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1. Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome

Author: Gowher Ali, Kyung Chul Shin, Nisar Ahmed, Wesal Habbab, Ghaneya Alkhadairi, Aleem Razzaq, Yosra Bejaoui, Nady El Hajj, Borbala Mifsud, Yongsoo Park, and Lawrence W. Stanton
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract: Abstract Rhabdomyosarcoma 2-associated transcript (RMST) long non-coding RNA has previously been shown to cause Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism (CHH) and olfactory dysfunction. In the present study, we generated large deletions of approximately 41.55 kb in the RMST gene in human pluripotent stem cells using CRISPR/Cas9 gene editing. To evaluate the impact of RMST deletion, these cells were differentiated into hypothalamic neurons that include 10–15% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in RMST did not impair the neurogenesis of GnRH neurons, however, the hypothalamic neurons were electro-physiologically hyperactive and had increased calcium influx activity compared to control. Transcriptomic and epigenetic analyses showed that RMST deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these RMST-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of RMST function in Kallmann syndrome and its role in hypothalamic neuronal development.
Published: 2024
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2. Multi-omic analysis of longitudinal acute myeloid leukemia patient samples reveals potential prognostic markers linked to disease progression

Author: Nisar Ahmed, Irene Cavattoni, William Villiers, Chiara Cugno, Sara Deola, and Borbala Mifsud
Subjects: AML relapse, multi-omic analyses, chromatin reorganization, epigenetic modifications, Omni-C, ATAC-seq, Genetics, QH426-470
Abstract: Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. We conducted a multi-omic analysis using Omni-C, ATAC-seq, and RNA-seq on longitudinal samples from two adult AML patients at diagnosis and relapse. Herein, we characterized genetic and epigenetic changes in AML progression to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omic approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions.
Published: 2024
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3. Loss of the yeast transporter Agp2 upregulates the pleiotropic drug-resistant pump Pdr5 and confers resistance to the protein synthesis inhibitor cycloheximide.

Author: Yusra Manzoor, Mustapha Aouida, Ramya Ramadoss, Balasubramanian Moovarkumudalvan, Nisar Ahmed, Abdallah Alhaj Sulaiman, Ashima Mohanty, Reem Ali, Borbala Mifsud, and Dindial Ramotar
Subjects: Medicine, Science
Abstract: The transmembrane protein Agp2, initially shown as a transporter of L-carnitine, mediates the high-affinity transport of polyamines and the anticancer drug bleomycin-A5. Cells lacking Agp2 are hyper-resistant to polyamine and bleomycin-A5. In these earlier studies, we showed that the protein synthesis inhibitor cycloheximide blocked the uptake of bleomycin-A5 into the cells suggesting that the drug uptake system may require de novo synthesis. However, our recent findings demonstrated that cycloheximide, instead, induced rapid degradation of Agp2, and in the absence of Agp2 cells are resistant to cycloheximide. These observations raised the possibility that the degradation of Agp2 may allow the cell to alter its drug resistance network to combat the toxic effects of cycloheximide. In this study, we show that membrane extracts from agp2Δ mutants accentuated several proteins that were differentially expressed in comparison to the parent. Mass spectrometry analysis of the membrane extracts uncovered the pleiotropic drug efflux pump, Pdr5, involved in the efflux of cycloheximide, as a key protein upregulated in the agp2Δ mutant. Moreover, a global gene expression analysis revealed that 322 genes were differentially affected in the agp2Δ mutant versus the parent, including the prominent PDR5 gene and genes required for mitochondrial function. We further show that Agp2 is associated with the upstream region of the PDR5 gene, leading to the hypothesis that cycloheximide resistance displayed by the agp2Δ mutant is due to the derepression of the PDR5 gene.
Published: 2024
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4. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Author: William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan van Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J.Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jørgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko, and Patricia B. Munroe
Subjects: Science
Abstract: The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease.
Published: 2023
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5. Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank

Author: Geethanjali Devadoss Gandhi, Waleed Aamer, Navaneethakrishnan Krishnamoorthy, Najeeb Syed, Elbay Aliyev, Aljazi Al-Maraghi, Muhammad Kohailan, Jamil Alenbawi, Mohammed Elanbari, Qatar Genome Program Research Consortium (QGPRC), Borbala Mifsud, Younes Mokrab, Charbel Abi Khalil, and Khalid A. Fakhro
Subjects: Cholesterol, Dyslipidemias, LDL, Lipoproteins/Receptors, Premature coronary artery disease, Dutch lipid Clinic Network, Medicine
Abstract: Abstract Background The genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine. Methods We evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry. Results Using DLCN criteria, we identify eight (0.1%) ‘definite’, 41 (0.7%) ‘probable’ and 334 (5.4%) ‘possible’ FH individuals, estimating a prevalence of ‘definite or probable’ FH in the Qatari cohort of ~ 1:125. We identify ten previously known pathogenic single-nucleotide variants (SNVs) and 14 putatively novel SNVs, as well as one novel copy number variant in PCSK9. Further, despite the modest sample size, we identify one homozygote for a known pathogenic variant (ABCG8, p. Gly574Arg, global MAF = 4.49E-05) associated with Sitosterolemia 2. Finally, calculation of polygenic risk scores found that individuals with ‘definite or probable’ FH have a significantly higher LDL-C SNP score than ‘unlikely’ individuals (p = 0.0003), demonstrating its utility in Arab populations. Conclusion We design and implement a standardized approach to phenotyping a population biobank for FH risk followed by systematically identifying known variants and assessing putative novel variants contributing to FH burden in Qatar. Our results motivate similar studies in population-level biobanks – especially those with globally under-represented ancestries – and highlight the importance of genetic screening programs for early detection and management of individuals with high FH risk in health systems.
Published: 2022
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6. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, and Patricia B. Munroe
Subjects: Science
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.
Published: 2022
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7. The immune landscape of solid pediatric tumors

Author: Shimaa Sherif, Jessica Roelands, William Mifsud, Eiman I. Ahmed, Christophe M. Raynaud, Darawan Rinchai, Abbirami Sathappan, Ata Maaz, Ayman Saleh, Erdener Ozer, Khalid A. Fakhro, Borbala Mifsud, Vésteinn Thorsson, Davide Bedognetti, and Wouter R. L. Hendrickx
Subjects: Pediatric cancer, Neuroblastoma, Osteosarcoma, Immune phenotypes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. Methods We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. Results A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. Conclusions We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
Published: 2022
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8. Gene-specific machine learning model to predict the pathogenicity of BRCA2 variants

Author: Mohannad N. Khandakji and Borbala Mifsud
Subjects: breast cancer, variant pathogenicity, in-silico predictions, variant prioritization, VUS, Genetics, QH426-470
Abstract: Background: Existing BRCA2-specific variant pathogenicity prediction algorithms focus on the prediction of the functional impact of a subtype of variants alone. General variant effect predictors are applicable to all subtypes, but are trained on putative benign and pathogenic variants and do not account for gene-specific information, such as hotspots of pathogenic variants. Local, gene-specific information have been shown to aid variant pathogenicity prediction; therefore, our aim was to develop a BRCA2-specific machine learning model to predict pathogenicity of all types of BRCA2 variants.Methods: We developed an XGBoost-based machine learning model to predict pathogenicity of BRCA2 variants. The model utilizes general variant information such as position, frequency, and consequence for the canonical BRCA2 transcript, as well as deleteriousness prediction scores from several tools. We trained the model on 80% of the expert reviewed variants by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium and tested its performance on the remaining 20%, as well as on an independent set of variants of uncertain significance with experimentally determined functional scores.Results: The novel gene-specific model predicted the pathogenicity of ENIGMA BRCA2 variants with an accuracy of 99.9%. The model also performed excellently on predicting the functional consequence of the independent set of variants (accuracy was up to 91.3%).Conclusion: This new, gene-specific model is an accurate method for interpreting the pathogenicity of variants in the BRCA2 gene. It is a valuable addition for variant classification and can prioritize unreviewed variants for functional analysis or expert review.
Published: 2022
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9. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, and Patricia B. Munroe
Subjects: Science
Abstract: On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
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10. Comparison of Capture Hi-C Analytical Pipelines

Author: Dina Aljogol, I. Richard Thompson, Cameron S. Osborne, and Borbala Mifsud
Subjects: epigenetics, gene regulation, computational pipeline, capture Hi-C, chromatin organization, Genetics, QH426-470
Abstract: It is now evident that DNA forms an organized nuclear architecture, which is essential to maintain the structural and functional integrity of the genome. Chromatin organization can be systematically studied due to the recent boom in chromosome conformation capture technologies (e.g., 3C and its successors 4C, 5C and Hi-C), which is accompanied by the development of computational pipelines to identify biologically meaningful chromatin contacts in such data. However, not all tools are applicable to all experimental designs and all structural features. Capture Hi-C (CHi-C) is a method that uses an intermediate hybridization step to target and select predefined regions of interest in a Hi-C library, thereby increasing effective sequencing depth for those regions. It allows researchers to investigate fine chromatin structures at high resolution, for instance promoter-enhancer loops, but it introduces additional biases with the capture step, and therefore requires specialized pipelines. Here, we compare multiple analytical pipelines for CHi-C data analysis. We consider the effect of retaining multi-mapping reads and compare the efficiency of different statistical approaches in both identifying reproducible interactions and determining biologically significant interactions. At restriction fragment level resolution, the number of multi-mapping reads that could be rescued was negligible. The number of identified interactions varied widely, depending on the analytical method, indicating large differences in type I and type II error rates. The optimal pipeline depends on the project-specific tolerance level of false positive and false negative chromatin contacts.
Published: 2022
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11. Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease

Author: Balasubramanian Moovarkumudalvan, Anupriya Madhukumar Geethakumari, Ramya Ramadoss, Kabir H. Biswas, and Borbala Mifsud
Subjects: COVID-19, SARS-CoV-2 main protease, structure-based virtual screening, molecular docking, FDA-approved drugs, natural products, Microbiology, QR1-502
Abstract: The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines’ ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.
Published: 2022
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12. 520 The immune landscape of pediatric tumors

Author: Davide Bedognetti, Wouter Hendrickx, Jessica Roelands, Darawan Rinchai, Chiara Cugno, Shimaa Sherif, William Mifsud, Blessing Dason, Adrian Charles, Ayman Saleh, Khalid Fakhro, and Borbala Mifsud
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2020
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13. Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages

Author: Stefan Schoenfelder, Borbala Mifsud, Claire E. Senner, Christopher D. Todd, Stephanie Chrysanthou, Elodie Darbo, Myriam Hemberger, and Miguel R. Branco
Subjects: Science
Abstract: The role of the genome structure in the establishment of the embryonic and trophoblast lineages is still not well understood. Here the authors perform promoter capture Hi-C in mouse trophoblast and embryonic stem cells and find divergent networks of repressive and active chromatin interactions between the two lineages.
Published: 2018
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14. Thirty loci identified for heart rate response to exercise and recovery implicate autonomic nervous system

Author: Julia Ramírez, Stefan van Duijvenboden, Ioanna Ntalla, Borbala Mifsud, Helen R Warren, Evan Tzanis, Michele Orini, Andrew Tinker, Pier D. Lambiase, and Patricia B. Munroe
Subjects: Science
Abstract: Genome-wide association studies have identified multiple loci for resting heart rate (HR) but the genetic factors associated with HR increase during and HR recovery after exercise are less well studied. Here, the authors examine both traits in a two-stage GWAS design in up to 67,257 individuals from UK Biobank.
Published: 2018
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15. Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression

Author: Gozde Kar, Jong Kyoung Kim, Aleksandra A. Kolodziejczyk, Kedar Nath Natarajan, Elena Torlai Triglia, Borbala Mifsud, Sarah Elderkin, John C. Marioni, Ana Pombo, and Sarah A. Teichmann
Subjects: Science
Abstract: Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.
Published: 2017
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16. Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications

Author: George D. Cresswell, John R. Apps, Tasnim Chagtai, Borbala Mifsud, Christopher C. Bentley, Mariana Maschietto, Sergey D. Popov, Mark E. Weeks, Øystein E. Olsen, Neil J. Sebire, Kathy Pritchard-Jones, Nicholas M. Luscombe, Richard D. Williams, and William Mifsud
Subjects: Intra-tumor genetic heterogeneity, Pediatric solid tumors, Wilms tumor, Tumor evolution, Tumor multisampling, Molecular biomarkers, Copy number aberrations, Medicine, Medicine (General), R5-920
Abstract: The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.
Published: 2016
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17. GOTHiC, a probabilistic model to resolve complex biases and to identify real interactions in Hi-C data.

Author: Borbala Mifsud, Inigo Martincorena, Elodie Darbo, Robert Sugar, Stefan Schoenfelder, Peter Fraser, and Nicholas M Luscombe
Subjects: Medicine, Science
Abstract: Hi-C is one of the main methods for investigating spatial co-localisation of DNA in the nucleus. However, the raw sequencing data obtained from Hi-C experiments suffer from large biases and spurious contacts, making it difficult to identify true interactions. Existing methods use complex models to account for biases and do not provide a significance threshold for detecting interactions. Here we introduce a simple binomial probabilistic model that resolves complex biases and distinguishes between true and false interactions. The model corrects biases of known and unknown origin and yields a p-value for each interaction, providing a reliable threshold based on significance. We demonstrate this experimentally by testing the method against a random ligation dataset. Our method outperforms previous methods and provides a statistical framework for further data analysis, such as comparisons of Hi-C interactions between different conditions. GOTHiC is available as a BioConductor package (http://www.bioconductor.org/packages/release/bioc/html/GOTHiC.html).
Published: 2017
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18. Flavin Adenine Dinucleotide (FAD) and Pyridoxal 5′-Phosphate (PLP) Bind to Sox9 and Alter the Expression of Key Pancreatic Progenitor Transcription Factors

Author: Zeyaul Islam, Noura Aldous, Sunkyu Choi, Frank Schmidt, Borbala Mifsud, Essam M. Abdelalim, and Prasanna R. Kolatkar
Subjects: Riboflavin, Organic Chemistry, General Medicine, Vitamins, Pancreatic Hormones, Catalysis, Computer Science Applications, Phosphates, Inorganic Chemistry, pancreatic progenitors, Sox9, FAD, PLP, transcription factor, Sox family, Pyridoxal Phosphate, Flavin-Adenine Dinucleotide, Physical and Theoretical Chemistry, Molecular Biology, Pancreas, Spectroscopy
Abstract: Cofactor flavin adenine dinucleotide (FAD), a compound with flavin moiety and a derivative of riboflavin (vitamin B2), is shown to bind to Sox9 (a key transcription factor in early pancreatic development) and, subsequently, induce a large increase in markers of pancreatic development, including Ngn3 and PTF1a. Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, also binds to Sox9 and results in a similar increase in pancreatic development markers. Sox9 is known to be specifically important for pancreatic progenitors. Previously, there was no known link between FAD, PLP, or other co-factors and Sox9 for function. Thus, our findings show the mechanism by which FAD and PLP interact with Sox9 and result in the altered expression of pancreatic progenitor transcription factors involved in the pancreas development.
Published: 2022
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19. Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders

Author: Michele Orini, Patricia B. Munroe, Borbala Mifsud, Andrew Tinker, Pier D. Lambiase, Julia Ramirez, Stefan van Duijvenboden, and William J Young
Subjects: AcademicSubjects/SCI01140, Male, Candidate gene, Cardiomyopathy, Disease, Biology, QT interval, Polymorphism, Single Nucleotide, Electrocardiography, Genetics, medicine, Humans, Association Studies Article, Molecular Biology, Genetics (clinical), Genetic association, Cardiovascular mortality, Myocardial repolarization, General Medicine, Genomics, medicine.disease, Biobank, Phenotype, Female, Genome-Wide Association Study
Abstract: The resting QT interval, an electrocardiographic (ECG) measure of ventricular myocardial repolarization, is a heritable risk marker of cardiovascular mortality, but the mechanisms remain incompletely understood. Previously reported candidate genes have provided insights into the regulatory mechanisms of the QT interval. However, there are still important knowledge gaps. We aimed to gain new insights by (i) providing new candidate genes, (ii) identifying pleiotropic associations with other cardiovascular traits, and (iii) scanning for sexually dimorphic genetic effects. We conducted a genome-wide association analysis for resting QT interval with ~9.8 million variants in 52 107 individuals of European ancestry without known cardiovascular disease from the UK Biobank. We identified 40 loci, 13 of which were novel, including 2 potential sex-specific loci, explaining ~11% of the trait variance. Candidate genes at novel loci were involved in myocardial structure and arrhythmogenic cardiomyopathy. Investigation of pleiotropic effects of QT interval variants using phenome-wide association analyses in 302 000 unrelated individuals from the UK Biobank and pairwise genome-wide comparisons with other ECG and cardiac imaging traits revealed genetic overlap with atrial electrical pathology. These findings provide novel insights into how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.
Published: 2021

20. THE FUTURE OF MEDICINE, healthcare innovation through precision medicine: policy case study of Qatar

Author: Lotfi Chouchane, Borbala Mifsud, Said I. Ismail, M. Walid Qoronfleh, and Maryam Al Emadi
Subjects: Evidence-based practice, Emerging technologies, media_common.quotation_subject, Review, Management, Monitoring, Policy and Law, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, 0302 clinical medicine, Healthcare research, Health care, Humans, Empowerment, Qatar, 030304 developmental biology, media_common, Cancer, 0303 health sciences, lcsh:R723-726, business.industry, Health Policy, Professional development, Precision medicine, Public relations, Primary care, Evidence-based research, Philosophy, 030220 oncology & carcinogenesis, Action plan, Public health policy, Personalized medicine, business, Population genomics, lcsh:Medical philosophy. Medical ethics, National policy
Abstract: In 2016, the World Innovation Summit for Health (WISH) published its Forum Report on precision medicine “PRECISION MEDICINE - A GLOBAL ACTION PLAN FOR IMPACT”. Healthcare is undergoing a transformation, and it is imperative to leverage new technologies to generate new data and support the advent of precision medicine (PM). Recent scientific breakthroughs and technological advancements have improved our disease knowledge and altered diagnosis and treatment approaches resulting in a more precise, predictive, preventative and personalized health care that is customized for the individual patient. Consequently, the big data revolution has provided an opportunity to apply artificial intelligence and machine learning algorithms to mine such a vast data set. Additionally, personalized medicine promises to revolutionize healthcare, with its key goal of providing the right treatment to the right patient at the right time and dose, and thus the potential of improving quality of life and helping to bring down healthcare costs. This policy briefing will look in detail at the issues surrounding continued development, sustained investment, risk factors, testing and approval of innovations for better strategy and faster process. The paper will serve as a policy bridge that is required to enhance a conscious decision among the powers-that-be in Qatar in order to find a way to harmonize multiple strands of activity and responsibility in the health arena. The end goal will be for Qatar to enhance public awareness and engagement and to integrate effectively the incredible advances in research into healthcare systems, for the benefit of all patients. The PM policy briefing provides concrete recommendations on moving forward with PM initiatives in Qatar and internationally. Equally important, integration of PM within a primary care setting, building a coalition of community champions through awareness and advocacy, finally, communicating PM value, patient engagement/empowerment and education/continued professional development programs of the healthcare workforce. Key recommendations for implementation of precision medicine inside and outside Qatar: Create Community Awareness and PM Education Programs Engage and Empower Patients Communicate PM Value Develop appropriate Infrastructure and Information Management Systems Integrate PM into standard Healthcare System and Ensure Access to Care PM is no longer futuristic. It is here. Implementing PM in routine clinical care does require some investment and infrastructure development. Invariably, cost and lack of expertise are cited as barriers to PM implementation. Equally consequential, are the curriculum and professional development of medical care experts. Policymakers need to lead and coordinate effort among stakeholders and consider cultural and faith perspectives to ensure success. It is essential that policymakers integrate PM approaches into national strategies to improve health and health care for all, and to drive towards the future of medicine precision health.
Published: 2020
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21. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author: Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki
Subjects: medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2021

22. Actionable genomic variants in 6045 participants from the Qatar Genome Program

Author: Amal, Elfatih, Borbala, Mifsud, Najeeb, Syed, Ramin, Badii, Hamdi, Mbarek, Fatemeh, Abbaszadeh, and Xavier, Estivill
Abstract: In a clinical setting, DNA sequencing can uncover findings unrelated to the purpose of genetic evaluation. The American College of Medical Genetics and Genomics (ACMG) recommends the evaluation and reporting of 59 genes from clinic genomic sequencing. While the prevalence of secondary findings is available from large population studies, these data lack Arab and other Middle Eastern populations. The Qatar Genome Program (QGP) generates whole-genome sequencing (WGS) data and combines it with phenotypic information to create a comprehensive database for studying the Qatari and wider Arab and Middle Eastern populations at the molecular level. This study identified and analyzed medically actionable variants in the 59 ACMG genes using WGS data from 6045 QGP participants. Our results identified a total of 60 pathogenic and likely pathogenic variants in 25 ACMG genes in 141 unique individuals. Overall, 2.3% of the QGP sequenced participants carried a pathogenic or likely pathogenic variant in one of the 59 ACMG genes. We evaluated the QGP phenotype-genotype association of additional nonpathogenic ACMG variants. These variants were found in patients from the Hamad Medical Corporation or reported incidental findings data in Qatar. We found a significant phenotype association for two variants, c.313+3AC in LDLR, and c.58CT (p.Gln20*) in the TPM1.
Published: 2021

23. Frequency and management of medically actionable incidental findings from genome and exome sequencing data: a systematic review

Author: Doua Abdelrahman, Amal Elfatih, Borbala Mifsud, and Idris Mohammed
Subjects: medicine.medical_specialty, Incidental Findings, medicine.diagnostic_test, Physiology, Genome, Human, Genomics, Computational biology, Biology, Genome, Polymorphism, Single Nucleotide, Systematic review, Epidemiology, Exome Sequencing, Genetics, medicine, Medical genetics, Humans, Exome, Genetic Testing, Likely pathogenic, Exome sequencing, Genetic testing
Abstract: The application of whole genome/exome sequencing technologies in clinical genetics and research has resulted in the discovery of incidental findings unrelated to the primary purpose of genetic testing. The American College of Medical Genetics and Genomics published guidelines for reporting pathogenic and likely pathogenic variants that are deemed to be medically actionable, which allowed us to learn about the epidemiology of incidental findings in different populations. However, consensus guidelines for variant reporting and classification are still lacking. We conducted a systematic literature review of incidental findings in whole genome/exome sequencing studies to obtain a comprehensive understanding of variable reporting and classification methods for variants that are deemed to be medically actionable across different populations. The review highlights the elements that demand further consideration or adjustment.
Published: 2021

24. The Immune landscape of pediatric solid tumors

Author: Eiman Ahmed, Wouter Hendrickx, Shimaa Sherif, Jessica Roelands, Davide Bedognetti, William Mifsud, and Borbala Mifsud
Subjects: Clear-cell sarcoma of the kidney, business.industry, medicine.medical_treatment, Wnt signaling pathway, Cancer, Wilms' tumor, Immunotherapy, medicine.disease, Immune system, Neuroblastoma, medicine, Cancer research, Osteosarcoma, business
Abstract: BackgroundImmunotherapy is quickly coming to the forefront of cancer treatment; however, the implementation of immunotherapy in solid pediatric cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters using analytes extracted from gene expression data.MethodsWe used RNAseq data from the publicly available TARGET studies for five pediatric solid tumor types (408 patients): Wilms tumor (WT), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of previously identified immune signatures like the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy. We also performed gene set enrichment analysis (ssGSEA) and clustering, using more than 100 immune signatures to define immune subtypes in pediatric tumors and compared the overall survival across subtypes. The expression of immune checkpoints and enrichment of oncogenic pathways were also assessed across the immune subtypes.ResultsThe five tumor types showed distinct ICR score distributions. A higher ICR score was associated with better survival in OS and NBL-HR-MYCN_NA, but with poorer survival in WT. The clustering of immune signatures revealed the same five principal modules observed in adult solid tumors: Wound Healing, TGF-B signaling, IFN-G signaling, Macrophages, and Lymphocytes. These modules clustered pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival and was characterized by low enrichment of the wound healing signature, high Th1, low Th2. Conversely, cluster S4 showed the worst survival and highest enrichment of wound healing signature, low Th1, and high Th2. Furthermore, the upregulation of the WNT/Beta-catenin pathway is associated with unfavorable outcomes and lack of T-cell infiltration in OS.ConclusionsWe demonstrated that extracranial solid pediatric tumors could be classified according to their immune disposition, unveiling similarity with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
Published: 2021
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25. Multi-Omics and Machine Learning Reveal Context-Specific Gene Regulatory Activities of PML-RARA in Acute Promyelocytic Leukemia

Author: Abdurrahman Elbasir, Audrey Kelly, Borbala Mifsud, Cameron S. Osborne, Richard Dillon, Halima Bensmail, Paul Lavender, Xiaohan He, and William Villiers
Subjects: Regulation of gene expression, Acute promyelocytic leukemia, business.industry, Retinoic acid, Biology, medicine.disease, Machine learning, computer.software_genre, Fusion protein, DNA binding site, chemistry.chemical_compound, chemistry, Gene expression, medicine, Artificial intelligence, Binding site, business, Gene, computer
Abstract: The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We apply a novel computational machine learning strategy to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
Published: 2021
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26. 520 The immune landscape of pediatric tumors

Author: Jessica Roelands, Darawan Rinchai, Chiara Cugno, William Mifsud, Ayman Saleh, Adrian Charles, Shimaa Sherif, Blessing Dason, Khalid Fakhro, Borbala Mifsud, Wouter Hendrickx, and Davide Bedognetti
Subjects: medicine.medical_treatment, Lymphocyte, Immunotherapy, Human leukocyte antigen, Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, lcsh:RC254-282, Immunosurveillance, Immune system, medicine.anatomical_structure, Immunity, Cancer research, medicine, Cytotoxic T cell, Osteosarcoma
Abstract: Background It is now well established that the immune system has a substantial role in controlling cancer growth and progression. Immunotherapy is quickly coming to the forefront of cancer treatment,however the implementation of immunotherapy in pediatric solid cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters(1)using analytes extracted from gene expression data. Methods We performed single sample GeneSet Enrichment Analysis for 105 immune signatures previously described on 5pediatric tumors (410patients) from TARGET dataset(1) to identify coherent signature modules. Then we clustered samples according to representative signatures (1)and compared survival across clusters. We completed the analysis by analyzing the enrichment of immune subpopulations and the expression of the immune checkpoints. The degree of dysregulation of oncogenic pathways was also assessed. The performance of previously identified immune signatures as the Immunologic Constant of Rejection(2,3),which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy, was also checked within each tumor subtype. Results We found 5main modules, in agreement with results obtained in adult solid tumors:Wound Healing,TGF-B signaling,IFN-G signaling, Macrophages and Lymphocytes (figure 1). These 5 modules clustered pediatric patients into 6 immune subtypes S1-S6 with distinct survival (S2vsS4,p=0.0044, adjusted for cancer type),S2 cluster has the best overall survival and characterized by low enrichment of wound healing signature, high Th1, low Th2 and high expression of HLA 1 and HLA2, while the opposite holds true for cluster S4 with the worst survival and highest enrichment of wound healing signature, high Th2, and low Th1.The S6 cluster is characterized by highest enrichment of lymphocyte signature, the highest expression of immune checkpoints accompanied by elevated expression of exhaustion markers, and an unpolarized immune response with high abundance of macrophages. Additionally, pan-cancer, the upregulation of WNT-Beta catenin pathway is associated with adverse outcome and lack of T-cell infiltration. In the per-cancer analysis, ICR is associated with better survival in osteosarcoma and with worse survival in Wilms’ tumors,similarly with what observed in adult kidney’s cancer despite the different embryological origin. Conclusions We demonstrated that pediatric solid cancers can be classified according to their immune disposition, unveiling unexpected similarity with adults’ tumors.Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune responsive tumors. This is the first pan-cancer immunogenomic analysis in children. References Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018. 48(4):812–830. Roelands J, Hendrickx W, et al. ‘Oncogenic states dictate the prognostic and predictive connotations of intratumoral immune response.’ Journal for immunotherapy of cancer 2020;vol. 8:1. Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 2013;39:11–26.
Published: 2020
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27. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020
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28. Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

Author: Athina Spiliopoulou, Paul M. McKeigue, Peter Orchard, Costantino Pitzalis, Suzanne M M Verstappen, John D. Isaacs, Richard M. Weinshilboum, Ronald F van Vollenhoven, Donna K. Arnett, Leonid Padyukov, John C. Taylor, Jackie L Nam, Jonathan Massey, Anne Barton, Jianmei Wang, Heather J. Cordell, Jennifer H. Barrett, Stella Aslibekyan, Ian C. Scott, Paul P. Tak, Marco Colombo, Iain B. McInnes, Borbala Mifsud, Darren Plant, Michael R. Barnes, Paul Emery, Michael D Morgan, Duncan Porter, Sarah Twigg, Jane E. Freeston, Michiaki Kubo, Tim Bongartz, Felix Agakov, Andrew P. Cope, Ann W. Morgan, Maria J. H. de Hair, Jenna L. Strathdee, S. Louis Bridges, and Taisei Mushiroda
Subjects: 0301 basic medicine, musculoskeletal diseases, medicine.medical_specialty, ResearchInstitutes_Networks_Beacons/MICRA, Arthritis, Single-nucleotide polymorphism, Genome-wide association study, Severity of Illness Index, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, RC925, Internal medicine, Statistical significance, Severity of illness, Genetics, medicine, Clinical endpoint, Humans, skin and connective tissue diseases, Neuregulins, 030203 arthritis & rheumatology, Pharmacology, business.industry, medicine.disease, C-Reactive Protein, Methotrexate, 030104 developmental biology, Manchester Institute for Collaborative Research on Ageing, Antirheumatic Agents, Rheumatoid arthritis, Molecular Medicine, business, Genome-Wide Association Study, Transcription Factors, medicine.drug
Abstract: Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
Published: 2018
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29. B-011-01 TRANS-ANCESTRY GWAS OF 252,730 INDIVIDUALS IDENTIFIES 114 NOVEL LOCI ASSOCIATED WITH THE QT INTERVAL

Author: William Young, Aaron Isaacs, Najim Lahrouchi, Borbala Mifsud, Patricia B. Munroe, Christopher H. Newton-Cheh, and Nona Sotoodehnia
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2021
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30. B-AB13-01 TRANS-ANCESTRY GWAS OF 252,730 INDIVIDUALS IDENTIFIES 114 NOVEL LOCI ASSOCIATED WITH THE QT INTERVAL

Author: Aaron Isaacs, Borbala Mifsud, Najim Lahrouchi, William J Young, Patricia B. Munroe, Nona Sotoodehnia, and Christopher Newton-Cheh
Subjects: Genetics, business.industry, Physiology (medical), Medicine, Genome-wide association study, Cardiology and Cardiovascular Medicine, business, QT interval
Published: 2021
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31. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author: Lorenz Risch, Igor Rudan, Hilma Holm, Christopher P. Nelson, Jan A. Kors, Stefanie Aeschbacher, Stefan Kääb, Peter W. Macfarlane, Lars Lind, Amanda A. Seyerle, Ozren Polasek, Daniel F. Gudbjartsson, Xiuqing Guo, Nilesh J. Samani, Bruce M. Psaty, Rosa B. Thorolfsdottir, Elsayed Z. Soliman, Yong Qian, Mary L. Biggs, Antti Jula, Vilmundur Gudnason, Paul L. Huang, Tamara B. Harris, Gianfranco Sinagra, Luisa Foco, Anubha Mahajan, Mika Kähönen, Lu-Chen Weng, Borbala Mifsud, Stefan van Duijvenboden, Terho Lehtimäki, Jennifer A. Brody, Paolo Gasparini, Kathleen A. Ryan, Marten E. van den Berg, James J. Cranley, Eric Boerwinkle, Cathy C. Laurie, Annette Peters, Joshua C. Bis, Raymond Noordam, Andrew P. Morris, Johan Sundström, Lenore J. Launer, Stefan Weiss, Rebecca D. Jackson, Alison D. Murray, Jeffrey R. O'Connell, Aki S. Havulinna, Dennis O. Mook-Kanamori, Sheila Ulivi, Renée de Mutsert, Eric A. Whitsel, Adrienne M. Stilp, James P. Cook, Nona Sotoodehnia, Antonio Luiz Pinho Ribeiro, Seung Hoan Choi, Mark J. Caulfield, Sébastien Thériault, Henry J. Lin, Dan M. Roden, J. Wouter Jukema, James F. Wilson, Veikko Salomaa, Honghuang Lin, Andrew A. Hicks, Christy L. Avery, Nina Mononen, Dan E. Arking, Ruth J. F. Loos, Yalda Jamshidi, André G. Uitterlinden, Nina Hutri-Kähönen, Andrew Tinker, Gudmar Thorleifsson, Daniel Levy, Martina Müller-Nurasyid, Alexander P. Reiner, Bruno H. Stricker, Caroline Hayward, Yordi J. van de Vegte, Ioanna Ntalla, Tim D. Spector, Niek Verweij, Michael R. Barnes, Martin Gögele, Nathan R. Tucker, Arie C. Maan, Eduardo Tarazona-Santos, Katri Sääksjärvi, Maria Pina Concas, Pim van der Harst, Georg Ehret, Cecilia M. Lindgren, David Conen, Cornelia M. van Duijn, Muhammad B. Riaz, Leo-Pekka Lyytikäinen, Amelia W. Hall, Peter P. Pramstaller, Maria Fernanda Lima-Costa, Vilmantas Giedraitis, Emelia J. Benjamin, M. Fabiola Del Greco, Thomas Meitinger, Erwin P. Bottinger, Francesco Cucca, Aaron Isaacs, Carolina Roselli, James H. Cartwright, Massimo Mangino, Adolfo Correa, Patrick Sulem, Thibaud Boutin, Michiel Rienstra, Stephan B. Felix, Julia Ramirez, Kathleen F. Kerr, Jonathan Marten, David J. Porteous, Kent D. Taylor, Patrick T. Ellinor, Michele Orini, Susan R. Heckbert, Olli T. Raitakari, Girish N. Nadkarni, Edward G. Lakatta, Anna F. Dominiczak, Jie Yao, Erik Ingelsson, Christopher Newton-Cheh, Katharina Schramm, Jerome I. Rotter, Michael J. Cutler, Pashupati P. Mishra, Diane Fatkin, Marcus Dörr, Ulrike Peters, Solmaz Assa, Christian Fuchsberger, M. Abdullah Said, Catriona L. K. Barnes, Peter K. Joshi, M. Yldau van der Ende, Alvaro Alonso, James G. Wilson, Jun Ding, Kathryn L. Lunetta, Kjell Nikus, Helen R. Warren, Charles Kooperberg, Moritz F. Sinner, Sandosh Padmanabhan, Patricia B. Munroe, Jeffrey Haessler, Albert V. Smith, Alan R. Shuldiner, Morten S. Olesen, Konstantin Strauch, Steven A. Lubitz, J. Gustav Smith, Renan P. Souza, Michael Preuss, Kirill V. Tarasov, M. Benjamin Shoemaker, Barry London, Melanie Waldenberger, Cristian Pattaro, David O. Arnar, Gardar Sveinbjornsson, Alessandro De Grandi, Ian Ford, Kenneth Rice, Mark Chaffin, Kari Stefansson, Hao Mei, Uwe Völker, Blair H. Smith, Nathalia M. Araujo, Harry Campbell, Pier D. Lambiase, Stephanie M. Gogarten, May E. Montasser, Unnur Thorsteinsdottir, Ivana Kolcic, and Stella Trompet
Subjects: 0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, Atrial fibrillation, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Endophenotype, Cardiac conduction, medicine, Cardiology, PR interval, business, education, 030304 developmental biology
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Published: 2019
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32. GOTHiC, a probabilistic model to resolve complex biases and to identify real interactions in Hi-C data

Author: Stefan Schoenfelder, Robert Sugar, Inigo Martincorena, Nicholas M. Luscombe, Peter Fraser, Borbala Mifsud, Elodie Darbo, Mifsud, Borbala [0000-0003-3429-3094], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Molecular biology, Computer science, Binomials, lcsh:Medicine, computer.software_genre, Polynomials, Biochemistry, Bioconductor, chemistry.chemical_compound, 0302 clinical medicine, Dna genetics, Genomic library, DNA libraries, lcsh:Science, Mammalian Genomics, Multidisciplinary, Chromosome Mapping, Genomics, Nucleic acids, Physical Sciences, Data mining, Research Article, Locus (genetics), DNA construction, Research and Analysis Methods, Genome Complexity, Chromosomes, Structural genomics, 03 medical and health sciences, Bias, Genetics, Molecular Biology Techniques, Models, Statistical, Biology and life sciences, Genome complexity, DNA manipulations, Gene Mapping, DNA fragment ligation, lcsh:R, Chromosome, Computational Biology, Statistical model, DNA, Genome Analysis, Genomic Libraries, Algebra, 030104 developmental biology, chemistry, Animal Genomics, Genetic Loci, Structural Genomics, lcsh:Q, Ligation, computer, Mathematics, 030217 neurology & neurosurgery, Software
Abstract: Hi-C is one of the main methods for investigating spatial co-localisation of DNA in the nucleus. However, the raw sequencing data obtained from Hi-C experiments suffer from large biases and spurious contacts, making it difficult to identify true interactions. Existing methods use complex models to account for biases and do not provide a significance threshold for detecting interactions. Here we introduce a simple binomial probabilistic model that resolves complex biases and distinguishes between true and false interactions. The model corrects biases of known and unknown origin and yields a p-value for each interaction, providing a reliable threshold based on significance. We demonstrate this experimentally by testing the method against a random ligation dataset. Our method outperforms previous methods and provides a statistical framework for further data analysis, such as comparisons of Hi-C interactions between different conditions. GOTHiC is available as a BioConductor package (http://www.bioconductor.org/packages/release/bioc/html/GOTHiC.html).
Published: 2019
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33. Practical Guide to ChIP-seq Data Analysis

Author: Borbala Mifsud, Kathi Zarnack, Anaïs F Bardet, Borbala Mifsud, Kathi Zarnack, and Anaïs F Bardet
Subjects: Chromatin, Molecular biology--Methodology
Abstract: Chromatin immunoprecipitation sequencing (ChIP-seq), which maps the genome-wide localization patterns of transcription factors and epigenetic marks, is among the most widely used methods in molecular biology. Practical Guide to ChIP-seq Data Analysis will guide readers through the steps of ChIP-seq analysis: from quality control, through peak calling, to downstream analyses. It will help experimental biologists to design their ChIP-seq experiments with the analysis in mind, and to perform the basic analysis steps themselves. It also aims to support bioinformaticians to understand how the data is generated, what the sources of biases are, and which methods are appropriate for different analyses.
Published: 2019

34. Genetic Basis and Prognostic Value of Exercise QT Dynamics

Author: William J Young, Patricia B. Munroe, Michele Orini, Borbala Mifsud, Julia Ramirez, Pier D. Lambiase, Stefan van Duijvenboden, and Andrew Tinker
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Risk predictor, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, cardiovascular disease, Risk Factors, Internal medicine, Heart rate, medicine, Humans, In patient, Exercise, Aged, Proportional Hazards Models, genome-wide association study, Basis (linear algebra), KCNQ Potassium Channels, business.industry, General Medicine, Original Articles, Middle Aged, Prognosis, mortality, Survival Analysis, 3. Good health, Long QT Syndrome, 030104 developmental biology, Genetic Loci, Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, business, Value (mathematics)
Abstract: Supplemental Digital Content is available in the text., Background: Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated. Methods: QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies were conducted to identify genetic variants and bioinformatics analyses were performed to prioritize candidate genes. The prognostic value of QT dynamics was evaluated for cardiovascular events (death or hospitalization) and all-cause mortality. Results: Heritability of QT dynamics during exercise and recovery were 10.7% and 5.4%, respectively. Genome-wide association studies identified 20 loci, of which 4 loci included genes implicated in mendelian long-QT syndrome. Five loci did not overlap with previously reported resting QT interval loci; candidate genes included KCNQ4 and KIAA1755. Genetic risk scores were not associated with cardiovascular events in 357 882 unrelated individuals from UK Biobank. We also did not observe associations of QT dynamics during exercise and recovery with cardiovascular events. Increased QT dynamics during recovery was significantly associated with all-cause mortality in the univariate Cox regression analysis (hazard ratio, 1.09 [95% CI, 1.05–1.13], P=2.28×10-5), but the association was not significant after adjusting for clinical risk factors. Conclusions: QT interval dynamics during exercise and recovery are heritable markers but do not carry independent prognostic information for clinical outcomes in the UK Biobank, a population-based cohort. Their prognostic importance may relate to cardiovascular disease cohorts where structural heart disease or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.
Published: 2020

35. ChIP-seq-specific Quality Control

Author: Borbala Mifsud
Subjects: Computer science, business.industry, Embedded system, media_common.quotation_subject, Control (management), Quality (business), Chip, business, media_common
Published: 2018
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36. Comparative Analysis

Author: Anaïs Bardet and Borbala Mifsud
Published: 2018
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37. Introduction to ChIP-seq

Author: Borbala Mifsud
Subjects: business.industry, Computer science, Embedded system, business, Chip
Published: 2018
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38. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018
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39. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author: Lorenz Risch, Anne-Claire Vergnaud, Nguyen Quang Tri, Rona J. Strawbridge, Alan F. Wright, Francesco Cucca, Evan Tzanis, Caterina Barbieri, Jaakko Tuomilehto, Louise V. Wain, Jonathan Marten, James F. Wilson, Christopher Newton-Cheh, Reedik Mägi, Olli T. Raitakari, Peter W.F. Wilson, Joris Deelen, Morris Brown, Anna Morgan, Nabi Shah, Weihua Zhang, Ganesh Chauhan, Gail Davies, Peter S. Braund, Bram P. Prins, Alison Pattie, Marcus Dörr, Zoltán Kutalik, Marco Brumat, Franco Giulianini, Rainer Rettig, Uwe Völker, Georgios Ntritsos, Teresa Nutile, Todd L. Edwards, Albertine J. Oldehinkel, Christopher J. O'Donnell, Jaume Marrugat, Evangelos Evangelou, Nilesh J. Samani, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Francis S. Collins, Tim D. Spector, Simon Thom, Sarah E. Harris, Heather J. Cordell, Helen R. Warren, Cinzia Sala, Peter P. Pramstaller, Seppo Koskinen, Paul F. O'Reilly, Aravinda Chakravarti, Joshua C. Bis, Archie Campbell, Bernard Keavney, Sébastien Thériault, Gonneke Willemsen, Lynda M. Rose, Massimiliano Cocca, Jennifer E. Huffman, Meixia Ren, Massimo Mangino, Markus Perola, Joanna M. M. Howson, David Mosen-Ansorena, Harriëtte Riese, Martin Farrall, Albert V. Smith, Lenore J. Launer, Marina Ciullo, Antti-Pekka Sarin, Veikko Salomaa, Ilaria Gandin, Kent D. Taylor, Peter S. Sever, Markku Laakso, André G. Uitterlinden, Yan V. Sun, Raymond Noordam, Renée de Mutsert, Alan L. James, Jing Hua Zhao, Stefan Enroth, Andrew D. Morris, David S. Siscovick, Andrew D. Johnson, Igor Rudan, Tõnu Esko, Jun Ding, David P. Strachan, Martin D. Tobin, Christopher P. Nelson, Daniela Toniolo, J. Wouter Jukema, Vilmundur Gudnason, Borbala Mifsud, Marty Larson, Andrew A. Hicks, Adriana M. Hung, Antonietta Robino, Ruifang Li-Gao, Paul Elliott, Anne U. Jackson, Michela Traglia, Martin H. de Borst, Germaine C. Verwoert, Rheinhold Schmidt, Fabiola M Del Greco, Åsa Johansson, Anders Hamsten, Csaba P. Kovesdy, Mark J. Caulfield, Cumhur Y Demirkale, John M. C. Connell, Jian'an Luan, K. Witkowska, Georg Ehret, Cecilia M. Lindgren, Oscar H. Franco, Yongmei Liu, Ioanna Tzoulaki, Eric Boerwinkle, Catharina A. Hartman, Muralidharan Sargurupremraj, Claudia Langenberg, J. Michael Gaziano, Peter K. Joshi, Cornelia M. van Duijn, Maris Laan, Nick Shrine, Peter J. van der Most, Michael Boehnke, Leo-Pekka Lyytikäinen, Samuli Ripatti, Ben A. Oostra, Robert A. Scott, Lingchan Lu, Edward G. Lakatta, Yasaman Saba, Daniel Levy, Li Lin, Harold Schneider, Alex S. F. Doney, Michael R. Barnes, Najaf Amin, Hugh Watkins, Paul M. Ridker, Janina S Reid, Ayush Giri, Sekar Kathiresan, Lorna M. Lopez, Mike A. Nalls, Marina Evangelou, Erik Ingelsson, Lili Milani, Alice Stanton, Ozren Polasek, Sara M. Willems, Colin N. A. Palmer, Stéphanie Debette, Dan E. Arking, Helena Schmidt, Paul Knekt, John M. Starr, Yong Qian, Cristina Menni, Yuri Milaneschi, Christophe Tzourio, Tamara B. Harris, Kristin L. Ayers, Peter Vollenweider, Paolo Gasparini, Dennis O. Mook-Kanamori, Rodney J. Scott, Sandosh Padmanabhan, Anubha Mahajan, Peter Almgren, Jacklyn N. Hellwege, Teemu J. Niiranen, Mika Kähönen, Shih-Jen Hwang, Elizabeth G. Holliday, Edith Hofer, Priyanka Nandakumar, Peter J. Munson, Rick Jansen, Andrew P. Morris, Walter Palmas, Ilja M. Nolte, Siim Sõber, Thibaud Boutin, Ahmad Vaez, Albert Hofman, He Gao, Brenda W.J.H. Penninx, Neil Poulter, Alan J. Gow, Caroline Hayward, Nicholas J. Wareham, Elin Org, Philip S. Tsao, Claudia P. Cabrera, Aki S. Havulinna, Dragana Vuckovic, Kelly Cho, Jie Yao, Lars Lind, Jerome I. Rotter, David J. Stott, Ivana Kolcic, Wei-Yu Lin, Tatijana Zemunik, Tineka Blake, Kenneth Rice, Veronique Vitart, Alanna C. Morrison, Kay-Tee Khaw, Marjo-Riitta Järvelin, Guillaume Paré, Jouke-Jan Hottenga, Giorgia Girotto, Chiara Batini, Niki Dimou, Stella Trompet, John Danesh, Annette Peters, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Morris A. Swertz, Jaspal S. Kooner, Niek Verweij, Ibrahim Karaman, Murielle Bochud, Christian Gieger, Ruth J. F. Loos, Daniella Ruggiero, Arno Palotie, David Conen, Raha Pazoki, Denis C. Shields, Rossella Sorice, Philippe Amouyel, Gonçalo R. Abecasis, Andres Metspalu, John Attia, Bruce M. Psaty, Sarah H. Wild, Patricia B. Munroe, Daniel I. Chasman, Ollie Melander, John C. Chambers, Roby Joehanes, Eleftheria Zeggini, Johan Sundström, Chrysovalanto Mamasoula, Benjamin Lehne, Kati Kristiansson, Christopher Oldmeadow, Eco J. C. de Geus, A. Mesut Erzurumluoglu, Anuj Goel, Adam S. Butterworth, Digna R. Velez Edwards, Xiuqing Guo, Antti Jula, Praveen Surendran, Terho Lehtimäki, Mattias Frånberg, Teresa Ferreira, Ian J. Deary, David C. Liewald, Pim van der Harst, Erwin P. Bottinger, Roberto Elosua, and Fu Liang Ng
Subjects: Genetics, 0303 health sciences, Diastole, Disease, 030204 cardiovascular system & hematology, Biology, Precision medicine, Genetic analysis, 3. Good health, Pulse pressure, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Disease prevention, 030304 developmental biology, Genetic association
Abstract: High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.
Published: 2017
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40. Corrigendum: Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Author: Neil R Poulter, Barnes, Danish Saleheen, Borbala Mifsud, Tobin, Aravinda Chakravarti, Ioanna Tzoulaki, Meixia Ren, Ching-Ti Liu, MA Said, Char Genome, Ron T. Gansevoort, Simon A. McG. Thom, Claudia P. Cabrera, Niek Verweij, Norihiro Kato, Evangelos Evangelou, Patricia B. Munroe, Igb Pressure, John M. C. Connell, Paul F. O'Reilly, R Magi, Peter S. Sever, Paul Elliott, Icbp Icbp, John C. Chambers, Morris J. Brown, J. Marten, Mps Lepe, Alice Stanton, Sandosh Padmanabhan, Daniel Levy, He Gao, Denis C. Shields, Marie Loh, Jmm Howson, Mark J. Caulfield, James P. Cook, Helen R. Warren, E-Shyong Tai, David J. Porteous, Fotios Drenos, Jaspal S. Kooner, Bernard Keavney, P. van der Harst, Maris Alver, Christopher Newton-Cheh, A. Metspalu, Martin Farrall, Praveen Surendran, Caroline Hayward, Joanne Knight, Maciej Tomaszewski, Jiang He, Ioanna Ntalla, C M Lindgren, Daniel I. Chasman, T Esko, Harold Snieder, Sjl Bakker, Ibrahim Karaman, Louise V. Wain, G. Ehret, Aldi T. Kraja, Rajiv Chowdhury, Nilesh J. Samani, and Pfizer Inc
Subjects: International Consortium of Blood Pressure (ICBP) 1000G Analyses, The CHD Exome+ Consortium, The ExomeBP Consortium, The T2D-GENES Consortium, The GoT2DGenes Consortium, The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium, The International Genomics of Blood Pressure (iGEN-BP) Consortium, College health, medicine.medical_specialty, media_common.quotation_subject, UK Biobank CardioMetabolic Consortium BP working group, Library science, Translational research, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Excellence, Health care, Genetics, medicine, Genome-Wide Association Analysis, media_common, business.industry, Public health, 11 Medical And Health Sciences, 06 Biological Sciences, Medical research, Biobank, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract: HRW, CPC, MR, MRB, PBM, MB and MJC were funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. HG was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. MR was a recipient from China Scholarship Council (No. 2011632047). BM holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. JMMH was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233). BK holds a British Heart Foundation Personal Chair (CH/13/2/30154). NJS holds a chair funded by the British Heart Foundation and is a NIHR Senior Investigator. FD was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). PSu was funded by the UK Medical Research Council (G0800270). CL and AK were funded by the NHLBI intramural funding. CNC was funded by the National Institutes of Health (HL113933, HL124262). PVDH was funded by the ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call: H2020- MSCA-IF-2014, Project ID: 661395). NV was supported by Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. NP received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. PS was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. ST was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. PFO received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). IK was supported by the EU PhenoMeNal project (Horizon 2020, 654241). AC was funded by the National Institutes of Health (HL128782, HL086694). MF was supported by the Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). CH was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. MJC is a National Institute for Health Research (NIHR) senior investigator. PE is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, PE acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK MEDical BIOinformatics partnership - aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO) which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111). Project title: Large-scale comprehensive genotyping of UK Biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium (UKCMC).
Published: 2017

41. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney

Author: Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: 0301 basic medicine, cardiovascular risk, Netherlands Twin Register (NTR), hypertension, NETHERLANDS, Sistema cardiovascular -- Malalties, GWAS, blood pressure, complex traits, eSNP, Locus (genetics), Genome-wide association study, Disease, Biology, PERIPHERAL-BLOOD, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Internal Medicine, Journal Article, Cardiac and Cardiovascular Systems, 1000 Genomes Project, Gene, CENTRIC ARRAY, METAANALYSIS, Genetics, ddc:616, Kardiologi, PULSE PRESSURE, COMMON VARIANTS, 1103 Clinical Sciences, ta3121, 3. Good health, INDIVIDUALS, 030104 developmental biology, Blood pressure, TARGET, Cardiovascular System & Hematology, complex trait, GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension, Hipertensió, Imputation (genetics), TRAITS
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017
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42. Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression

Author: John C. Marioni, Kedar Nath Natarajan, Sarah A. Teichmann, Elena Torlai Triglia, Gozde Kar, Sarah Elderkin, Ana Pombo, Borbala Mifsud, Aleksandra A. Kolodziejczyk, Jong Kyoung Kim, Torlai Triglia, Elena [0000-0002-6059-0116], Mifsud, Borbala [0000-0003-3429-3094], Pombo, Ana [0000-0002-7493-6288], and Apollo - University of Cambridge Repository
Subjects: Genetic Markers, 0301 basic medicine, animal structures, Transcription, Genetic, Science, Ubiquitin-Protein Ligases, Polycomb-Group Proteins, Gene Expression, General Physics and Astronomy, Genomics, RNA polymerase II, macromolecular substances, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Cell Line, Tumor, Gene expression, Animals, RNA, Messenger, Enhancer, Gene, 030304 developmental biology, Computational & Systems Biology, Mice, Knockout, Polycomb Repressive Complex 1, Transcriptional bursting, Genetics, 0303 health sciences, Multidisciplinary, Base Sequence, General Chemistry, Tumour Biology, Cell biology, Chromatin, 030104 developmental biology, Histone, Gene Expression Regulation, biology.protein, Genetics & Genomics, 030217 neurology & neurosurgery
Abstract: Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development., Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.
Published: 2017
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43. Discovery of novel heart rate-associated loci using the Exome Chip

Author: Massimo Mangino, Alison D. Murray, Kathleen Stirrups, Antonella Mulas, Claudia P. Cabrera, Stephan B. Felix, Martin D. Tobin, Jerome I. Rotter, Jan A. Kors, Arno W. Hoes, Bruno H. Stricker, David J. Porteous, Cornelia M. van Duijn, Yi-Ping Fu, George Dedoussis, Ozren Polasek, Nathan A. Bihlmeyer, Ruben N. Eppinga, Marco Orru, Torben Hansen, Elsayed Z. Soliman, James G. Wilson, Martina Müller-Nurasyid, Stefan Weiss, Peter W. Macfarlane, Oluf Pedersen, Honghuang Lin, Joshua C. Bis, Mika Kähönen, Farid Radmanesh, Sandosh Padmanabhan, Xiuqing Guo, Henry J. Lin, Tamara B. Harris, Magdalena Zoledziewska, Nabi Shah, Ilonca Vaartjes, Niels Grarup, Mark J. Caulfield, Yalda Jamshidi, Bram P. Prins, J. Wouter Jukema, Nona Sotoodehnia, Andrew Tinker, Jørgen K. Kanters, Patrick T. Ellinor, Alvaro Alonso, Leanne M. Hall, Helen R. Warren, Man Li, Marcus Dörr, Hugoline G. de Haan, Charles Kooperberg, Moritz F. Sinner, Eleftheria Zeggini, Lihong Qi, Aaron Isaacs, Susan R. Heckbert, Carolina Roselli, Serena Sanna, Bruce M. Psaty, Niek Verweij, Dennis O. Mook-Kanamori, Shih-Jen Hwang, Stefan Kääb, Melanie Waldenberger, Rudolf A. de Boer, Caroline Hayward, Annette Peters, Uwe Völker, Giorgio Pistis, Jeffrey Haessler, Folkert W. Asselbergs, Alex S. F. Doney, Albert V. Smith, Yanick Hagemeijer, Lenore J. Launer, Steven A. Lubitz, Peter S. Sever, André G. Uitterlinden, Jonathan Rosand, Renée de Mutsert, Anna F. Dominiczak, Colin N. A. Palmer, Jennifer A. Brody, Naveed Sattar, Ivana Kolcic, Paul L. Huang, Stella Trompet, Aiman Entwistle, Terho Lehtimäki, Peter van der Meer, Nilesh J. Samani, Alice Stanton, Ruifang Li-Gao, Patricia B. Munroe, Pim van der Harst, Kent D. Taylor, Andrew D. Morris, Igor Rudan, Christopher P. Nelson, Simin Liu, Neil R Poulter, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Marten E. van den Berg, Allan Linneberg, Zhijun Xie, Claudia Tamar Silva, Jessica van Setten, Jonathan Marten, Jie Yao, Olli T. Raitakari, Christopher J. O'Donnell, Vilmundur Gudnason, Borbala Mifsud, Mark Eijgelsheim, Panos Deloukas, Hao Mei, Tim D. Spector, Dan E. Arking, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Medical Informatics, Epidemiology, Internal Medicine, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.01 - Blood proteins & engineering, and Zorgwetenschappen
Subjects: 0301 basic medicine, Male, Candidate gene, PROTEIN, Genome-wide association study, VARIANTS, DISEASE, Gene Frequency, Heart Rate, Risk Factors, Exome, Genetics(clinical), Genetics (clinical), Oligonucleotide Array Sequence Analysis, ALL-CAUSE MORTALITY, Genetics, Genetics & Heredity, Association Studies Articles, General Medicine, Single Nucleotide, 11 Medical And Health Sciences, Middle Aged, 3. Good health, Female, Life Sciences & Biomedicine, PROJECT, Adult, Biochemistry & Molecular Biology, Genotype, European Continental Ancestry Group, Locus (genetics), Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, RISK-FACTOR, Heart rate, Journal Article, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, GENOME-WIDE ASSOCIATION, Allele frequency, Molecular Biology, Alleles, Science & Technology, IDENTIFICATION, ta1184, COMPLEX TRAITS, ta1182, heart rate, exome, meta-analysis, ta3121, 06 Biological Sciences, GENE, Genetic architecture, 030104 developmental biology, Genetic Loci, Genome-Wide Association Study
Abstract: Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.\ud \ud Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.\ud \ud We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.\ud \ud Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
Published: 2017
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44. Novel blood pressure locus and gene discovery using GWAS and expression datasets from blood and the kidney

Author: Ganesh Chauhan, Dragana Vuckovic, Yingchang Lu, Bernard Keavney, Patricia B. Munroe, Tim D. Spector, Tamara B. Harris, Chiara Batini, Harold Snieder, Yusuf Demirkale, Ulf Gyllensten, Heather J. Cordell, Christopher Newton-Cheh, Anne-Claire Vergnaud, Christophe Tzourio, Giorgia Girotto, Morris A. Swertz, John C. Chambers, Xiuqing Guo, Caterina Barbieri, Joris Deelen, Morris Brown, Igor Rudan, Christopher P. Nelson, Paul Knekt, Antti-Pekka Sarin, Peter Vollenweider, Lynda M. Rose, Ozren Polasek, Nilesh J. Samani, Murielle Bochud, James F. Wilson, Anna Morgan, Gail Davies, Ian J. Deary, Massimiliano Cocca, Antti Jula, Ioanna Tzoulaki, Jaspal S. Kooner, Sarah H Wild, Peter S. Braund, John M. Starr, Simon Thom, Christian Gieger, Rainer Rettig, John M. C. Connell, Marina Ciullo, Jian'an Luan, Rodney J. Scott, Franco Giulianini, Brenda W.J.H. Penninx, Mika Kähönen, Alison Pattie, Nabi Shah, Weihua Zhang, Ruth J. F. Loos, Maris Laan, Martin Farrall, Rick Jansen, Albert V. Smith, Sarah E. Harris, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Paul M. Ridker, John Attia, Alanna C. Morrison, Kay-Tee Khaw, Jaume Marrugat, Hugh Watkins, David C. Liewald, Pim van der Harst, Benjamin Lehne, Jennifer E. Huffman, Meixia Ren, Zoltán Kutalik, Lars Lind, Walter Palmas, Teresa Ferreira, David J. Stott, Janina S. Ried, Bruce M. Psaty, Paul F. O'Reilly, Massimo Mangino, Tõnu Esko, Jonathan Marten, Nick Shrine, Anders Hamsten, Tineka Blake, Yuri Milaneschi, Jing Hua Zhao, David Conen, Kristin L. Ayers, Germaine C. Verwoert, Veikko Salomaa, Olli T. Raitakari, Jaakko Tuomilehto, Louise V. Wain, Jennie Hui, Elin Org, Gonçalo R. Abecasis, Vilmundur Gudnason, Andrew A. Hicks, Rossella Sorice, Borbala Mifsud, Helen R. Warren, Jerome I. Rotter, Erwin P. Bottinger, Roberto Elosua, Antonietta Robino, Ilaria Gandin, Andres Metspalu, Marjo-Riitta Järvelin, Guillaume Paré, Anne U. Jackson, Jie Yao, Kent D. Taylor, Denis C. Shields, Andrew D. Morris, Daniela Ruggiero, Samuli Ripatti, C M Lindgren, Mike A. Nalls, Erik Ingelsson, Michela Traglia, Jeffrey Damman, J. Wouter Jukema, Catharina A. Hartman, Eco J. C. de Geus, Colin N. A. Palmer, Peter J. van der Most, Neil Poulter, Robert A. Scott, Anuj Goel, Aude Saint Pierre, Annette Peters, Paul Elliott, Daniel I. Chasman, Marco Brumat, Dennis O. Mook-Kanamori, Priyanka Nandakumar, Roby Joehanes, Cornelia M. van Duijn, Joshua C. Bis, Eleftheria Zeggini, Archie Campbell, Ivana Kolcic, Terho Lehtimäki, Mattias Frånberg, David S. Siscovick, Dan E. Arking, Shih-Jen Hwang, Stella Trompet, Christopher Oldmeadow, A. Mesut Erzurumluoglu, Nicholas J. Wareham, Alice Stanton, Chrysovalanto Mamasoula, Seppo Koskinen, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Peter J. Munson, Aarno Palotie, Daniela Toniolo, He Gao, Ruifang Li-Gao, Claudia Langenberg, Kati Kristiansson, Åsa Johansson, Johan Sundström, Francis S. Collins, Alan J. Gow, Caroline Hayward, Markus Perola, Renée de Mutsert, Alan James, Ben A. Oostra, Alexander Teumer, Joanne Knight, Vilmantas Giedraitis, Marty Larson, Helena Schmidt, Sébastien Thériault, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, Marc A. Seelen, Georg Ehret, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Stéphanie Debette, Paolo Gasparini, Teemu J. Niiranen, Stefan Enroth, Mark J. Caulfield, Andrew P. Morris, Aki S. Havulinna, Cinzia Sala, Peter P. Pramstaller, Marcus Dörr, Quang Tri Nguyen, Claudia P. Cabrera, Bram P. Prins, Peter K. Joshi, Sekar Kathiresan, Lorna M. Lopez, Reinhold Schmidt, Sandosh Padmanabhan, Teresa Nutile, Gonneke Willemsen, François Mach, Michael Boehnke, John Beilby, Leo-Pekka Lyytikäinen, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Aravinda Chakravarti, Jouke-Jan Hottenga, Fabiola M. Del Greco, Yasaman Saba, Daniel Levy, Li Lin, Michael R. Barnes, Rona J. Strawbridge, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, and Martin D. Tobin
Subjects: Genetics, 0303 health sciences, Genomics, Locus (genetics), Genome-wide association study, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Genetic variation, 1000 Genomes Project, Gene, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology
Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150,134 European ancestry individuals and sought significant evidence for independent replication in a further 228,245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12,607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in BP regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Published: 2017
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45. Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia

Author: William Villiers, Audrey Kelly, Xiaohan He, James Kaufman-Cook, Abdurrahman Elbasir, Halima Bensmail, Paul Lavender, Richard Dillon, Borbála Mifsud, and Cameron S. Osborne
Subjects: Science
Abstract: The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
Published: 2023
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46. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd
Subjects: Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018
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47. GENETIC ANALYSIS OF OVER ONE MILLION PEOPLE IDENTIFIES 535 NOVEL LOCI ASSOCIATED WITH BLOOD PRESSURE AND RISK OF CARDIOVASCULAR DISEASE

Author: T Esko, Mark J. Caulfield, Marina Evangelou, Jacklyn N. Hellwege, Paul Elliott, A. Metspalu, Niki Dimou, Raha Pazoki, Louise V. Wain, H. Gao, D. Mosen, Helen R. Warren, Michael R. Barnes, Ioanna Tzoulaki, Borbala Mifsud, Anil K. Giri, Georgios Ntritsos, and Evangelos Evangelou
Subjects: 0301 basic medicine, Genetics, Physiology, business.industry, Genetic variants, Disease, Genetic analysis, Genetic architecture, 03 medical and health sciences, 030104 developmental biology, Blood pressure, Internal Medicine, Trait, Medicine, Cardiology and Cardiovascular Medicine, business
Abstract: Objective:Hypertension is the leading cause of cardiovascular morbidity. High blood pressure is highly heritable (∼30–50%), however all genetic variants identified so far only explain ∼3–4% of the trait variance. Hence much of the genetic architecture of blood pressure remains unexplained.Design and
Published: 2018
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48. The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements

Author: Robert Sugar, Yulia Katsman, Elodie Darbo, Moorthy Sakthidevi, Lucas Brandon Edelman, Kristina Tabbada, Stefan Schoenfelder, Emilia Dimitrova, Biola M. Javierre, Filipe Tavares-Cadete, Borbala Mifsud, Simon Andrews, Andy Higgs, Bram Herman, Mayra Furlan-Magaril, Andrew Dimond, Peter Fraser, Steven W. Wingett, Jennifer A. Mitchell, Takashi Nagano, Cameron S. Osborne, Sarah Elderkin, Nicholas M. Luscombe, and Emily M LeProust
Subjects: Resource, Bioinformatics, Computational biology, Biology, Trans-regulatory element, Epigenesis, Genetic, Histones, Mice, Genetics, Animals, Promoter Regions, Genetic, Transcription factor, Genetics (clinical), ChIA-PET, Locus control region, Embryonic Stem Cells, Regulation of gene expression, Binding Sites, Gene Expression Regulation, Developmental, Promoter, 11 Medical And Health Sciences, 06 Biological Sciences, Chromatin, Mice, Inbred C57BL, Enhancer Elements, Genetic, Liver, Transcription Factor Gene, Transcription Factors
Abstract: The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their long-range interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.
Published: 2015
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49. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C

Author: Stefan Schoenfelder, Steven W. Wingett, Philip Ewels, George A. Follows, Emily M LeProust, Nicholas M. Luscombe, Simon Andrews, Alice N Young, Andy Higgs, Robert Sugar, Borbala Mifsud, Lauren Ferreira, Filipe Tavares-Cadete, Scott Happe, Cameron S. Osborne, Bram Herman, William Grey, and Peter Fraser
Subjects: Regulation of gene expression, Genetics, Genome, Human, Chromosome Mapping, Promoter, Epistasis, Genetic, Biology, Genome, Polymorphism, Single Nucleotide, Cell Line, Chromosome conformation capture, Gene Expression Regulation, Humans, Human genome, Gene Regulatory Networks, Enhancer, Promoter Regions, Genetic, Gene, Functional genomics
Abstract: Transcriptional control in large genomes often requires looping interactions between distal DNA elements, such as enhancers and target promoters. Current chromosome conformation capture techniques do not offer sufficiently high resolution to interrogate these regulatory interactions on a genomic scale. Here we use Capture Hi-C (CHi-C), an adapted genome conformation assay, to examine the long-range interactions of almost 22,000 promoters in 2 human blood cell types. We identify over 1.6 million shared and cell type-restricted interactions spanning hundreds of kilobases between promoters and distal loci. Transcriptionally active genes contact enhancer-like elements, whereas transcriptionally inactive genes interact with previously uncharacterized elements marked by repressive features that may act as long-range silencers. Finally, we show that interacting loci are enriched for disease-associated SNPs, suggesting how distal mutations may disrupt the regulation of relevant genes. This study provides new insights and accessible tools to dissect the regulatory interactions that underlie normal and aberrant gene regulation.
Published: 2014

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