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The exceptions that prove the rule—a historical view of bedaquiline susceptibility Genome Med. (IF 12.3) Pub Date : 2024-03-13 Paolo Miotto, Daniela M. Cirillo, Thomas Schön, Claudio U. Köser
In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 (Rv0678), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve the design and analysis of clinical trials, as well as the World Health Organization catalogue
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Untargeted metabolomic profiling reveals molecular signatures associated with type 2 diabetes in Nigerians Genome Med. (IF 12.3) Pub Date : 2024-03-05 Ayo P. Doumatey, Daniel Shriner, Jie Zhou, Lin Lei, Guanjie Chen, Omolara Oluwasola-Taiwo, Susan Nkem, Adela Ogundeji, Sally N. Adebamowo, Amy R. Bentley, Mateus H. Gouveia, Karlijn A. C. Meeks, Clement A. Adebamowo, Adebowale A. Adeyemo, Charles N. Rotimi
Type 2 diabetes (T2D) has reached epidemic proportions globally, including in Africa. However, molecular studies to understand the pathophysiology of T2D remain scarce outside Europe and North America. The aims of this study are to use an untargeted metabolomics approach to identify: (a) metabolites that are differentially expressed between individuals with and without T2D and (b) a metabolic signature
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Long-term beneficial effect of faecal microbiota transplantation on colonisation of multidrug-resistant bacteria and resistome abundance in patients with recurrent Clostridioides difficile infection Genome Med. (IF 12.3) Pub Date : 2024-02-28 Sam Nooij, Karuna E. W. Vendrik, Romy D. Zwittink, Quinten R. Ducarmon, Josbert J. Keller, Ed J. Kuijper, Elisabeth M. Terveer
Multidrug-resistant (MDR) bacteria are a growing global threat, especially in healthcare facilities. Faecal microbiota transplantation (FMT) is an effective prevention strategy for recurrences of Clostridioides difficile infections and can also be useful for other microbiota-related diseases. We study the effect of FMT in patients with multiple recurrent C. difficile infections on colonisation with
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Deciphering cancer cell state plasticity with single-cell genomics and artificial intelligence Genome Med. (IF 12.3) Pub Date : 2024-02-26 Emily Holton, Walter Muskovic, Joseph E Powell
Cancer stem cell plasticity refers to the ability of tumour cells to dynamically switch between states—for example, from cancer stem cells to non-cancer stem cell states. Governed by regulatory processes, cells transition through a continuum, with this transition space often referred to as a cell state landscape. Plasticity in cancer cell states leads to divergent biological behaviours, with certain
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Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features Genome Med. (IF 12.3) Pub Date : 2024-02-19 Srinivasa Rao, Clare Verrill, Lucia Cerundolo, Nasullah Khalid Alham, Zeynep Kaya, Miriam O’Hanlon, Alicia Hayes, Adam Lambert, Martha James, Iain D. C. Tullis, Jane Niederer, Shelagh Lovell, Altan Omer, Francisco Lopez, Tom Leslie, Francesca Buffa, Richard J. Bryant, Alastair D. Lamb, Boris Vojnovic, David C. Wedge, Ian G. Mills, Dan J. Woodcock, Ian Tomlinson, Freddie C. Hamdy
Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate
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Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis Genome Med. (IF 12.3) Pub Date : 2024-02-19 Camus Nimmo, Arturo Torres Ortiz, Cedric C. S. Tan, Juanita Pang, Mislav Acman, James Millard, Nesri Padayatchi, Alison D. Grant, Max O’Donnell, Alex Pym, Ola B. Brynildsrud, Vegard Eldholm, Louis Grandjean, Xavier Didelot, François Balloux, Lucy van Dorp
Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants
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Recent advances in polygenic scores: translation, equitability, methods and FAIR tools Genome Med. (IF 12.3) Pub Date : 2024-02-19 Ruidong Xiang, Martin Kelemen, Yu Xu, Laura W. Harris, Helen Parkinson, Michael Inouye, Samuel A. Lambert
Polygenic scores (PGS) can be used for risk stratification by quantifying individuals’ genetic predisposition to disease, and many potentially clinically useful applications have been proposed. Here, we review the latest potential benefits of PGS in the clinic and challenges to implementation. PGS could augment risk stratification through combined use with traditional risk factors (demographics, disease-specific
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Genome sequencing as a generic diagnostic strategy for rare disease Genome Med. (IF 12.3) Pub Date : 2024-02-14 Gaby Schobers, Ronny Derks, Amber den Ouden, Hilde Swinkels, Jeroen van Reeuwijk, Ermanno Bosgoed, Dorien Lugtenberg, Su Ming Sun, Jordi Corominas Galbany, Marjan Weiss, Marinus J. Blok, Richelle A. C. M. Olde Keizer, Tom Hofste, Debby Hellebrekers, Nicole de Leeuw, Alexander Stegmann, Erik-Jan Kamsteeg, Aimee D. C. Paulussen, Marjolijn J. L. Ligtenberg, Xiangqun Zheng Bradley, John Peden, Alejandra
To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease. We performed short-read
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Implementation of type 1 diabetes genetic risk screening in children in diverse communities: the Virginia PrIMeD project Genome Med. (IF 12.3) Pub Date : 2024-02-14 Kristin A. Guertin, David R. Repaske, Julia F. Taylor, Eli S. Williams, Suna Onengut-Gumuscu, Wei-Min Chen, Sarah R. Boggs, Liping Yu, Luke Allen, Lacey Botteon, Louis Daniel, Katherine G. Keating, Mika K. Labergerie, Tyler S. Lienhart, Jorge A. Gonzalez-Mejia, Matt J. Starnowski, Stephen S. Rich
Population screening for risk of type 1 diabetes (T1D) has been proposed to identify those with islet autoimmunity (presence of islet autoantibodies). As islet autoantibodies can be transient, screening with a genetic risk score has been proposed as an entry into autoantibody testing. Children were recruited from eight general pediatric and specialty clinics across Virginia with diverse community settings
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An atlas of cell-type-specific interactome networks across 44 human tumor types Genome Med. (IF 12.3) Pub Date : 2024-02-12 Zekun Li, Gerui Liu, Xiaoxiao Yang, Meng Shu, Wen Jin, Yang Tong, Xiaochuan Liu, Yuting Wang, Jiapei Yuan, Yang Yang
Biological processes are controlled by groups of genes acting in concert. Investigating gene–gene interactions within different cell types can help researchers understand the regulatory mechanisms behind human complex diseases, such as tumors. We collected extensive single-cell RNA-seq data from tumors, involving 563 patients with 44 different tumor types. Through our analysis, we identified various
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Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study Genome Med. (IF 12.3) Pub Date : 2024-02-12 Vignesh Arunachalam, Rodney Lea, Wendy Hoy, Simon Lee, Susan Mott, Judith Savige, John D. Mathews, Brendan J. McMorran, Shivashankar H. Nagaraj
Chronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population
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Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial Genome Med. (IF 12.3) Pub Date : 2024-02-12 Giselle L. Saulnier Sholler, Genevieve Bergendahl, Elizabeth C. Lewis, Jacqueline Kraveka, William Ferguson, Abhinav B. Nagulapally, Karl Dykema, Valerie I. Brown, Michael S. Isakoff, Joseph Junewick, Deanna Mitchell, Jawhar Rawwas, William Roberts, Don Eslin, Javier Oesterheld, Randal K. Wada, Devang Pastakia, Virginia Harrod, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang,
Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors. Subjects were
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Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity Genome Med. (IF 12.3) Pub Date : 2024-02-08 Sajan C. Raju, Antonio Molinaro, Ayodeji Awoyemi, Silje F. Jørgensen, Peder R. Braadland, Andraz Nendl, Ingebjørg Seljeflot, Per M. Ueland, Adrian McCann, Pål Aukrust, Beate Vestad, Cristiane Mayerhofer, Kaspar Broch, Lars Gullestad, Knut T. Lappegård, Bente Halvorsen, Karsten Kristiansen, Johannes R. Hov, Marius Trøseid
Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for
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Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination Genome Med. (IF 12.3) Pub Date : 2024-02-06 Matthew R. Lawrence-Paul, Tien-chi Pan, Dhruv K. Pant, Natalie N. C. Shih, Yan Chen, George K. Belka, Michael Feldman, Angela DeMichele, Lewis A. Chodosh
Evolutionary models of breast cancer progression differ on the extent to which metastatic potential is pre-encoded within primary tumors. Although metastatic recurrences often harbor putative driver mutations that are not detected in their antecedent primary tumor using standard sequencing technologies, whether these mutations were acquired before or after dissemination remains unclear. To ascertain
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Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans Genome Med. (IF 12.3) Pub Date : 2024-02-05 Rufus O. Akinyemi, Hemant K. Tiwari, Vinodh Srinivasasainagendra, Onoja Akpa, Fred S. Sarfo, Albert Akpalu, Kolawole Wahab, Reginald Obiako, Morenikeji Komolafe, Lukman Owolabi, Godwin O. Osaigbovo, Olga A. Mamaeva, Brian A. Halloran, Joshua Akinyemi, Daniel Lackland, Olugbo Y. Obiabo, Taofik Sunmonu, Innocent I. Chukwuonye, Oyedunni Arulogun, Carolyn Jenkins, Abiodun Adeoye, Atinuke Agunloye, Okechukwu
African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. Cases were consecutively recruited consenting
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Pro-inflammatory feedback loops define immune responses to pathogenic Lentivirus infection Genome Med. (IF 12.3) Pub Date : 2024-02-05 Aaron J. Wilk, Joshua O. Marceau, Samuel W. Kazer, Ira Fleming, Vincent N. Miao, Jennyfer Galvez-Reyes, Jason T. Kimata, Alex K. Shalek, Susan Holmes, Julie Overbaugh, Catherine A. Blish
The Lentivirus human immunodeficiency virus (HIV) causes chronic inflammation and AIDS in humans, with variable rates of disease progression between individuals driven by both host and viral factors. Similarly, simian lentiviruses vary in their pathogenicity based on characteristics of both the host species and the virus strain, yet the immune underpinnings that drive differential Lentivirus pathogenicity
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Historic methicillin-resistant Staphylococcus aureus: expanding current knowledge using molecular epidemiological characterization of a Swiss legacy collection Genome Med. (IF 12.3) Pub Date : 2024-02-05 Vanni Benvenga, Aline Cuénod, Srinithi Purushothaman, Gottfried Dasen, Maja Weisser, Stefano Bassetti, Tim Roloff, Martin Siegemund, Ulrich Heininger, Julia Bielicki, Marianne Wehrli, Paul Friderich, Reno Frei, Andreas Widmer, Kathrin Herzog, Hans Fankhauser, Oliver Nolte, Thomas Bodmer, Martin Risch, Olivier Dubuis, Sigrid Pranghofer, Romana Calligaris-Maibach, Susanne Graf, Vincent Perreten, Helena
Few methicillin-resistant Staphylococcus aureus (MRSA) from the early years of its global emergence have been sequenced. Knowledge about evolutionary factors promoting the success of specific MRSA multi-locus sequence types (MLSTs) remains scarce. We aimed to characterize a legacy MRSA collection isolated from 1965 to 1987 and compare it against publicly available international and local genomes. We
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Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification Genome Med. (IF 12.3) Pub Date : 2024-02-05 Xinan Wang, Ziwei Zhang, Yi Ding, Tony Chen, Lorelei Mucci, Demetrios Albanes, Maria Teresa Landi, Neil E. Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D. McKay, John K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney
Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each
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Biological basis of extensive pleiotropy between blood traits and cancer risk Genome Med. (IF 12.3) Pub Date : 2024-02-02 Miguel Angel Pardo-Cea, Xavier Farré, Anna Esteve, Joanna Palade, Roderic Espín, Francesca Mateo, Eric Alsop, Marc Alorda, Natalia Blay, Alexandra Baiges, Arzoo Shabbir, Francesc Comellas, Antonio Gómez, Montserrat Arnan, Alex Teulé, Monica Salinas, Laura Berrocal, Joan Brunet, Paula Rofes, Conxi Lázaro, Miquel Conesa, Juan Jose Rojas, Lars Velten, Wojciech Fendler, Urszula Smyczynska, Dipanjan Chowdhury
The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Multivariate Cox regression was used to
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Integrative analysis of spatial and single-cell transcriptome data from human pancreatic cancer reveals an intermediate cancer cell population associated with poor prognosis Genome Med. (IF 12.3) Pub Date : 2024-01-31 Seongryong Kim, Galam Leem, Junjeong Choi, Yongjun Koh, Suho Lee, Sang-Hee Nam, Jin Su Kim, Chan Hee Park, Ho Kyoung Hwang, Kyoung Il Min, Jung Hyun Jo, Hee Seung Lee, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song, Eui-Cheol Shin, Chang Moo Kang, Seungmin Bang, Jong-Eun Park
Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity. We performed single-cell RNA sequencing using
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Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions Genome Med. (IF 12.3) Pub Date : 2024-01-31 Asha Kar, Marcus Alvarez, Kristina M. Garske, Huiling Huang, Seung Hyuk T. Lee, Milena Deal, Sankha Subhra Das, Amogha Koka, Zoeb Jamal, Karen L. Mohlke, Markku Laakso, Sini Heinonen, Kirsi H. Pietiläinen, Päivi Pajukanta
Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation
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Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions Genome Med. (IF 12.3) Pub Date : 2024-01-29 Shenglin Mei, Adele M. Alchahin, Ioanna Tsea, Youmna Kfoury, Taghreed Hirz, Nathan Elias Jeffries, Ting Zhao, Yanxin Xu, Hanyu Zhang, Hirak Sarkar, Shulin Wu, Alexander O. Subtelny, John Inge Johnsen, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A. Randolph, David T. Scadden, Douglas M. Dahl, John Shin, Peter V. Kharchenko, Philip J. Saylor, David B. Sykes, Ninib Baryawno
Despite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards
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SRT-Server: powering the analysis of spatial transcriptomic data Genome Med. (IF 12.3) Pub Date : 2024-01-26 Sheng Yang, Xiang Zhou
Spatial resolved transcriptomics (SRT) encompasses a rapidly developing set of technologies that enable the measurement of gene expression in tissue while retaining spatial localization information. SRT technologies and the enabled SRT studies have provided unprecedent insights into the structural and functional underpinnings of complex tissues. As SRT technologies have advanced and an increasing number
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mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors Genome Med. (IF 12.3) Pub Date : 2024-01-25 Vrunda Trivedi, Changlin Yang, Kelena Klippel, Oleg Yegorov, Christina von Roemeling, Lan Hoang-Minh, Graeme Fenton, Elizabeth Ogando-Rivas, Paul Castillo, Ginger Moore, Kaytora Long-James, Kyle Dyson, Bently Doonan, Catherine Flores, Duane A. Mitchell
Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the
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Gut microbiome for predicting immune checkpoint blockade-associated adverse events Genome Med. (IF 12.3) Pub Date : 2024-01-19 Muni Hu, Xiaolin Lin, Tiantian Sun, Xiaoyan Shao, Xiaowen Huang, Weiwei Du, Mengzhe Guo, Xiaoqiang Zhu, Yilu Zhou, Tianying Tong, Fangfang Guo, Ting Han, Xiuqi Wu, Yi Shi, Xiuying Xiao, Youwei Zhang, Jie Hong, Haoyan Chen
The impact of the gut microbiome on the initiation and intensity of immune-related adverse events (irAEs) prompted by immune checkpoint inhibitors (ICIs) is widely acknowledged. Nevertheless, there is inconsistency in the gut microbial associations with irAEs reported across various studies. We performed a comprehensive analysis leveraging a dataset that included published microbiome data (n = 317)
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Non-canonical antigens are the largest fraction of peptides presented by MHC class I in mismatch repair deficient murine colorectal cancer Genome Med. (IF 12.3) Pub Date : 2024-01-19 Giuseppe Rospo, Rosaria Chilà, Vittoria Matafora, Veronica Basso, Simona Lamba, Alice Bartolini, Angela Bachi, Federica Di Nicolantonio, Anna Mondino, Giovanni Germano, Alberto Bardelli
Immunotherapy based on checkpoint inhibitors is highly effective in mismatch repair deficient (MMRd) colorectal cancer (CRC). These tumors carry a high number of mutations, which are predicted to translate into a wide array of neoepitopes; however, a systematic classification of the neoantigen repertoire in MMRd CRC is lacking. Mass spectrometry peptidomics has demonstrated the existence of MHC class
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Spatial multi-omics: novel tools to study the complexity of cardiovascular diseases Genome Med. (IF 12.3) Pub Date : 2024-01-18 Paul Kiessling, Christoph Kuppe
Spatial multi-omic studies have emerged as a promising approach to comprehensively analyze cells in tissues, enabling the joint analysis of multiple data modalities like transcriptome, epigenome, proteome, and metabolome in parallel or even the same tissue section. This review focuses on the recent advancements in spatial multi-omics technologies, including novel data modalities and computational approaches
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The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young Genome Med. (IF 12.3) Pub Date : 2024-01-16 Megan J. Puckelwartz, Lorenzo L. Pesce, Edgar J. Hernandez, Gregory Webster, Lisa M. Dellefave-Castillo, Mark W. Russell, Sarah S. Geisler, Samuel D. Kearns, Felix Karthik, Susan P. Etheridge, Tanner O. Monroe, Tess D. Pottinger, Prince J. Kannankeril, M. Benjamin Shoemaker, Darlene Fountain, Dan M. Roden, Meghan Faulkner, Heather M. MacLeod, Kristin M. Burns, Mark Yandell, Martin Tristani-Firouzi
Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to
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Multimodal epigenetic sequencing analysis (MESA) of cell-free DNA for non-invasive colorectal cancer detection Genome Med. (IF 12.3) Pub Date : 2024-01-16 Yumei Li, Jianfeng Xu, Chaorong Chen, Zhenhai Lu, Desen Wan, Diange Li, Jason S. Li, Allison J. Sorg, Curt C. Roberts, Shivani Mahajan, Maxime A. Gallant, Itai Pinkoviezky, Ya Cui, David J. Taggart, Wei Li
Detecting human cancers through cell-free DNA (cfDNA) in blood is a sensitive and non-invasive option. However, capturing multiple forms of epigenetic information remains a technical and financial challenge. To address this, we developed multimodal epigenetic sequencing analysis (MESA), a flexible and sensitive approach to capturing and integrating a diverse range of epigenetic features in cfDNA using
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Unsupervised spatially embedded deep representation of spatial transcriptomics Genome Med. (IF 12.3) Pub Date : 2024-01-12 Hang Xu, Huazhu Fu, Yahui Long, Kok Siong Ang, Raman Sethi, Kelvin Chong, Mengwei Li, Rom Uddamvathanak, Hong Kai Lee, Jingjing Ling, Ao Chen, Ling Shao, Longqi Liu, Jinmiao Chen
Optimal integration of transcriptomics data and associated spatial information is essential towards fully exploiting spatial transcriptomics to dissect tissue heterogeneity and map out inter-cellular communications. We present SEDR, which uses a deep autoencoder coupled with a masked self-supervised learning mechanism to construct a low-dimensional latent representation of gene expression, which is
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Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy Genome Med. (IF 12.3) Pub Date : 2024-01-12 Gengshen Yin, Liyuan Liu, Ting Yu, Lixiang Yu, Man Feng, Chengjun Zhou, Xiaoying Wang, Guoxin Teng, Zhongbing Ma, Wenzhong Zhou, Chunmiao Ye, Jialin Zhang, Changhua Ji, Linfeng Zhao, Peng Zhou, Yaxun Guo, Xingchen Meng, Qinye Fu, Qiang Zhang, Liang Li, Fei Zhou, Chao Zheng, Yujuan Xiang, Mingming Guo, Yongjiu Wang, Fei Wang, Shuya Huang, Zhigang Yu
Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity
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Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations Genome Med. (IF 12.3) Pub Date : 2024-01-10 Samuel Ghatan, Jeroen van Rooij, Mandy van Hoek, Cindy G. Boer, Janine F. Felix, Maryam Kavousi, Vincent W. Jaddoe, Eric J. G. Sijbrands, Carolina Medina-Gomez, Fernando Rivadeneira, Ling Oei
Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations
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Transcriptional signals of transformation in human cancer Genome Med. (IF 12.3) Pub Date : 2024-01-09 Gerda Kildisiute, Maria Kalyva, Rasa Elmentaite, Stijn van Dongen, Christine Thevanesan, Alice Piapi, Kirsty Ambridge, Elena Prigmore, Muzlifah Haniffa, Sarah A. Teichmann, Karin Straathof, Isidro Cortés-Ciriano, Sam Behjati, Matthew D. Young
As normal cells transform into cancers, their cell state changes, which may drive cancer cells into a stem-like or more primordial, foetal, or embryonic cell state. The transcriptomic profile of this final state may encode information about cancer’s origin and how cancers relate to their normal cell counterparts. Here, we used single-cell atlases to study cancer transformation in transcriptional terms
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Rare copy-number variants as modulators of common disease susceptibility Genome Med. (IF 12.3) Pub Date : 2024-01-08 Chiara Auwerx, Maarja Jõeloo, Marie C. Sadler, Nicolò Tesio, Sven Ojavee, Charlie J. Clark, Reedik Mägi, Alexandre Reymond, Zoltán Kutalik
Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described. Assessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British
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MAGPIE: accurate pathogenic prediction for multiple variant types using machine learning approach Genome Med. (IF 12.3) Pub Date : 2024-01-08 Yicheng Liu, Tianyun Zhang, Ningyuan You, Sai Wu, Ning Shen
Identifying pathogenic variants from the vast majority of nucleotide variation remains a challenge. We present a method named Multimodal Annotation Generated Pathogenic Impact Evaluator (MAGPIE) that predicts the pathogenicity of multi-type variants. MAGPIE uses the ClinVar dataset for training and demonstrates superior performance in both the independent test set and multiple orthogonal validation
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Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease Genome Med. (IF 12.3) Pub Date : 2024-01-06 Alfredo Dueñas Rey, Marta del Pozo Valero, Manon Bouckaert, Katherine A Wood, Filip Van den Broeck, Malena Daich Varela, Huw B Thomas, Mattias Van Heetvelde, Marieke De Bruyne, Stijn Van de Sompele, Miriam Bauwens, Hanne Lenaerts, Quinten Mahieu, Dragana Josifova, Carlo Rivolta, Raymond T O’Keefe, Jamie Ellingford, Andrew R Webster, Gavin Arno, Carmen Ayuso, Julie De Zaeytijd, Bart P Leroy, Elfride
5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact of 5’UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5’UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). We performed an
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Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 Genome Med. (IF 12.3) Pub Date : 2024-01-06 Daniela Matuozzo, Estelle Talouarn, Astrid Marchal, Peng Zhang, Jeremy Manry, Yoann Seeleuthner, Yu Zhang, Alexandre Bolze, Matthieu Chaldebas, Baptiste Milisavljevic, Adrian Gervais, Paul Bastard, Takaki Asano, Lucy Bizien, Federica Barzaghi, Hassan Abolhassani, Ahmad Abou Tayoun, Alessandro Aiuti, Ilad Alavi Darazam, Luis M. Allende, Rebeca Alonso-Arias, Andrés Augusto Arias, Gokhan Aytekin, Peter
Correction: Genome Medicine 15, 22 (2023) https://doi.org/10.1186/s13073-023-01173-8 The original publication of this article [1] contained an incorrect author name. The incorrect and correct information is listed in this correction article. The original article has been updated. Incorrect Alessio Fiorentino Correct Alessia Fiorentino Matuozzo, et al. Rare predicted loss-of-function variants of type
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Using multi-scale genomics to associate poorly annotated genes with rare diseases Genome Med. (IF 12.3) Pub Date : 2024-01-04 Christina Canavati, Dana Sherill-Rofe, Lara Kamal, Idit Bloch, Fouad Zahdeh, Elad Sharon, Batel Terespolsky, Islam Abu Allan, Grace Rabie, Mariana Kawas, Hanin Kassem, Karen B. Avraham, Paul Renbaum, Ephrat Levy-Lahad, Moien Kanaan, Yuval Tabach
Next-generation sequencing (NGS) has significantly transformed the landscape of identifying disease-causing genes associated with genetic disorders. However, a substantial portion of sequenced patients remains undiagnosed. This may be attributed not only to the challenges posed by harder-to-detect variants, such as non-coding and structural variations but also to the existence of variants in genes
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Single-cell transcriptomic analysis reveals tumor cell heterogeneity and immune microenvironment features of pituitary neuroendocrine tumors Genome Med. (IF 12.3) Pub Date : 2024-01-02 Nan Yan, Weiyan Xie, Dongfang Wang, Qiuyue Fang, Jing Guo, Yiyuan Chen, Xinqi Li, Lei Gong, Jialin Wang, Wenbo Guo, Xuegong Zhang, Yazhuo Zhang, Jin Gu, Chuzhong Li
Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood. We performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of
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Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes Genome Med. (IF 12.3) Pub Date : 2023-12-25 Seulki Song, Youngil Koh, Seokhyeon Kim, Sang Mi Lee, Hyun Uk Kim, Jung Min Ko, Se-Hoon Lee, Sung-Soo Yoon, Solip Park
Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. Here, we introduce a generalized log-regression
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Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss Genome Med. (IF 12.3) Pub Date : 2023-12-18 Sihan Liu, Mingjun Zhong, Yu Huang, Qian Zhang, Ting Chen, Xiaofei Xu, Wan Peng, Xiaolu Wang, Xiaoshu Feng, Lu Kang, Yu Lu, Jing Cheng, Fengxiao Bu, Huijun Yuan
The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case–control cohorts is lacking. To address this gap, we evaluated and established PS4 thresholds using
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De novo identification of expressed cancer somatic mutations from single-cell RNA sequencing data Genome Med. (IF 12.3) Pub Date : 2023-12-18 Tianyun Zhang, Hanying Jia, Tairan Song, Lin Lv, Doga C. Gulhan, Haishuai Wang, Wei Guo, Ruibin Xi, Hongshan Guo, Ning Shen
Identifying expressed somatic mutations from single-cell RNA sequencing data de novo is challenging but highly valuable. We propose RESA – Recurrently Expressed SNV Analysis, a computational framework to identify expressed somatic mutations from scRNA-seq data. RESA achieves an average precision of 0.77 on three in silico spike-in datasets. In extensive benchmarking against existing methods using 19
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Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases Genome Med. (IF 12.3) Pub Date : 2023-12-14 Lama AlAbdi, Hanan E. Shamseldin, Ebtissal Khouj, Rana Helaby, Bayan Aljamal, Mashael Alqahtani, Aisha Almulhim, Halima Hamid, Mais O. Hashem, Firdous Abdulwahab, Omar Abouyousef, Amal Jaafar, Tarfa Alshidi, Mohammed Al-Owain, Amal Alhashem, Saeed Al Tala, Arif O. Khan, Elham Mardawi, Hisham Alkuraya, Eissa Faqeih, Manal Afqi, Salwa Alkhalifi, Zuhair Rahbeeni, Samya T. Hagos, Wijdan Al-Ahmadi, Seba
Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience
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Publisher Correction: Analysis of transcriptomic features reveals molecular endotypes of SLE with clinical implications Genome Med. (IF 12.3) Pub Date : 2023-12-13 Erika L. Hubbard, Prathyusha Bachali, Kathryn M. Kingsmore, Yisha He, Michelle D. Catalina, Amrie C. Grammer, Peter E. Lipsky
Publisher Correction: Genome Med 15, 84 (2023) https://doi.org/10.1186/s13073-023-01237-9 Figure 5 in the original publication of this article [1] was incorrectly cut-off during the publication process. The incorrect and correct version of Fig. 5 are shown in this correction article. Furthermore, in figure 7 the annotation bars above and below the heatmap were not properly represented, the correct
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Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis Genome Med. (IF 12.3) Pub Date : 2023-12-13 Hui Xiao, Huiyao Chen, Xiang Chen, Yulan Lu, Bingbing Wu, Huijun Wang, Yun Cao, Liyuan Hu, Xinran Dong, Wenhao Zhou, Lin Yang
In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. A cohort of 723 SGA and 1317 appropriate for gestational age (AGA)
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Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy Genome Med. (IF 12.3) Pub Date : 2023-12-12 Jae Kwang Yun, Sugyeong Kim, Hongyul An, Geun Dong Lee, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Sehoon Choi, Youngil Koh
Clonal hematopoiesis (CH) frequently progresses after chemotherapy or radiotherapy. We evaluated the clinical impact of preoperative CH on the survival outcomes of patients with non-small cell lung cancer (NSCLC) who underwent surgical resection followed by adjuvant therapy. A total of 415 consecutive patients with NSCLC who underwent surgery followed by adjuvant therapy from 2011 to 2017 were analyzed
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Evaluating the use of paralogous protein domains to increase data availability for missense variant classification Genome Med. (IF 12.3) Pub Date : 2023-12-12 Adam Colin Gunning, Caroline Fiona Wright
Classification of rare missense variants remains an ongoing challenge in genomic medicine. Evidence of pathogenicity is often sparse, and decisions about how to weigh different evidence classes may be subjective. We used a Bayesian variant classification framework to investigate the performance of variant co-localisation, missense constraint, and aggregating data across paralogous protein domains (“meta-domains”)
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Acute ischemia induces spatially and transcriptionally distinct microglial subclusters Genome Med. (IF 12.3) Pub Date : 2023-12-11 Huiya Li, Pinyi Liu, Bing Zhang, Zengqiang Yuan, Mengdi Guo, Xinxin Zou, Yi Qian, Shiji Deng, Liwen Zhu, Xiang Cao, Tao Tao, Shengnan Xia, Xinyu Bao, Yun Xu
Damage in the ischemic core and penumbra after stroke affects patient prognosis. Microglia immediately respond to ischemic insult and initiate immune inflammation, playing an important role in the cellular injury after stroke. However, the microglial heterogeneity and the mechanisms involved remain unclear. We first performed single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) on
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Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development Genome Med. (IF 12.3) Pub Date : 2023-12-06 Oleksii Nikolaienko, Hans P. Eikesdal, Elisabet Ognedal, Bjørnar Gilje, Steinar Lundgren, Egil S. Blix, Helge Espelid, Jürgen Geisler, Stephanie Geisler, Emiel A. M. Janssen, Synnøve Yndestad, Laura Minsaas, Beryl Leirvaag, Reidun Lillestøl, Stian Knappskog, Per E. Lønning
Normal cell BRCA1 epimutations have been associated with increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may have BRCA1 epimutations as their underlying cause is unknown. Neither are the time of occurrence and the potential inheritance patterns of BRCA1 epimutations established. To address these questions, we analyzed BRCA1 methylation status in breast cancer
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Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes Genome Med. (IF 12.3) Pub Date : 2023-12-04 Karlijn A. C. Meeks, Amy R. Bentley, Themistocles L. Assimes, Nora Franceschini, Adebowale A. Adeyemo, Charles N. Rotimi, Ayo P. Doumatey
In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization
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Mobilizable plasmids drive the spread of antimicrobial resistance genes and virulence genes in Klebsiella pneumoniae Genome Med. (IF 12.3) Pub Date : 2023-12-01 Jianfeng Zhang, Yanping Xu, Meng Wang, Xiaobin Li, Zhiyuan Liu, Dai Kuang, Zixin Deng, Hong-Yu Ou, Jieming Qu
Klebsiella pneumoniae is a notorious clinical pathogen and frequently carries various plasmids, which are the main carriers of antimicrobial resistance and virulence genes. In comparison to self-transmissible conjugative plasmids, mobilizable plasmids have received much less attention due to their defects in conjugative elements. However, the contribution of mobilizable plasmids to the horizontal transfer
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Personalized tumor combination therapy optimization using the single-cell transcriptome Genome Med. (IF 12.3) Pub Date : 2023-12-01 Chen Tang, Shaliu Fu, Xuan Jin, Wannian Li, Feiyang Xing, Bin Duan, Xiaojie Cheng, Xiaohan Chen, Shuguang Wang, Chenyu Zhu, Gaoyang Li, Guohui Chuai, Yayi He, Ping Wang, Qi Liu
The precise characterization of individual tumors and immune microenvironments using transcriptome sequencing has provided a great opportunity for successful personalized cancer treatment. However, the cancer treatment response is often characterized by in vitro assays or bulk transcriptomes that neglect the heterogeneity of malignant tumors in vivo and the immune microenvironment, motivating the need
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Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set Genome Med. (IF 12.3) Pub Date : 2023-11-30 David Stein, Meltem Ece Kars, Yiming Wu, Çiğdem Sevim Bayrak, Peter D. Stenson, David N. Cooper, Avner Schlessinger, Yuval Itan
Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method
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Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity Genome Med. (IF 12.3) Pub Date : 2023-11-29 Sheng-Jia Lin, Barbara Vona, Tracy Lau, Kevin Huang, Maha S. Zaki, Huda Shujaa Aldeen, Ehsan Ghayoor Karimiani, Clarissa Rocca, Mahmoud M. Noureldeen, Ahmed K. Saad, Cassidy Petree, Tobias Bartolomaeus, Rami Abou Jamra, Giovanni Zifarelli, Aditi Gotkhindikar, Ingrid M. Wentzensen, Mingjuan Liao, Emalyn Elise Cork, Pratishtha Varshney, Narges Hashemi, Mohammad Hasan Mohammadi, Aboulfazl Rad, Juanita
Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Using an unbiased genotype-first approach, we screened large
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A phenome-wide scan reveals convergence of common and rare variant associations Genome Med. (IF 12.3) Pub Date : 2023-11-28 Dan Zhou, Yuan Zhou, Yue Xu, Ran Meng, Eric R. Gamazon
Common and rare variants contribute to the etiology of complex traits. However, the extent to which the phenotypic effects of common and rare variants involve shared molecular mediators remains poorly understood. The question is essential to the basic and translational goals of the science of genomics, with critical basic-science, methodological, and clinical consequences. Leveraging the latest release
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GITR and TIGIT immunotherapy provokes divergent multicellular responses in the tumor microenvironment of gastrointestinal cancers Genome Med. (IF 12.3) Pub Date : 2023-11-26 Anuja Sathe, Carlos Ayala, Xiangqi Bai, Susan M. Grimes, Byrne Lee, Cindy Kin, Andrew Shelton, George Poultsides, Hanlee P. Ji
Understanding the mechanistic effects of novel immunotherapy agents is critical to improving their successful clinical translation. These effects need to be studied in preclinical models that maintain the heterogenous tumor microenvironment (TME) and dysfunctional cell states found in a patient’s tumor. We investigated immunotherapy perturbations targeting co-stimulatory molecule GITR and co-inhibitory
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Massive underrepresentation of Arabs in genomic studies of common disease Genome Med. (IF 12.3) Pub Date : 2023-11-22 Romit Bhattacharya, NingNing Chen, Injeong Shim, Hiroyuki Kuwahara, Xin Gao, Fowzan S. Alkuraya, Akl C. Fahed
Arabs represent 5% of the world population and have a high prevalence of common disease, yet remain greatly underrepresented in genome-wide association studies, where only 1 in 600 individuals are Arab. We highlight the persistent and unaddressed underrepresentation of Arabs in genomic databases and discuss its impact on public health genomics and missed opportunities for biological discovery.
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Loss of p53-DREAM-mediated repression of cell cycle genes as a driver of lymph node metastasis in head and neck cancer Genome Med. (IF 12.3) Pub Date : 2023-11-17 Kevin Brennan, Almudena Espín-Pérez, Serena Chang, Nikita Bedi, Saumyaa Saumyaa, June Ho Shin, Sylvia K. Plevritis, Olivier Gevaert, John B. Sunwoo, Andrew J. Gentles
The prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data. We performed meta-analysis across 29 gene expression studies
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The role of admixture in the rare variant contribution to inflammatory bowel disease Genome Med. (IF 12.3) Pub Date : 2023-11-15 Courtney Astore, Shivam Sharma, Sini Nagpal, David J. Cutler, John D. Rioux, Judy H. Cho, Dermot P. B. McGovern, Steven R. Brant, Subra Kugathasan, I. King Jordan, Greg Gibson
Identification of rare variants involved in complex, polygenic diseases like Crohn’s disease (CD) has accelerated with the introduction of whole exome/genome sequencing association studies. Rare variants can be used in both diagnostic and therapeutic assessments; however, since they are likely to be restricted to specific ancestry groups, their contributions to risk assessment need to be evaluated
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Rapid profiling of Plasmodium parasites from genome sequences to assist malaria control Genome Med. (IF 12.3) Pub Date : 2023-11-10 Jody E. Phelan, Anna Turkiewicz, Emilia Manko, Joseph Thorpe, Leen N. Vanheer, Marga van de Vegte-Bolmer, Nguyen Thi Hong Ngoc, Nguyen Thi Huong Binh, Nguyen Quang Thieu, Jesse Gitaka, Debbie Nolder, Khalid B. Beshir, Jamille G. Dombrowski, Silvia Maria Di Santi, Teun Bousema, Colin J. Sutherland, Susana Campino, Taane G. Clark
Malaria continues to be a major threat to global public health. Whole genome sequencing (WGS) of the underlying Plasmodium parasites has provided insights into the genomic epidemiology of malaria. Genome sequencing is rapidly gaining traction as a diagnostic and surveillance tool for clinical settings, where the profiling of co-infections, identification of imported malaria parasites, and detection