attentions due to its lead-free benefits and process convenience. However, it has a long-standing drawback, its process limit in crystalline film thickness, whose minimum is almost fixed as ∼100 nm. Hence, operation voltage of any P(VDF-TrFE)-based ferroelectric memory field-effect transistors (FeFETs) has always been over 10 V. Here, innovatively thinned ∼20 nm P(VDF-TrFE) crystalline layers are fabricated on Pt and Au gate, empowering FeFETs with two dimensional (2D) MoTe₂ channel to operate under minimum 3 V pulse. Such thin crystalline layer is achieved through spin-coating after initial growth of 5 nm-thin crystalline seed layer, P(VDF-TrFE)-brush. This ultrathin P(VDF-TrFE)-brush effectively inhibits the de-wetting problem of P(VDF-TrFE)-solution during spin-coating, leading to good surface-energy matching and pinhole-free conformal coating of classical P(VDF-TrFE). As a result, 3–4 V pulse operations of p-MoTe₂ nonvolatile memory FETs are nicely realized without leakage current loss. These numbers may be regarded as one of the lowest values in report.</div></div>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"161 ","pages":"Article 100859"},"PeriodicalIF":31.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142417834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic African ancestry modifies the biology of acute myeloid leukemia","authors":"Evelyn M. Jiagge","doi":"10.1038/s41588-024-01869-6","DOIUrl":"10.1038/s41588-024-01869-6","url":null,"abstract":"African American patients were under-represented in the studies that led to the current patient classification system for acute myeloid leukemia (AML). A new in-depth analysis of the genetics of AML in African Americans suggests that this omission has implications for patient care.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"56 11","pages":"2299-2301"},"PeriodicalIF":31.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-specific putative causal variants shape quantitative traits","authors":"Satoshi Koyama,&nbsp;Xiaoxi Liu,&nbsp;Yoshinao Koike,&nbsp;Keiko Hikino,&nbsp;Masaru Koido,&nbsp;Wei Li,&nbsp;Kotaro Akaki,&nbsp;Kohei Tomizuka,&nbsp;Shuji Ito,&nbsp;Nao Otomo,&nbsp;Hiroyuki Suetsugu,&nbsp;Soichiro Yoshino,&nbsp;Masato Akiyama,&nbsp;Kohei Saito,&nbsp;Yuki Ishikawa,&nbsp;Christian Benner,&nbsp;Pradeep Natarajan,&nbsp;Patrick T. Ellinor,&nbsp;Taisei Mushiroda,&nbsp;Momoko Horikoshi,&nbsp;Masashi Ikeda,&nbsp;Nakao Iwata,&nbsp;Koichi Matsuda,&nbsp;Biobank Japan Project,&nbsp;Shumpei Niida,&nbsp;Kouichi Ozaki,&nbsp;Yukihide Momozawa,&nbsp;Shiro Ikegawa,&nbsp;Osamu Takeuchi,&nbsp;Kaoru Ito,&nbsp;Chikashi Terao","doi":"10.1038/s41588-024-01913-5","DOIUrl":"10.1038/s41588-024-01913-5","url":null,"abstract":"Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10−15 and odds ratio = 4.5, 95% confidence interval = 3.1–6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3′ untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations. Genome-wide association and fine-mapping analyses in approximately 260,000 Japanese individuals combined with a newly constructed Japanese-specific genotype reference panel identify hundreds of new loci and putative causal variants for 63 quantitative traits.","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"56 10","pages":"2027-2035"},"PeriodicalIF":31.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01913-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}