Author: "Roberts, David J" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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1. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author: Chen, Ming-Huei, Raffield, Laura M, Mousas, Abdou, Sakaue, Saori, Huffman, Jennifer E, Moscati, Arden, Trivedi, Bhavi, Jiang, Tao, Akbari, Parsa, Vuckovic, Dragana, Bao, Erik L, Zhong, Xue, Manansala, Regina, Laplante, Véronique, Chen, Minhui, Lo, Ken Sin, Qian, Huijun, Lareau, Caleb A, Beaudoin, Mélissa, Hunt, Karen A, Akiyama, Masato, Bartz, Traci M, Ben-Shlomo, Yoav, Beswick, Andrew, Bork-Jensen, Jette, Bottinger, Erwin P, Brody, Jennifer A, van Rooij, Frank JA, Chitrala, Kumaraswamynaidu, Cho, Kelly, Choquet, Hélène, Correa, Adolfo, Danesh, John, Di Angelantonio, Emanuele, Dimou, Niki, Ding, Jingzhong, Elliott, Paul, Esko, Tõnu, Evans, Michele K, Floyd, James S, Broer, Linda, Grarup, Niels, Guo, Michael H, Greinacher, Andreas, Haessler, Jeff, Hansen, Torben, Howson, Joanna MM, Huang, Qin Qin, Huang, Wei, Jorgenson, Eric, Kacprowski, Tim, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Karthikeyan, Savita, Koskeridis, Fotis, Lange, Leslie A, Lehtimäki, Terho, Lerch, Markus M, Linneberg, Allan, Liu, Yongmei, Lyytikäinen, Leo-Pekka, Manichaikul, Ani, Martin, Hilary C, Matsuda, Koichi, Mohlke, Karen L, Mononen, Nina, Murakami, Yoshinori, Nadkarni, Girish N, Nauck, Matthias, Nikus, Kjell, Ouwehand, Willem H, Pankratz, Nathan, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M, Raitakari, Olli T, Roberts, David J, Rich, Stephen S, Rodriguez, Benjamin AT, Rosen, Jonathan D, Rotter, Jerome I, Schubert, Petra, Spracklen, Cassandra N, Surendran, Praveen, Tang, Hua, Tardif, Jean-Claude, Trembath, Richard C, Ghanbari, Mohsen, Völker, Uwe, Völzke, Henry, Watkins, Nicholas A, Zonderman, Alan B, Program, VA Million Veteran, Wilson, Peter WF, Li, Yun, Butterworth, Adam S, Gauchat, Jean-François, Chiang, Charleston WK, and Li, Bingshan
Subjects: Genetics, Good Health and Well Being, Asian People, Genome-Wide Association Study, HEK293 Cells, Humans, Interleukin-7, Mutation, Missense, Phenotype, Polymorphism, Single Nucleotide, White People, VA Million Veteran Program, interleukin-7, genetic architecture, fine-mapping, selective sweeps, polygenic trait score, phenome-wide association study, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
Published: 2020

2. Summary results of the 2014-2015 DARPA Chikungunya challenge

Author: Del Valle, Sara Y, McMahon, Benjamin H, Asher, Jason, Hatchett, Richard, Lega, Joceline C, Brown, Heidi E, Leany, Mark E, Pantazis, Yannis, Roberts, David J, Moore, Sean, Peterson, A Townsend, Escobar, Luis E, Qiao, Huijie, Hengartner, Nicholas W, and Mukundan, Harshini
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Rare Diseases, Vector-Borne Diseases, Prevention, Biodefense, Infectious Diseases, Vaccine Related, Infection, Good Health and Well Being, Chikungunya Fever, Demography, Dengue, Disease Outbreaks, Forecasting, Humans, Infection Control, Organizational Innovation, Research Design, Security Measures, United States, United States Department of Defense, Zika Virus Infection, Chikungunya, Mechanistic models, Morphological models, Microbiology, Medical Microbiology, Clinical sciences, Medical microbiology, Public health
Abstract: BackgroundEmerging pathogens such as Zika, chikungunya, Ebola, and dengue viruses are serious threats to national and global health security. Accurate forecasts of emerging epidemics and their severity are critical to minimizing subsequent mortality, morbidity, and economic loss. The recent introduction of chikungunya and Zika virus to the Americas underscores the need for better methods for disease surveillance and forecasting.MethodsTo explore the suitability of current approaches to forecasting emerging diseases, the Defense Advanced Research Projects Agency (DARPA) launched the 2014-2015 DARPA Chikungunya Challenge to forecast the number of cases and spread of chikungunya disease in the Americas. Challenge participants (n=38 during final evaluation) provided predictions of chikungunya epidemics across the Americas for a six-month period, from September 1, 2014 to February 16, 2015, to be evaluated by comparison with incidence data reported to the Pan American Health Organization (PAHO). This manuscript presents an overview of the challenge and a summary of the approaches used by the winners.ResultsParticipant submissions were evaluated by a team of non-competing government subject matter experts based on numerical accuracy and methodology. Although this manuscript does not include in-depth analyses of the results, cursory analyses suggest that simpler models appear to outperform more complex approaches that included, for example, demographic information and transportation dynamics, due to the reporting biases, which can be implicitly captured in statistical models. Mosquito-dynamics, population specific information, and dengue-specific information correlated best with prediction accuracy.ConclusionWe conclude that with careful consideration and understanding of the relative advantages and disadvantages of particular methods, implementation of an effective prediction system is feasible. However, there is a need to improve the quality of the data in order to more accurately predict the course of epidemics.
Published: 2018

3. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Author: Ji, Sun-Gou, Juran, Brian D, Mucha, Sören, Folseraas, Trine, Jostins, Luke, Melum, Espen, Kumasaka, Natsuhiko, Atkinson, Elizabeth J, Schlicht, Erik M, Liu, Jimmy Z, Shah, Tejas, Gutierrez-Achury, Javier, Boberg, Kirsten M, Bergquist, Annika, Vermeire, Severine, Eksteen, Bertus, Durie, Peter R, Farkkila, Martti, Müller, Tobias, Schramm, Christoph, Sterneck, Martina, Weismüller, Tobias J, Gotthardt, Daniel N, Ellinghaus, David, Braun, Felix, Teufel, Andreas, Laudes, Mattias, Lieb, Wolfgang, Jacobs, Gunnar, Beuers, Ulrich, Weersma, Rinse K, Wijmenga, Cisca, Marschall, Hanns-Ulrich, Milkiewicz, Piotr, Pares, Albert, Kontula, Kimmo, Chazouillères, Olivier, Invernizzi, Pietro, Goode, Elizabeth, Spiess, Kelly, Moore, Carmel, Sambrook, Jennifer, Ouwehand, Willem H, Roberts, David J, Danesh, John, Floreani, Annarosa, Gulamhusein, Aliya F, Eaton, John E, Schreiber, Stefan, Coltescu, Catalina, Bowlus, Christopher L, Luketic, Velimir A, Odin, Joseph A, Chopra, Kapil B, Kowdley, Kris V, Chalasani, Naga, Manns, Michael P, Srivastava, Brijesh, Mells, George, Sandford, Richard N, Alexander, Graeme, Gaffney, Daniel J, Chapman, Roger W, Hirschfield, Gideon M, de Andrade, Mariza, Rushbrook, Simon M, Franke, Andre, Karlsen, Tom H, Lazaridis, Konstantinos N, and Anderson, Carl A
Subjects: Human Genome, Digestive Diseases, Autoimmune Disease, Digestive Diseases - (Gallbladder), Genetics, Rare Diseases, Inflammatory Bowel Disease, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Adaptor Proteins, Signal Transducing, Alleles, Cholangitis, Sclerosing, Colitis, Ulcerative, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, RNA, Messenger, Risk Factors, UK-PSC Consortium, International IBD Genetics Consortium, International PSC Study Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.
Published: 2017

4. Accelerated waning of the humoral response to COVID-19 vaccines in obesity

Author: van der Klaauw, Agatha A, Horner, Emily C, Pereyra-Gerber, Pehuén, Agrawal, Utkarsh, Foster, William S, Spencer, Sarah, Vergese, Bensi, Smith, Miriam, Henning, Elana, Ramsay, Isobel D, Smith, Jack A, Guillaume, Stephane M, Sharpe, Hayley J, Hay, Iain M, Thompson, Sam, Innocentin, Silvia, Booth, Lucy H, Robertson, Chris, McCowan, Colin, Kerr, Steven, Mulroney, Thomas E, O'Reilly, Martin J, Gurugama, Thevinya P, Gurugama, Lihinya P, Rust, Maria A, Ferreira, Alex, Ebrahimi, Soraya, Ceron-Gutierrez, Lourdes, Scotucci, Jacopo, Kronsteiner, Barbara, Dunachie, Susanna J, Klenerman, Paul, PITCH Consortium, Park, Adrian J, Rubino, Francesco, Lamikanra, Abigail A, Stark, Hannah, Kingston, Nathalie, Estcourt, Lise, Harvala, Heli, Roberts, David J, Doffinger, Rainer, Linterman, Michelle A, Matheson, Nicholas J, Sheikh, Aziz, Farooqi, I Sadaf, Thaventhiran, James ED, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Population and Behavioural Science Division, van der Klaauw, Agatha A [0000-0001-6971-8828], Horner, Emily C [0000-0003-2226-1028], Agrawal, Utkarsh [0000-0001-5181-6120], Foster, William S [0000-0002-7103-3657], Ramsay, Isobel D [0000-0002-9954-2023], Smith, Jack A [0000-0001-6654-5706], Guillaume, Stephane M [0000-0003-2007-4608], Sharpe, Hayley J [0000-0002-4723-298X], Hay, Iain M [0000-0002-5451-1768], McCowan, Colin [0000-0002-9466-833X], O'Reilly, Martin J [0000-0003-1095-0328], Ferreira, Alex [0000-0002-1964-1049], Kronsteiner, Barbara [0000-0003-0867-2867], Dunachie, Susanna J [0000-0001-5665-6293], Klenerman, Paul [0000-0003-4307-9161], Park, Adrian J [0000-0003-2713-7595], Linterman, Michelle A [0000-0001-6047-1996], Matheson, Nicholas J [0000-0002-3318-1851], Sheikh, Aziz [0000-0001-7022-3056], Farooqi, I Sadaf [0000-0001-7609-3504], Thaventhiran, James ED [0000-0001-8616-074X], and Apollo - University of Cambridge Repository
Subjects: MCC, COVID-19 Vaccines, SARS-CoV-2, Vaccination, COVID-19, DAS, Antibodies, Viral, Antibodies, Neutralizing, Obesity, Morbid, SDG 3 - Good Health and Well-being, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, Humans, Longitudinal Studies, Prospective Studies, Obesity
Abstract: Funding: EAVE II is funded by the Medical Research Council (MRC) (MC_PC_19075) with the support of BREATHE—The Health Data Research Hub for Respiratory Health (MC_PC_19004), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20058) and National Core Studies–Immunity. Additional support was provided through Public Health Scotland, the Scottish Government Director-General Health and Social Care and the University of Edinburgh. The SCORPIO study was supported by the MRC (MR/W020564/1, a core award to J.E.T.; MC_UU_0025/12 and MR/T032413/1, awards to N.J.M.) and the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798). Additional support was provided by NHS Blood and Transplant (WPA15-02 to N.J.M.), the Wellcome Trust (Institutional Strategic Support Fund 204845/Z/16/Z to N.J.M.), Addenbrooke’s Charitable Trust (900239 to N.J.M.) and the NIHR Cambridge Biomedical Research Centre and NIHR BioResource. M.A.L is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/B/000C0427 and BBS/E/B/000C0428) and is a Lister Institute Fellow and an EMBO Young Investigator. I.M.H. is supported by a Cambridge Institute for Medical Research PhD studentship. H.J.S. is supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (109407), and a BBSRC institutional program grant (BBS/E/B/000C0433). I.S.F. is supported by the Wellcome Trust (207462/Z/17/Z), the Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and an NIHR Senior Investigator Award. Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies. Publisher PDF
Published: 2023

5. Cost-effectiveness of alternative minimum recall intervals between whole blood donations

Author: Sadique, Zia, Willis, Sarah, Corte, Kaat De, Pennington, Mark, Moore, Carmel, Kaptoge, Stephen, Angelantonio, Emanuele Di, Miflin, Gail, Roberts, David J, Grieve, Richard, Sadique, Zia [0000-0001-5814-0258], Corte, Kaat De [0000-0002-4370-2606], and Apollo - University of Cambridge Repository
Subjects: Medicine and health sciences, Male, Multidisciplinary, Biology and life sciences, Cost-Benefit Analysis, FOS: Social sciences, Blood Donors, Social sciences, Research and analysis methods, Hemoglobins, Quality of Life, Humans, Female, People and places, Research Article
Abstract: Funder: National Institute for Health Research (NIHR), BACKGROUND: The INTERVAL trial showed shorter inter-donation intervals could safely increase the frequency of whole-blood donation. We extended the INTERVAL trial to consider the relative cost-effectiveness of reduced inter-donation intervals. METHODS: Our within-trial cost-effectiveness analysis (CEA) used data from 44,863 whole-blood donors randomly assigned to 12, 10 or 8 week (males), and 16, 14 or 12 week inter-donation intervals (females). The CEA analysed the number of whole-blood donations, deferrals including low- haemoglobin deferrals, and donors' health-related quality of life (QoL) to report costs and cost-effectiveness over two years. FINDINGS: The mean number of blood donation visits over two years was higher for the reduced interval strategies, for males (7.76, 6.60 and 5.68 average donations in the 8-, 10- and 12- week arms) and for females (5.10, 4.60 and 4.01 donations in the 12-, 14- and 16- week arms). For males, the average rate of deferral for low haemoglobin per session attended, was 5.71% (8- week arm), 3.73% (10- week), and 2.55% (12- week), and for females the rates were: 7.92% (12-week), 6.63% (14- week), and 5.05% (16- week). Donors' QoL was similar across strategies, although self-reported symptoms were increased with shorter donation intervals. The shorter interval strategies increased average cost, with incremental cost-effectiveness ratios of £9.51 (95% CI 9.33 to 9.69) per additional whole-blood donation for the 8- versus 12- week interval for males, and £10.17 (95% CI 9.80 to 10.54) for the 12- versus 16- week interval arm for females. CONCLUSIONS: Over two years, reducing the minimum donation interval could provide additional units of whole-blood at a small additional cost, including for those donor subgroups whose blood type is in relatively high demand. However, the significance of self-reported symptoms needs to be investigated further before these policies are expanded.
Published: 2022
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6. Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

Author: Bomba, Lorenzo, Walter, Klaudia, Guo, Qi, Surendran, Praveen, Kundu, Kousik, Nongmaithem, Suraj, Karim, Mohd Anisul, Stewart, Isobel D, Langenberg, Claudia, Danesh, John, Di Angelantonio, Emanuele, Roberts, David J, Ouwehand, Willem H, INTERVAL Study, Dunham, Ian, Butterworth, Adam S, Soranzo, Nicole, Langenberg, Claudia [0000-0002-5017-7344], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Whole Genome Sequencing, sequencing, endophenotypes, metabolomics, metabolon, loss-of-function, rare genetic variant, proteomics, Gene Frequency, drug targets, Exome Sequencing, WES, Humans, Exome, Prospective Studies, WGS
Abstract: Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.
Published: 2022
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7. Highly sensitive lineage discrimination of SARS-CoV-2 variants through allele-specific probe PCR

Author: Ratcliff, Jeremy, Al-Beidh, Farah, Bibi, Sagida, Bonsall, David, Costa Clemens, Sue Ann, Estcourt, Lise, Evans, Amy, Fish, Matthew, Folegatti, Pedro M, Gordon, Anthony C, Jay, Cecilia, Jennings, Aislinn, Laing, Emma, Lambe, Teresa, MacIntyre-Cockett, George, Menon, David, Mouncey, Paul R, Nguyen, Dung, Pollard, Andrew J, Ramasamy, Maheshi N, Roberts, David J, Rowan, Kathryn M, Rynne, Jennifer, Shankar-Hari, Manu, Williams, Sarah, Harvala, Heli, Golubchik, Tanya, Simmonds, Peter, AMPHEUS Project, REMAP-CAP Immunoglobulin Domain UK Investigators, NIHR, Ratcliff, Jeremy [0000-0001-6522-138X], Bonsall, David [0000-0003-2187-0550], Jay, Cecilia [0000-0003-2387-9225], Shankar-Hari, Manu [0000-0002-5338-2538], Golubchik, Tanya [0000-0003-2765-9828], Simmonds, Peter [0000-0002-7964-4700], Apollo - University of Cambridge Repository, Project, AMPHEUS, Investigators, REMAP-CAP Immunoglobulin Domain UK, and Group, Oxford COVID-19 Vaccine Trial
Subjects: Microbiology (medical), allele-specific probe PCR, SARS-CoV-2, viruses, COVID-19, AMPHEUS Project, REMAP-CAP Immunoglobulin Domain UK Investigators, and Oxford COVID-19 Vaccine Trial Group, 06 Biological Sciences, variants of concern, Polymerase Chain Reaction, Microbiology, 07 Agricultural and Veterinary Sciences, diagnostics, Humans, next-generation sequencing, variant identification, Alleles, 11 Medical and Health Sciences
Abstract: Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.
Published: 2022

8. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Author: Chen, Lingyan, Peters, James E, Prins, Bram, Persyn, Elodie, Traylor, Matthew, Surendran, Praveen, Karthikeyan, Savita, Yonova-Doing, Ekaterina, Di Angelantonio, Emanuele, Roberts, David J, Watkins, Nicholas A, Ouwehand, Willem H, Danesh, John, Lewis, Cathryn M, Bronson, Paola G, Markus, Hugh S, Burgess, Stephen, Butterworth, Adam S, Howson, Joanna MM, Chen, Lingyan [0000-0003-3750-6761], Peters, James E [0000-0002-9415-3440], Prins, Bram [0000-0001-5774-034X], Persyn, Elodie [0000-0001-9104-1972], Ouwehand, Willem H [0000-0002-7744-1790], Lewis, Cathryn M [0000-0002-8249-8476], Bronson, Paola G [0000-0001-9996-9812], Burgess, Stephen [0000-0001-5365-8760], Butterworth, Adam S [0000-0002-6915-9015], Howson, Joanna MM [0000-0001-7618-0050], and Apollo - University of Cambridge Repository
Subjects: Multidisciplinary, 631/208/2489/144, 45, Proteome, 45/43, article, General Physics and Astronomy, General Chemistry, Blood Proteins, Mendelian Randomization Analysis, 692/699/75, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Stroke, Diabetes Mellitus, Type 2, Risk Factors, Atrial Fibrillation, Humans, Genetic Predisposition to Disease, 692/499, Genome-Wide Association Study
Abstract: Funder: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.
Published: 2021

9. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author: Writing Committee for the REMAP-CAP Investigators, Estcourt, Lise J, Turgeon, Alexis F, McQuilten, Zoe K, McVerry, Bryan J, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Arnold, Donald M, Beane, Abigail, Bégin, Philippe, van Bentum-Puijk, Wilma, Berry, Lindsay R, Bhimani, Zahra, Birchall, Janet E, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Callum, Jeannie L, Chassé, Michaël, Cheng, Allen C, Cove, Matthew E, Daly, James, Derde, Lennie, Detry, Michelle A, De Jong, Menno, Evans, Amy, Fergusson, Dean A, Fish, Matthew, Fitzgerald, Mark, Foley, Claire, Goossens, Herman, Gordon, Anthony C, Gosbell, Iain B, Green, Cameron, Haniffa, Rashan, Harvala, Heli, Higgins, Alisa M, Hills, Thomas E, Hoad, Veronica C, Horvat, Christopher, Huang, David T, Hudson, Cara L, Ichihara, Nao, Laing, Emma, Lamikanra, Abigail A, Lamontagne, François, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, MacLennan, Sheila, Marshall, John, McAuley, Daniel F, McDyer, John F, McGlothlin, Anna, McGuinness, Shay, Miflin, Gail, Montgomery, Stephanie, Mouncey, Paul R, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane C, Priddee, Nicole, Purcell, Damian FJ, Reyes, Luis F, Richardson, Peter, Robitaille, Nancy, Rowan, Kathryn M, Rynne, Jennifer, Saito, Hiroki, Santos, Marlene, Saunders, Christina T, Serpa Neto, Ary, Seymour, Christopher W, Silversides, Jon A, Tinmouth, Alan A, Triulzi, Darrell J, Turner, Anne M, van de Veerdonk, Frank, Walsh, Timothy S, Wood, Erica M, Berry, Scott, Lewis, Roger J, Menon, David K, McArthur, Colin, Zarychanski, Ryan, Angus, Derek C, Webb, Steve A, Roberts, David J, Shankar-Hari, Manu, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Investigators, Writing Committee for the REMAP-CAP, Writing Comm REMAP-CAP Investigators, Hôpital Raymond Poincaré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Institutes of Health, NIH, National Institute of Child Health and Human Development, NICHD, Pittsburgh Foundation, Breast Cancer Research Foundation, BCRF, Bristol-Myers Squibb, BMS, GlaxoSmithKline, GSK, Medtronic, Baxter International, Manitoba Medical Service Foundation, MMSF, CancerCare Manitoba Foundation, CCMF, Wellcome Trust, WT, University of Manitoba, UM, Health Research Board, HRB: PHRC-20-0147, National Blood Authority, NBA, Llywodraeth Cymru, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, CTN 2014-012, Medical Research Council, MRC, National Institute for Health Research, NIHR, Department of Health and Social Care, DH, European Commission, EC: APP194811, National Heart and Lung Institute, NHLI, National Health and Medical Research Council, NHMRC: 2015-06-18, 2016-16-011, APP1101719, APP2002132, Health Research Council of New Zealand, HRC: 16/631, 447335, Monash University, MU, Ministère des Affaires Sociales et de la Santé: 215522, Seventh Framework Programme, FP7, Université Pierre et Marie Curie, UPMC, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Minderoo Foundation, Dr Fitzgerald reported receiving grants from the PREPARE Network and the European Commission. Dr Gordon reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. Dr Gosbell reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Haniffa reported receiving grants from the Wellcome Trust Innovations Project, the Minderoo Foundation, and the UK Research and Innovation African Critical Care Registry Network. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the National Blood Authority. Dr Hills reported receiving grants from the Health Research Council of New Zealand. Dr Hoad reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development. Dr Huang reported receiving grants from the Breast Cancer Research Foundation. Dr Lamontagne reported receiving grants from the Canadian Institutes of Health Research. Dr Lawler reported receiving consulting fees from Novartis, Coronna LLC, and Brigham and Women’s Hospital, receiving royalties from McGraw-Hill Publishing, and receiving grants from the Canadian Institutes of Health Research, the LifeArc Foundation, the National Institutes of Health, the Peter Munk Cardiac Centre, the Ted Rogers Centre for Heart Research, the Thistledown Foundation, and the province of Ontario. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Marshall reported receiving personal fees from AM-Pharma (data and safety monitoring board chair) and Critical Care Medicine (associate editor). Dr McAuley reported receiving personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Faron Pharmaceuticals, and Sobi, receiving grants from the National Institute for Health Research, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, and holding a patent for an anti-inflammatory treatment that was issued to Queen’s University Belfast. Dr McGlothlin reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Mr Mouncey reported receiving grants from the European Union, the PREPARE Network, the National Institute for Health Research, and European Union Horizon 2020. Dr Nichol reported receiving grants from the Health Research Board of Ireland and Baxter and receiving personal fees from AM-Pharma. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Ms Parker reported receiving grants from Monash University. Mr Richardson reported receiving funding from the Welsh government. Dr Rowan reported receiving grants from the European Commission and the National Institute for Health Research. Dr Saunders reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Dr Serpa Neto reported receiving personal fees from Drager and Endpoint Health. Dr Tinmouth reported receiving grants and personal fees from the Canadian Blood Services. Ms Turner reported receiving grants from the Health Research Council of New Zealand. Dr van de Veerdonk reported receiving personal fees from Gilead, Sobi, and GlaxoSmithKline. Dr Wood reported receiving grants from the Australian Medical Research Future Fund. Dr S. Berry reported being an employee of Berry Consultants with an ownership role. Dr Lewis reported being an employee of Berry Consultants. Dr Menon reported receiving grants from the National Institute for Health Research. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Zarychanski reported receiving grants from the Canadian Institutes of Health Research, the University of Manitoba, LifeArc, the Thistledown Foundation, Research Manitoba, the CancerCare Manitoba Foundation, the Victoria General Hospital Foundation, the Peter Munk Cardiac Centre, and the Manitoba Medical Services Foundation. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Shankar-Hari reported receiving grants from the National Institute for Clinical Research. No other disclosures were reported., nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor), Utrecht Medical Center, Utrecht, the Netherlands (European sponsor), St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor), and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). This study was additionally funded by grant 602525 FP7-health-2013-innovation-1 from the European Union Platform for European Preparedness Against Reemerging Epidemics, grants APP1101719 and APP1116530 from the Australian National Health and Medical Research Council, grant APP2002132 from the Australian Medical Research Future Fund, grant 16/631 from the New Zealand Health Research Council, grant 447335 from the Canadian Institutes of Health Research COVID-19 Rapid Research, grant 158584 from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, grant CTN 2014-012 from the Health Research Board of Ireland, grant PHRC-20-0147 from the French Ministry of Health, and grant 215522 from the Wellcome Trust Innovations Project and funding from the National Institute for Health Research, the Department of Health and Social Care, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the National Institute for Health Research, the National Institute for Health Research Imperial Biomedical Research Centre, the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the Pittsburgh Foundation, and the Minderoo Foundation. The Australian government funds the Australian Red Cross Lifeblood for the provision of blood products and services. The collection of plasma in the United Kingdom was funded by European Union SoHo grants from the Department of Health and Social Care. Dr Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Dr McQuilten is supported by emerging leader fellowship APP194811 from the National Health and Medical Research Council. Dr Gordon is funded by research professorship 2015-06-18 from the National Institute for Health Research. Dr Shankar-Hari is funded by clinician scientist fellowship 2016-16-011 from the National Institute for Health Research., In Canada, the trial has been funded by the Canadian Institute of Health Research, Strategy for Patient-Oriented Research (CIHR-SPOR) Innovative Clinical Trials Program Grant (no. 158584) for CAD $1,497,200, for the recruitment of 300 patients., The Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium is funded by the European Union (FP7-HEALTH-2013-INNOVATION-1, grant number 602525). Within the PREPARE consortium, the trial has funding for the recruitment of approximately 4000 patients., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands (RCC-Net)., Funding sources for the REMAP-CAP trial are specified in the core protocol documents. This domain has received domain-specific funding from the Australian Medical Research Future Fund (MRFF)., reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. Dr Turgeon reported receiving grants from the Canadian Institutes of Health Research. Dr McQuilten reported receiving grants from the Australian Medical Research Future Fund. Dr McVerry reported receiving grants from the Pittsburgh Foundation, the Translational Breast Cancer Research Consortium, UPMC Learning While Doing Program, National Heart, Lung, and Blood Institute, and Bayer Pharmaceuticals and receiving personal fees from Boehringer Ingelheim. Dr Annane reported receiving grants from the French Ministry of Health and Solidarity. Dr Arnold reported receiving grants from the Canadian Institutes of Health Research. Ms Beane reported receiving grants and salary support from Wellcome Trust. Ms Bentum-Puijk reported receiving grants from the European Commission and the European Union. Dr L. Berry reported receiving grants from Berry Consultants. Dr Bradbury reported receiving personal fees from Lilly, Bristol Myers Squibb, Pfizer, Bayer, Amgen, Novartis, Janssen, Portola Advisors, and Ablynx. Dr Buxton reported receiving personal fees from the Breast Cancer Research Foundation, Amgen, and Eisai. Dr Callum reported receiving grants from the Canadian Blood Services and Octapharma. Dr Cove reported receiving grants from National University Health System, receiving consulting fees from Medtronic and Baxter, and holding a US patent for removal of carbon dioxide via dialysis. Dr Daly reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Derde reported receiving grants from University Medical Center Utrecht, being a member of the COVID-19 guideline committee of the Surviving Sepsis Campaign/ European Society of Intensive Care Medicine and European Society of Intensive Care Medicine COVID-19 taskforce, and serving as chair of the Dutch intensivists taskforce acute infectious threats. Dr Detry reported receiving grants from the European Union Platform for European Preparedness Against Reemerging Epidemics (PREPARE) consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the UPMC Learning While Doing Program. Dr De Jong reported receiving personal fees from Roche Scientific, Shionogi Scientific, and Janssen., The current regions are: x Europe, with funding from a European Union FP7 grant (FP7-HEALTH-2013-INNOVATION-1, grant number 602525), to support the enrollment of 4000 participants. This funding terminates in 2021. x Australia and New Zealand. In Australia the project has received funding from a NHMRC Project Grant (APP1101719), to support the enrollment of 2000 participants. This funding terminates in December 2021, although some extension may be feasible. In New Zealand the project has received funding from a HRC Programme Grant (16/631), to support the enrollment of 800 participants. This funding terminates in November 2021. x Canada. In Canada the project has received funding for a CIHR grant (158584), to support the enrollment of 300 participants. This funding terminates in 2022. x United States. In the US, funding has been received from UPMC health system for recruitment internally at all UPMC hospitals (>40) and to support a US regional coordinating center. Philanthropic support is being provided through GCAR. Additional funds are being pursued., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Trials Group, the Irish Critical Care, European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Medical Microbiology and Infection Prevention, AII - Infectious diseases, and Intensive Care Medicine
Subjects: Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Critical Illness/therapy, Vasoconstrictor Agents, 030212 general & internal medicine, Hospital Mortality, Treatment Failure, 11 Medical and Health Sciences, Original Investigation, Mortality rate, General Medicine, Middle Aged, Intensive care unit, Writing Committee for the REMAP-CAP Investigators, 3. Good health, Female, Life Sciences & Biomedicine, COVID-19/therapy, Adult, medicine.medical_specialty, Randomization, Respiration, Artificial/statistics & numerical data, Critical Illness, ABO Blood-Group System, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, medicine, Humans, Adverse effect, COVID-19 Serotherapy, Aged, Mechanical ventilation, Science & Technology, business.industry, Immunization, Passive, Vasoconstrictor Agents/therapeutic use, COVID-19, Odds ratio, Length of Stay, Respiration, Artificial, Logistic Models, Human medicine, business
Abstract: Importance The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.Objective To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.Design, Setting, and Participants The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.Interventions The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).Main Outcomes and Measures The primary ordinal end point was organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned –1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support–free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support–free days; cardiovascular support–free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.Results Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support–free days was 0 (IQR, –1 to 16) in the convalescent plasma group and 3 (IQR, –1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR Conclusions and Relevance Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days.Trial Registration ClinicalTrials.gov Identifier: NCT02735707
Published: 2021
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10. Comparison of four methods to measure haemoglobin concentrations in whole blood donors (COMPARE): A diagnostic accuracy study

Author: Bell, Steven, Sweeting, Michael, Ramond, Anna, Chung, Ryan, Kaptoge, Stephen, Walker, Matthew, Bolton, Thomas, Sambrook, Jennifer, Moore, Carmel, McMahon, Amy, Fahle, Sarah, Cullen, Donna, Mehenny, Susan, Wood, Angela M, Armitage, Jane, Ouwehand, Willem H, Miflin, Gail, Roberts, David J, Danesh, John, Di Angelantonio, Emanuele, COMPARE Study Group, Bell, Steven [0000-0001-6774-3149], Sweeting, Michael [0000-0003-0980-8965], Ramond, Anna [0000-0002-9958-3693], Fahle, Sarah [0000-0002-4359-9952], Wood, Angela M [0000-0002-7937-304X], Armitage, Jane [0000-0001-8691-9226], Ouwehand, Willem H [0000-0002-7744-1790], Di Angelantonio, Emanuele [0000-0001-8776-6719], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Adolescent, haemoglobin screening, Blood Donors, gravimetry, inappropriate bleeding, Sensitivity and Specificity, Donor Selection, Hemoglobins, Young Adult, HemoCue, Humans, non-invasive haemoglobin measurement, Aged, Aged, 80 and over, inappropriate deferral, Cross-Over Studies, Anemia, Middle Aged, Reference Standards, Spectrophotometry, whole blood donor, Hemoglobinometry, Female, Biomarkers
Abstract: OBJECTIVE: To compare four haemoglobin measurement methods in whole blood donors. BACKGROUND: To safeguard donors, blood services measure haemoglobin concentration in advance of each donation. NHS Blood and Transplant's (NHSBT) customary method have been capillary gravimetry (copper sulphate), followed by venous spectrophotometry (HemoCue) for donors failing gravimetry. However, NHSBT's customary method results in 10% of donors being inappropriately bled (ie, with haemoglobin values below the regulatory threshold). METHODS: We compared the following four methods in 21 840 blood donors (aged ≥18 years) recruited from 10 NHSBT centres in England, with the Sysmex XN-2000 haematology analyser, the reference standard: (1) NHSBT's customary method; (2) "post donation" approach, that is, estimating current haemoglobin concentration from that measured by a haematology analyser at a donor's most recent prior donation; (3) "portable haemoglobinometry" (using capillary HemoCue); (4) non-invasive spectrometry (using MBR Haemospect or Orsense NMB200). We assessed sensitivity; specificity; proportion who would have been inappropriately bled, or rejected from donation ("deferred") incorrectly; and test preference. RESULTS: Compared with the reference standard, the methods ranged in test sensitivity from 17.0% (MBR Haemospect) to 79.0% (portable haemoglobinometry) in men, and from 19.0% (MBR Haemospect) to 82.8% (portable haemoglobinometry) in women. For specificity, the methods ranged from 87.2% (MBR Haemospect) to 99.9% (NHSBT's customary method) in men, and from 74.1% (Orsense NMB200) to 99.8% (NHSBT's customary method) in women. The proportion of donors who would have been inappropriately bled ranged from 2.2% in men for portable haemoglobinometry to 18.9% in women for MBR Haemospect. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% in men for NHSBT's customary method to 20.3% in women for OrSense. Most donors preferred non-invasive spectrometry. CONCLUSION: In the largest study reporting head-to-head comparisons of four methods to measure haemoglobin prior to blood donation, our results support replacement of NHSBT's customary method with portable haemoglobinometry.
Published: 2021
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11. Time-to-death is a potential confounder in observational studies of blood transfusion in severe malaria

Author: Watson, James A, Leopold, Stije J, Dondorp, Arjen M, White, Nicholas J, Ackerman, Hans, Olola, Christopher HO, Krishna, Sanjeev, Roberts, David J, Kremsner, Peter G, Newton, Charles R, Taylor, Terrie, Valim, Clarissa, and Casals-Pascual, Climent
Subjects: medicine.medical_specialty, Blood transfusion, business.industry, medicine.medical_treatment, Hematology, Time to death, Article, Hospitals, Malaria, Medicine, Potential confounder, Humans, Severe Malaria, Observational study, Blood Transfusion, Prospective Studies, Malaria, Falciparum, business, Intensive care medicine, Child
Published: 2020

12. Accuracy of UK Rapid Test Consortium (UK-RTC) 'AbC-19 Rapid Test' for detection of previous SARS-CoV-2 infection in key workers: test accuracy study

Author: Mulchandani, Ranya, Jones, Hayley E, Taylor-Phillips, Sian, Shute, Justin, Perry, Keith, Jamarani, Shabnam, Brooks, Tim, Charlett, Andre, Hickman, Matthew, Oliver, Isabel, Kaptoge, Stephen, Danesh, John, Di Angelantonio, Emanuele, Ades, Anthony E, Wyllie, David H, Armitage, Jane, Borrow, Ray, Boyes, John, Cullen, Donna, Hormis, Anil, Linley, Ezra, Mehenny, Susan, Miflin, Gail, Moore, Carmel, Moore, Philippa, Reckless, Ian, Roberts, David J, Sambrook, Jennifer, and Todd, Neil
Subjects: Male, medicine.medical_specialty, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Health Personnel, Population, Pneumonia, Viral, serology, 030204 cardiovascular system & hematology, Sensitivity and Specificity, Serology, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, COVID-19 Testing, Predictive Value of Tests, Internal medicine, False positive paradox, medicine, Humans, 030212 general & internal medicine, education, Pandemics, Immunoassay, education.field_of_study, medicine.diagnostic_test, business.industry, Clinical Laboratory Techniques, SARS-CoV-2, Research, lateral flow immunoassay, COVID-19, Covid19, General Medicine, test accuracy, Confidence interval, Police, United Kingdom, Test (assessment), Predictive value of tests, Firefighters, Female, Reagent Kits, Diagnostic, business, Coronavirus Infections
Abstract: Objective To assess the accuracy of the AbC-19 Rapid Test lateral flow immunoassay for the detection of previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design Test accuracy study. Setting Laboratory based evaluation. Participants 2847 key workers (healthcare staff, fire and rescue officers, and police officers) in England in June 2020 (268 with a previous polymerase chain reaction (PCR) positive result (median 63 days previously), 2579 with unknown previous infection status); and 1995 pre-pandemic blood donors. Main outcome measures AbC-19 sensitivity and specificity, estimated using known negative (pre-pandemic) and known positive (PCR confirmed) samples as reference standards and secondly using the Roche Elecsys anti-nucleoprotein assay, a highly sensitive laboratory immunoassay, as a reference standard in samples from key workers. Results Test result bands were often weak, with positive/negative discordance by three trained laboratory staff for 3.9% of devices. Using consensus readings, for known positive and negative samples sensitivity was 92.5% (95% confidence interval 88.8% to 95.1%) and specificity was 97.9% (97.2% to 98.4%). Using an immunoassay reference standard, sensitivity was 94.2% (90.7% to 96.5%) among PCR confirmed cases but 84.7% (80.6% to 88.1%) among other people with antibodies. This is consistent with AbC-19 being more sensitive when antibody concentrations are higher, as people with PCR confirmation tended to have more severe disease whereas only 62% (218/354) of seropositive participants had had symptoms. If 1 million key workers were tested with AbC-19 and 10% had actually been previously infected, 84 700 true positive and 18 900 false positive results would be projected. The probability that a positive result was correct would be 81.7% (76.8% to 85.8%). Conclusions AbC-19 sensitivity was lower among unselected populations than among PCR confirmed cases of SARS-CoV-2, highlighting the scope for overestimation of assay performance in studies involving only PCR confirmed cases, owing to “spectrum bias.” Assuming that 10% of the tested population have had SARS-CoV-2 infection, around one in five key workers testing positive with AbC-19 would be false positives. Study registration ISRCTN 56609224.
Published: 2020
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13. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Vuckovic, Dragana, Bao, Erik L, Akbari, Parsa, Lareau, Caleb A, Mousas, Abdou, Jiang, Tao, Chen, Ming-Huei, Raffield, Laura M, Tardaguila, Manuel, Huffman, Jennifer E, Ritchie, Scott C, Megy, Karyn, Ponstingl, Hannes, Penkett, Christopher J, Albers, Patrick K, Wigdor, Emilie M, Sakaue, Saori, Moscati, Arden, Manansala, Regina, Lo, Ken Sin, Qian, Huijun, Akiyama, Masato, Bartz, Traci M, Ben-Shlomo, Yoav, Beswick, Andrew, Bork-Jensen, Jette, Bottinger, Erwin P, Brody, Jennifer A, Van Rooij, Frank JA, Chitrala, Kumaraswamy N, Wilson, Peter WF, Choquet, Hélène, Danesh, John, Di Angelantonio, Emanuele, Dimou, Niki, Ding, Jingzhong, Elliott, Paul, Esko, Tõnu, Evans, Michele K, Felix, Stephan B, Floyd, James S, Broer, Linda, Grarup, Niels, Guo, Michael H, Guo, Qi, Greinacher, Andreas, Haessler, Jeff, Hansen, Torben, Howson, Joanna MM, Huang, Wei, Jorgenson, Eric, Kacprowski, Tim, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Karthikeyan, Savita, Koskeridis, Fotios, Lange, Leslie A, Lehtimäki, Terho, Linneberg, Allan, Liu, Yongmei, Lyytikäinen, Leo-Pekka, Manichaikul, Ani, Matsuda, Koichi, Mohlke, Karen L, Mononen, Nina, Murakami, Yoshinori, Nadkarni, Girish N, Nikus, Kjell, Pankratz, Nathan, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M, Raitakari, Olli T, Rich, Stephen S, Rodriguez, Benjamin AT, Rosen, Jonathan D, Rotter, Jerome I, Schubert, Petra, Spracklen, Cassandra N, Surendran, Praveen, Tang, Hua, Tardif, Jean-Claude, Ghanbari, Mohsen, Völker, Uwe, Völzke, Henry, Watkins, Nicholas A, Weiss, Stefan, VA Million Veteran Program, Cai, Na, Kundu, Kousik, Watt, Stephen B, Walter, Klaudia, Zonderman, Alan B, Cho, Kelly, Li, Yun, Loos, Ruth JF, Knight, Julian C, Georges, Michel, Stegle, Oliver, Evangelou, Evangelos, Okada, Yukinori, Roberts, David J, Inouye, Michael, Johnson, Andrew D, Auer, Paul L, Astle, William J, Reiner, Alexander P, Butterworth, Adam S, Ouwehand, Willem H, Lettre, Guillaume, Sankaran, Vijay G, Soranzo, Nicole, Ritchie, Scott [0000-0002-8454-9548], Megy, Karyn [0000-0002-2826-3879], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Kundu, Kousik [0000-0002-1019-8351], Inouye, Michael [0000-0001-9413-6520], Astle, William [0000-0001-8866-6672], Butterworth, Adam [0000-0002-6915-9015], Ouwehand, Willem [0000-0002-7744-1790], Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository
Subjects: Male, UK Biobank, Multifactorial Inheritance, polygenic risk, rare disease, Polymorphism, Single Nucleotide, hematopoiesis, splicing, Phenotype, fine-mapping, blood, chromatin, Humans, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, omnigenic, Genome-Wide Association Study
Abstract: Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
Published: 2020
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14. Optimal individualized decision rules from a multi-arm trial: A comparison of methods and an application to tailoring inter-donation intervals among blood donors in the UK

Author: Xu, Yuejia, Wood, Angela M, Sweeting, Michael J, Roberts, David J, Tom, Brian Dm, Xu, Yuejia [0000-0002-8263-7018], and Apollo - University of Cambridge Repository
Subjects: Male, Time Factors, England, Precision medicine, multi-arm trial, blood donation, Humans, utility function, Blood Donors, individualized treatment rule, United Kingdom
Abstract: There is a growing interest in precision medicine where individual heterogeneity is incorporated into decision-making and treatments are tailored to individuals to provide better healthcare. One important aspect of precision medicine is the estimation of the optimal individualized treatment rule (ITR) that optimizes the expected outcome. Most methods developed for this purpose are restricted to the setting with two treatments, while clinical studies with more than two treatments are common in practice. In this work, we summarize methods to estimate the optimal ITR in the multi-arm setting and compare their performance in large-scale clinical trials via simulation studies. We then illustrate their utilities with a case study using the data from the INTERVAL trial, which randomly assigned over 20,000 male blood donors from England to one of the three inter-donation intervals (12-week, 10-week, and eight-week) over two years. We estimate the optimal individualized donation strategies under three different objectives. Our findings are fairly consistent across five different approaches that are applied: when we target the maximization of the total units of blood collected, almost all donors are assigned to the eight-week inter-donation interval, whereas if we aim at minimizing the low hemoglobin deferral rates, almost all donors are assigned to donate every 12 weeks. However, when the goal is to maximize the utility score that "discounts" the total units of blood collected by the incidences of low hemoglobin deferrals, we observe some heterogeneity in the optimal inter-donation interval across donors and the optimal donor assignment strategy is highly dependent on the trade-off parameter in the utility function.
Published: 2020

15. Development and validation of a universal blood donor genotyping platform: a multinational prospective study

Author: Gleadall, Nicholas S, Veldhuisen, Barbera, Gollub, Jeremy, Butterworth, Adam S, Ord, John, Penkett, Christopher J, Timmer, Tiffany C, Sauer, Carolin M, Van Der Bolt, Nieke, Brown, Colin, Brugger, Kim, Dilthey, Alexander T, Duarte, Daniel, Grimsley, Shane, Van Den Hurk, Katja, Jongerius, John M, Luken, Jessie, Megy, Karyn, Miflin, Gail, Nelson, Christopher S, Prinsze, Femmeke J, Sambrook, Jennifer, Simeoni, Ilenia, Sweeting, Michael, Thornton, Nicole, Trompeter, Sara, Tuna, Salih, Varma, Ram, Walker, Matthew R, NIHR BioResource, Danesh, John, Roberts, David J, Ouwehand, Willem H, Stirrups, Kathleen E, Rendon, Augusto, Westhoff, Connie M, Di Angelantonio, Emanuele, Van Der Schoot, C Ellen, Astle, William J, Watkins, Nicholas A, Lane, William J, Butterworth, Adam [0000-0002-6915-9015], Sauer, Carolin [0000-0003-2168-6630], Megy, Karyn [0000-0002-2826-3879], Danesh, John [0000-0003-1158-6791], Ouwehand, Willem [0000-0002-7744-1790], Johnson, Kathleen [0000-0002-6823-3252], Rendon Restrepo, Augusto [0000-0001-8994-0039], Di Angelantonio, Emanuele [0000-0001-8776-6719], Astle, William [0000-0001-8866-6672], and Apollo - University of Cambridge Repository
Subjects: Genotype, Isoantibodies, Humans, Blood Donors, Blood Transfusion, Prospective Studies
Abstract: Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.
Published: 2020

16. January 2020: What lies ahead?

Author: Roberts, David J.
Subjects: 2019-20 coronavirus outbreak, Blood transfusion, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, Medicine, Humans, Blood Transfusion, Hematology, Periodicals as Topic, business, Virology
Published: 2020

17. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author: Petersen, Romina, Lambourne, John J., Javierre, Biola M., Grassi, Luigi, Kreuzhuber, Roman, Ruklisa, Dace, Rosa, Isabel M., Tomé, Ana R., Elding, Heather, van Geffen, Johanna P., Jiang, Tao, Farrow, Samantha, Cairns, Jonathan, Al-Subaie, Abeer M., Ashford, Sofie, Attwood, Antony, Batista, Joana, Bouman, Heleen, Burden, Frances, Choudry, Fizzah A., Clarke, Laura, Flicek, Paul, Garner, Stephen F., Haimel, Matthias, Kempster, Carly, Ladopoulos, Vasileios, Lenaerts, An-Sofie, Materek, Paulina M., McKinney, Harriet, Meacham, Stuart, Mead, Daniel, Nagy, Magdolna, Penkett, Christopher J., Rendon, Augusto, Seyres, Denis, Sun, Benjamin, Tuna, Salih, van der Weide, Marie-Elise, Wingett, Steven W., Martens, Joost H., Stegle, Oliver, Richardson, Sylvia, Vallier, Ludovic, Roberts, David J., Freson, Kathleen, Wernisch, Lorenz, Stunnenberg, Hendrik G., Danesh, John, Fraser, Peter, Soranzo, Nicole, Butterworth, Adam S., Heemskerk, Johan W., Turro, Ernest, Spivakov, Mikhail, Ouwehand, Willem H., Astle, William J., Downes, Kate, Kostadima, Myrto, Frontini, Mattia, Lambourne, John [0000-0003-2460-0759], Grassi, Luigi [0000-0002-6308-7540], Haimel, Matthias [0000-0002-0320-0214], Rendon Restrepo, Augusto [0000-0001-8994-0039], Seyres, Denis [0000-0002-2066-6980], Sun, Ben [0000-0001-6347-2281], Tuna, Salih [0000-0003-3606-4367], Richardson, Sylvia [0000-0003-1998-492X], Vallier, Ludovic [0000-0002-3848-2602], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Butterworth, Adam [0000-0002-6915-9015], Turro Bassols, Ernest [0000-0002-1820-6563], Ouwehand, Willem [0000-0002-7744-1790], Astle, William [0000-0001-8866-6672], Downes, Kate [0000-0003-0366-1579], Frontini, Mattia [0000-0001-8074-6299], Apollo - University of Cambridge Repository, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, and Biochemie
Subjects: Blood Platelets, GENE-REGULATION, BLOOD, Erythroblasts, Science, Genetic Variation, OPEN CHROMATIN, DISEASE, Article, Chromatin, DNA-BINDING PROTEINS, THROMBUS FORMATION, GENOME, HUMAN CELL-TYPES, SEQ, Enhancer Elements, Genetic, TRAIT LOCI, Humans, Promoter Regions, Genetic, Megakaryocytes
Abstract: Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions., Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.
Published: 2017

18. Life in times of<scp>COVID</scp>‐19

Author: Roberts, David J.
Subjects: 2019-20 coronavirus outbreak, biology, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, COVID-19, Hematology, biology.organism_classification, Virology, Betacoronavirus, Pandemic, Hong Kong, Humans, Medicine, Coronavirus Infections, business, Pandemics
Published: 2020
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19. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author: Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Martins, Jade, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Christa Meisinger, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mikaelsdottir, Evgenia K., Milaneschi, Yuri, Miliku, Kozeta, Mishra, Pashupati P., Veteran Program, V. A. Million, Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., Nadkarni, Girish N, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, ilja M., Noordam, Raymond, O’Connell, Jeffrey, O’Donoghue, Michelle L., Olafsson, Isleifur, Oldehinkel, Albertine J., Orho-Melander, Marju, Ouwehand, Willem H., Padmanabhan, Sandosh, Palmer, Nicholette D., Palsson, Runolfur, Penninx, Brenda W. J. H., Perls, Thomas, Perola, Markus, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Podgornaia, Anna I., Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Pramstaller, Peter P., Preuss, Michael H., Prins, Bram P., Province, Michael A., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Ridker, Paul M., Rivadeneira, Fernando, Rizzi, Federica, Roberts, David J., Robino, Antonietta, Rossing, Peter, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Sabanayagam, Charumathi, Salomaa, Veikko, Salvi, Erika, Saum, Kai-Uwe, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Schupf, Nicole, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Smith, Blair H., Soranzo, Nicole, Spracklen, Cassandra N., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Svensson, Per O., Szymczak, Silke, Tai, E-Shyong, Tajuddin, Salman M., Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorleifsson, Gudmar, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Tzoulaki, Ioanna, Uitterlinden, André G., Vaccargiu, Simona, van Dam, Rob M., van der Harst, Pim, van Duijn, Cornelia M., Velez Edward, Digna R., Verweij, Niek, Vogelezang, suzanne, Völker, üwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Wallentin, Lars, Wang, Ya Xing, Wang, Chaolong, Waterworth, Dawn M., Bin Wei, Wen, White, Harvey, Whitfield, John B., Wild, Sarah H., Wilson, James F., Wojczynski, Mary K., Wong, Charlene, Wong, Tien-Yin, Xu, Liang, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Weihua, Zonderman, Alan B., Rotter, Jerome I., Bochud, Murielle, Psaty, Bruce M., Vitart, Veronique, Wilson, James G., Dehghan, Abbas, Parsa, Afshin, Chasman, Daniel I., Ho, Kevin, Morris, Andrew P., Devuyst, Olivier, Akilesh, Shreeram, Pendergrass, Sarah A., Sim, Xueling, Böger, Carsten A., Okada, Yukinori, Edwards, Todd L., Snieder, Harold, Stefansson, Kari, Hung, Adriana M., Heid, Iris M., Markus Scholz, Teumer, Alexander, Köttgen, Anna, Pattaro, Cristian, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Internal Medicine, Epidemiology, Erasmus MC other, Pediatrics, Psychiatry, APH - Mental Health, APH - Digital Health, Wuttke, M, Li, Y, Li, M, Sieber, Kb, Feitosa, Mf, Gorski, M, Tin, A, Wang, L, Chu, Ay, Hoppmann, A, Kirsten, H, Giri, A, Chai, Jf, Sveinbjornsson, G, Tayo, Bo, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, Pj, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, T, Almgren, P, Amin, N, Ärnlöv, J, Bakker, Sjl, Bansal, N, Baptista, D, Bergmann, S, Biggs, Ml, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, Ep, Boutin, T, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, A, Campana, Eric, Campbell, A, Campbell, H, Canouil, M, Carroll, Rj, Catamo, E, Chambers, Jc, Chee, Ml, Chen, X, Cheng, Cy, Cheng, Y, Christensen, K, Cifkova, R, Ciullo, M, Concas, Mp, Cook, Jp, Coresh, J, Corre, T, Sala, Cf, Cusi, D, Danesh, J, Daw, Ew, de Borst, Mh, De Grandi, A, de Mutsert, R, de Vries, Apj, Degenhardt, F, Delgado, G, Demirkan, A, Di Angelantonio, E, Dittrich, K, Divers, J, Dorajoo, R, Eckardt, Ku, Ehret, G, Elliott, P, Endlich, K, Evans, Mk, Felix, Jf, Foo, Vhx, Franco, Oh, Franke, A, Freedman, Bi, Freitag-Wolf, S, Friedlander, Y, Froguel, P, Gansevoort, Rt, Gao, H, Gasparini, P, Gaziano, Jm, Giedraitis, V, Gieger, C, Girotto, G, Giulianini, F, Gögele, M, Gordon, Sd, Gudbjartsson, Df, Gudnason, V, Haller, T, Hamet, P, Harris, Tb, Hartman, Ca, Hayward, C, Hellwege, Jn, Heng, Ck, Hicks, Aa, Hofer, E, Huang, W, Hutri-Kähönen, N, Hwang, Sj, Ikram, Ma, Indridason, O, Ingelsson, E, Ising, M, Jaddoe, Vwv, Jakobsdottir, J, Jonas, Jb, Joshi, Pk, Josyula, N, Jung, B, Kähönen, M, Kamatani, Y, Kammerer, Cm, Kanai, M, Kastarinen, M, Kerr, Sm, Khor, Cc, Kiess, W, Kleber, Me, Koenig, W, Kooner, J, Körner, A, Kovacs, P, Kraja, At, Krajcoviechova, A, Kramer, H, Krämer, Bk, Kronenberg, F, Kubo, M, Kühnel, B, Kuokkanen, M, Kuusisto, J, La Bianca, M, Laakso, M, Lange, La, Langefeld, Cd, Lee, Jj, Lehne, B, Lehtimäki, T, Lieb, W, Lifelines Cohort, Study, Lim, Sc, Lind, L, Lindgren, Cm, Liu, J, Loeffler, M, Loos, Rjf, Lucae, S, Lukas, Ma, Lyytikäinen, Lp, Mägi, R, Magnusson, Pke, Mahajan, A, Martin, Ng, Martins, J, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mikaelsdottir, Ek, Milaneschi, Y, Miliku, K, Mishra, Pp, V. A., Million Veteran Program, Mohlke, Kl, Mononen, N, Montgomery, Gw, Mook-Kanamori, Do, Mychaleckyj, Jc, Nadkarni, Gn, Nalls, Ma, Nauck, M, Nikus, K, Ning, B, Nolte, Im, Noordam, R, O'Connell, J, O'Donoghue, Ml, Olafsson, I, Oldehinkel, Aj, Orho-Melander, M, Ouwehand, Wh, Padmanabhan, S, Palmer, Nd, Palsson, R, Penninx, Bwjh, Perls, T, Perola, M, Pirastu, M, Pirastu, N, Pistis, G, Podgornaia, Ai, Polasek, O, Ponte, B, Porteous, Dj, Poulain, T, Pramstaller, Pp, Preuss, Mh, Prins, Bp, Province, Ma, Rabelink, Tj, Raffield, Lm, Raitakari, Ot, Reilly, Df, Rettig, R, Rheinberger, M, Rice, Km, Ridker, Pm, Rivadeneira, F, Rizzi, F, Roberts, Dj, Robino, A, Rossing, P, Rudan, I, Rueedi, R, Ruggiero, D, Ryan, Ka, Saba, Y, Sabanayagam, C, Salomaa, V, Salvi, E, Saum, Ku, Schmidt, H, Schmidt, R, Schöttker, B, Schulz, Ca, Schupf, N, Shaffer, Cm, Shi, Y, Smith, Av, Smith, Bh, Soranzo, N, Spracklen, Cn, Strauch, K, Stringham, Hm, Stumvoll, M, Svensson, Po, Szymczak, S, Tai, E, Tajuddin, Sm, Tan, Nyq, Taylor, Kd, Teren, A, Tham, Yc, Thiery, J, Thio, Chl, Thomsen, H, Thorleifsson, G, Toniolo, D, Tönjes, A, Tremblay, J, Tzoulaki, I, Uitterlinden, Ag, Vaccargiu, S, van Dam, Rm, van der Harst, P, van Duijn, Cm, Velez Edward, Dr, Verweij, N, Vogelezang, S, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Wallentin, L, Wang, Yx, Wang, C, Waterworth, Dm, Bin Wei, W, White, H, Whitfield, Jb, Wild, Sh, Wilson, Jf, Wojczynski, Mk, Wong, C, Wong, Ty, Xu, L, Yang, Q, Yasuda, M, Yerges-Armstrong, Lm, Zhang, W, Zonderman, Ab, Rotter, Ji, Bochud, M, Psaty, Bm, Vitart, V, Wilson, Jg, Dehghan, A, Parsa, A, Chasman, Di, Ho, K, Morris, Ap, Devuyst, O, Akilesh, S, Pendergrass, Sa, Sim, X, Böger, Ca, Okada, Y, Edwards, Tl, Snieder, H, Stefansson, K, Hung, Am, Heid, Im, Scholz, M, Teumer, A, Köttgen, A, and Pattaro, C.
Subjects: catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract: Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Published: 2019
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20. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

Author: Lane, William J, Westhoff, Connie M, Gleadall, Nicholas S, Aguad, Maria, Smeland-Wagman, Robin, Vege, Sunitha, Simmons, Daimon P, Mah, Helen H, Lebo, Matthew S, Walter, Klaudia, Soranzo, Nicole, Di Angelantonio, Emanuele, Danesh, John, Roberts, David J, Watkins, Nick A, Ouwehand, Willem H, Butterworth, Adam S, Kaufman, Richard M, Rehm, Heidi L, Silberstein, Leslie E, Green, Robert C, MedSeq Project, Soranzo, Nicole [0000-0003-1095-3852], Di Angelantonio, Emanuele [0000-0001-8776-6719], Danesh, John [0000-0003-1158-6791], Ouwehand, Willem [0000-0002-7744-1790], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, Blood Platelets, Erythrocytes, Rh-Hr Blood-Group System, Adolescent, Whole Genome Sequencing, Genome, Human, Middle Aged, ABO Blood-Group System, Young Adult, Blood Grouping and Crossmatching, Databases, Genetic, Humans, Antigens, Human Platelet, Algorithms, Aged, Randomized Controlled Trials as Topic
Abstract: BACKGROUND: There are more than 300 known red blood cell (RBC) antigens and 33 platelet antigens that differ between individuals. Sensitisation to antigens is a serious complication that can occur in prenatal medicine and after blood transfusion, particularly for patients who require multiple transfusions. Although pre-transfusion compatibility testing largely relies on serological methods, reagents are not available for many antigens. Methods based on single-nucleotide polymorphism (SNP) arrays have been used, but typing for ABO and Rh-the most important blood groups-cannot be done with SNP typing alone. We aimed to develop a novel method based on whole-genome sequencing to identify RBC and platelet antigens. METHODS: This whole-genome sequencing study is a subanalysis of data from patients in the whole-genome sequencing arm of the MedSeq Project randomised controlled trial (NCT01736566) with no measured patient outcomes. We created a database of molecular changes in RBC and platelet antigens and developed an automated antigen-typing algorithm based on whole-genome sequencing (bloodTyper). This algorithm was iteratively improved to address cis-trans haplotype ambiguities and homologous gene alignments. Whole-genome sequencing data from 110 MedSeq participants (30 × depth) were used to initially validate bloodTyper through comparison with conventional serology and SNP methods for typing of 38 RBC antigens in 12 blood-group systems and 22 human platelet antigens. bloodTyper was further validated with whole-genome sequencing data from 200 INTERVAL trial participants (15 × depth) with serological comparisons. FINDINGS: We iteratively improved bloodTyper by comparing its typing results with conventional serological and SNP typing in three rounds of testing. The initial whole-genome sequencing typing algorithm was 99·5% concordant across the first 20 MedSeq genomes. Addressing discordances led to development of an improved algorithm that was 99·8% concordant for the remaining 90 MedSeq genomes. Additional modifications led to the final algorithm, which was 99·2% concordant across 200 INTERVAL genomes (or 99·9% after adjustment for the lower depth of coverage). INTERPRETATION: By enabling more precise antigen-matching of patients with blood donors, antigen typing based on whole-genome sequencing provides a novel approach to improve transfusion outcomes with the potential to transform the practice of transfusion medicine. FUNDING: National Human Genome Research Institute, Doris Duke Charitable Foundation, National Health Service Blood and Transplant, National Institute for Health Research, and Wellcome Trust.
Published: 2018

21. Automated Typing of Red Blood Cell and Platelet Antigens from Whole Genome Sequencing

Author: Lane, William J., Westhoff, Connie M., Gleadall, Nicholas S., Aguad, Maria, Smeland-Wagman, Robin, Vege, Sunitha, Simmons, Daimon P., Mah, Helen H., Lebo, Matthew S., Walter, Klaudia, Soranzo, Nicole, Angelantonio, Emanuele Di, Danesh, John, Roberts, David J., Watkins, Nick A., Ouwehand, Willem H., Butterworth, Adam S., Kaufman, Richard M., Rehm, Heidi L., Silberstein, Leslie E., and Green, Robert C.
Subjects: Adult, Aged, 80 and over, Blood Platelets, Erythrocytes, Rh-Hr Blood-Group System, Adolescent, Whole Genome Sequencing, Genome, Human, Middle Aged, Article, ABO Blood-Group System, Young Adult, Blood Grouping and Crossmatching, Databases, Genetic, Humans, Antigens, Human Platelet, Algorithms, Aged, Randomized Controlled Trials as Topic
Abstract: BACKGROUND: There are over 300 known red blood cell (RBC) antigens and 33 platelet (PLT) antigens that differ between individuals. Sensitization to antigens is a serious complication in prenatal medicine and following blood transfusion, especially for patients requiring multiple transfusions. Although current pre-transfusion compatibility testing largely relies on serologic methods, reagents are not available for many antigens. DNA-based single nucleotide polymorphisms (SNP) array methods have been applied, but typing for ABO and Rh, the most important blood groups, cannot be done by SNP typing alone. New methods are needed for RBC and PLT antigen determination. METHODS: The MedSeq Project was a randomized clinical trial designed to examine the integration of wide-ranging genomic information into the practice of medicine. Subjects were enrolled by participating physicians during visits for primary care for generally healthy adults and subspecialty care for patients with cardiomyopathy. All participants underwent a standardized family history assessment after which they were block-randomized into either the whole genome sequencing (WGS) arm or the no sequencing arm. The primary endpoint of the overall MedSeq Project was to study the effect of adding WGS to medical care. This study has been completed and is registered with ClinicalTrials.gov, number NCT01736566. The WGS based RBC and PLT antigen typing presented here is a substudy of the WGS arm with no measured patient outcomes (n=110). A curated database of RBC and PLT antigen molecular changes was created (http://bloodantigens.com), followed by the development of an automated WGS-based antigen typing algorithm (bloodTyper). WGS data from 110 MedSeq participants (30x depth) were used to evaluate bloodTyper against conventional serology and SNP typing for 38 RBC antigens in 12 blood group systems (17 serology and 35 SNP) and 22 PLT antigens (22 SNP). Additional validation was performed using WGS data from 200 INTERVAL participants (15x depth) with serologic comparison (21 RBC antigens). FINDINGS: The WGS typing algorithm was iteratively improved to address cis-trans haplotype ambiguities and homologous gene alignments. The initial WGS typing algorithm was 99.5% concordant over the first 20 MedSeq genomes. Addressing the discordances led to the development of an improved algorithm which was 99.8% concordant for the remaining 90 MedSeq genomes. Additional, modifications led to the final algorithm which was 99.2% concordant over 200 INTERVAL genomes (or 99.9% after adjustment for the lower depth of coverage). INTERPRETATION: By enabling more precise antigen-matching of patients with blood donors, WGS-based antigen typing provides a novel approach to improve transfusion outcomes with the potential to transform the practice of transfusion medicine. FUNDING: National Human Genome Research Institute, Doris Duke Charitable Foundation, and NHS Blood and Transplant, National Institute for Health Research, and Wellcome Trust.
Published: 2018

22. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Author: Schormair, Barbara, Zhao, Chen, Bell, Steven, Tilch, Erik, Salminen, Aaro V., Pütz, Benno, Dauvilliers, Yves, Stefani, Ambra, Högl, Birgit, Poewe, Werner, Kemlink, David, Sonka, Karel, Bachmann, Cornelius G., Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H., Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M., Polo, Olli, Fietze, Ingo, Ross, Owen A., Wszolek, Zbigniew, Butterworth, Adam S., Soranzo, Nicole, Ouwehand, Willem H., Roberts, David J., Danesh, John, Allen, Richard P., Earley, Christopher J., Ondo, William G., Xiong, Lan, Montplaisir, Jacques, Gan-Or, Ziv, Perola, Markus, Vodicka, Pavel, Dina, Christian, Franke, Andre, Tittmann, Lukas, Stewart, Alexandre F. R., Shah, Svati H., Gieger, Christian, Peters, Annette, Rouleau, Guy A., Berger, Klaus, Oexle, Konrad, Di Angelantonio, Emanuele, Hinds, David A., Müller-Myhsok, Bertram, Winkelmann, Juliane, Team, 23andMe Research, group, DESIR, Institute of Human Genetics, Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Statistical Genetics Group, Metacohorts Consortium, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Neurology, Innsbruck Medical University [Austria] (IMU), Charles University [Prague]-1st Faculty of Medicine, First Faculty of Medicine and General Teaching Hospital [Prague, Czech Republic], Charles university in Prague (CZECH REPUBLIC), Department of Clinical Neurophysiology [Göttingen], Georg-August-University [Göttingen], Paracelsus Elena Klinik, Centre for Parkinson's Disease & Movement Disorders, University of Tartu, Sleep Research Unit, University of Turku, Department of Pulmonary Medicine, Tampere University Hospital, Interdisciplinary Center of Sleep Medicine, Universitätsmedizin Berlin-Internetseiten der Charité, Centre for Molecular Medicine and Therapeutics, University of British Columbia (UBC), Department of Public Health & Primary Care, University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Center of Excellence in Neuroscience, CHU de Montréal, Hôpital du Sacré-Coeur de Montréal, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (ASCR), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Center For Narcolepsy, Stanford University [Stanford], Center of Excellence in Neuromics, University of Montreal, Institute of Human Genetics, Technische Universität München, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Bell, Steven [0000-0001-6774-3149], Butterworth, Adam [0000-0002-6915-9015], Soranzo, Nicole [0000-0003-1095-3852], Ouwehand, Willem [0000-0002-7744-1790], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Charles University [Prague] (CU)-1st Faculty of Medicine, Charles University [Prague] (CU), Czech Academy of Sciences [Prague] (CAS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Stanford University, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), and Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: DNA-Binding Proteins, Restless Legs Syndrome, [SDV]Life Sciences [q-bio], European Continental Ancestry Group, Humans, Genetic Predisposition to Disease, Nerve Tissue Proteins, Semaphorins, GPI-Linked Proteins, Transcription Factors, Genome-Wide Association Study
Abstract: International audience; BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
Published: 2017
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23. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author: Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Turki, Saeed H Al, Thienpont, Bernard, McRae, Jeremy, Fitzgerald, Tomas W, Singh, Tarjinder, Swaminathan, Ganesh Jawahar, Prigmore, Elena, Rajan, Diana, Abdul-Khaliq, Hashim, Banka, Siddharth, Bauer, Ulrike MM, Bentham, Jamie, Berger, Felix, Bhattacharya, Shoumo, Bu'Lock, Frances, Canham, Natalie, Colgiu, Irina-Gabriela, Cosgrove, Catherine, Cox, Helen, Daehnert, Ingo, Daly, Allan, Danesh, John, Fryer, Alan, Gewillig, Marc, Hobson, Emma, Hoff, Kirstin, Homfray, Tessa, INTERVAL Study, Kahlert, Anne-Karin, Ketley, Ami, Kramer, Hans-Heiner, Lachlan, Katherine, Lampe, Anne Katrin, Louw, Jacoba J, Manickara, Ashok Kumar, Manase, Dorin, McCarthy, Karen P, Metcalfe, Kay, Moore, Carmel, Newbury-Ecob, Ruth, Omer, Seham Osman, Ouwehand, Willem H, Park, Soo-Mi, Parker, Michael J, Pickardt, Thomas, Pollard, Martin O, Robert, Leema, Roberts, David J, Sambrook, Jennifer, Setchfield, Kerry, Stiller, Brigitte, Thornborough, Chris, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers EF, Keavney, Bernard, Goodship, Judith, UK10K Consortium, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F, Firth, Helen V, Barrett, Jeffrey C, Devriendt, Koenraad, FitzPatrick, David R, Brook, J David, Deciphering Developmental Disorders Study, Hurles, Matthew E, Sifrim, Alejandro [0000-0001-8247-4020], Thienpont, Bernard [0000-0002-8772-6845], Banka, Siddharth [0000-0002-8527-2210], Pollard, Martin O [0000-0001-8738-0920], Mital, Seema [0000-0002-7643-4484], Keavney, Bernard [0000-0001-9573-0812], Barrett, Jeffrey C [0000-0002-1152-370X], and Apollo - University of Cambridge Repository
Subjects: Heart Defects, Congenital, Male, Protein Conformation, Syndrome, Autoantigens, CDC2 Protein Kinase, Mutation, Humans, Exome, Female, cardiovascular diseases, Protein Kinase C, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sequence Deletion
Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
Published: 2016

24. Clinical iron deficiency disturbs normal human responses to hypoxia

Author: Frise, Matthew C., Cheng, Hung-Yuan, Nickol, Annabel H., Curtis, M. Kate, Pollard, Karen A., Roberts, David J., Ratcliffe, Peter J., Dorrington, Keith L., and Robbins, Peter A.
Subjects: Adult, Male, Interleukin-6, Hypertension, Pulmonary, Iron, Respiration, Iron Deficiencies, Middle Aged, Pulmonary Artery, Echocardiography, Doppler, Hepcidins, Case-Control Studies, Oxyhemoglobins, Humans, Arterial Pressure, Female, Prospective Studies, Clinical Medicine, Cardiac Output, Hypoxia, Erythropoietin, Signal Transduction
Abstract: BACKGROUND: Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia.METHODS: We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography.RESULTS: Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7-9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, -8.3 to -0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups.CONCLUSION: Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health.TRIAL REGISTRATION: ClinicalTrials.gov (NCT01847352).FUNDING: M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.
Published: 2016
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25. Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

Author: Weston, Cathryn, Lu, Jing, Li, Naichang, Barkan, Kerry, Richards, Gareth O, Roberts, David J, Skerry, Timothy M, Poyner, David, Pardamwar, Meenakshi, Reynolds, Christopher A, Dowell, Simon J, Willars, Gary B, Ladds, Graham, Ladds, Graham [0000-0001-7320-9612], and Apollo - University of Cambridge Repository
Subjects: endocrine system, digestive, oral, and skin physiology, G protein-coupled receptor (GPCR), glucagon receptor, receptor activity-modifying proteins (RAMPs), Glucagon, Ligands, Receptor Activity-Modifying Protein 2, Glucagon-Like Peptide-1 Receptor, HEK293 Cells, glucagon-like peptide-1, Humans, type 2 diabetes, pharmacology, signal bias, signal transduction, hormones, hormone substitutes, and hormone antagonists
Abstract: The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.
Published: 2015

26. Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

Author: Kaptoge, Stephen, Di Angelantonio, Emanuele, Moore, Carmel, Walker, Matthew, Armitage, Jane, Ouwehand, Willem H, Roberts, David J, Danesh, John, Thompson, Simon G, and INTERVAL Trial Group
Subjects: Adult, Male, Time Factors, Adolescent, Anemia, Iron-Deficiency, Iron, Blood Donors, Efficiency, Risk Assessment, 3. Good health, Hemoglobins, Young Adult, Sex Factors, Ferritins, Quality of Life, Humans, Female, Patient Safety
Abstract: BACKGROUND: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. METHODS: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. FINDINGS: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7-1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04-0·17; p=0·0003) in men and 0·06 units per year (0·01-0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21-0·25) in men and 0·14 units per year (0·12-0·15) in women (both p0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p

27. Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income

Author: Hill, W David, Davies, Neil M, Ritchie, Stuart J, Skene, Nathan G, Bryois, Julien, Bell, Steven, Di Angelantonio, Emanuele, Roberts, David J, Xueyi, Shen, Davies, Gail, Liewald, David CM, Porteous, David J, Hayward, Caroline, Butterworth, Adam S, McIntosh, Andrew M, Gale, Catharine R, and Deary, Ian J
Subjects: Adult, Male, Genotype, Intelligence, Quantitative Trait Loci, Middle Aged, Polymorphism, Single Nucleotide, United Kingdom, 3. Good health, Social Class, Income, Humans, Female, Aged, Genome-Wide Association Study
Abstract: Socioeconomic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. In a sample of 286,301 participants from UK Biobank, we identify 30 (29 previously unreported) independent-loci associated with income. Using a method to meta-analyze data from genetically-correlated traits, we identify an additional 120 income-associated loci. These loci show clear evidence of functionality, with transcriptional differences identified across multiple cortical tissues, and links to GABAergic and serotonergic neurotransmission. By combining our genome wide association study on income with data from eQTL studies and chromatin interactions, 24 genes are prioritized for follow up, 18 of which were previously associated with intelligence. We identify intelligence as one of the likely causal, partly-heritable phenotypes that might bridge the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. These results indicate that, in modern era Great Britain, genetic effects contribute towards some of the observed socioeconomic inequalities.

28. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Author: Axfors, Cathrine, Janiaud, Perrine, Schmitt, Andreas M, Van't Hooft, Janneke, Smith, Emily R, Haber, Noah A, Abayomi, Akin, Abduljalil, Manal, Abdulrahman, Abdulkarim, Acosta-Ampudia, Yeny, Aguilar-Guisado, Manuela, Al-Beidh, Farah, Alejandria, Marissa M, Alfonso, Rachelle N, Ali, Mohammad, AlQahtani, Manaf, AlZamrooni, Alaa, Anaya, Juan-Manuel, Ang, Mark Angelo C, Aomar, Ismael F, Argumanis, Luis E, Averyanov, Alexander, Baklaushev, Vladimir P, Balionis, Olga, Benfield, Thomas, Berry, Scott, Birocco, Nadia, Bonifacio, Lynn B, Bowen, Asha C, Bown, Abbie, Cabello-Gutierrez, Carlos, Camacho, Bernardo, Camacho-Ortiz, Adrian, Campbell-Lee, Sally, Cao, Damon H, Cardesa, Ana, Carnate, Jose M, Castillo, German Jr J, Cavallo, Rossana, Chowdhury, Fazle R, Chowdhury, Forhad UH, Ciccone, Giovannino, Cingolani, Antonella, Climacosa, Fresthel Monica M, Compernolle, Veerle, Cortez, Carlo Francisco N, Costa Neto, Abel, D'Antico, Sergio, Daly, James, Danielle, Franca, Davis, Joshua S, De Rosa, Francesco Giuseppe, Denholm, Justin T, Denkinger, Claudia M, Desmecht, Daniel, Díaz-Coronado, Juan C, Díaz Ponce-Medrano, Juan A, Donneau, Anne-Françoise, Dumagay, Teresita E, Dunachie, Susanna, Dungog, Cecile C, Erinoso, Olufemi, Escasa, Ivy Mae S, Estcourt, Lise J, Evans, Amy, Evasan, Agnes LM, Fareli, Christian J, Fernandez-Sanchez, Veronica, Galassi, Claudia, Gallo, Juan E, Garcia, Patricia J, Garcia, Patricia L, Garcia, Jesus A, Garigliany, Mutien, Garza-Gonzalez, Elvira, Gauiran, Deonne Thaddeus V, Gaviria García, Paula A, Giron-Gonzalez, Jose-Antonio, Gómez-Almaguer, David, Gordon, Anthony C, Gothot, André, Grass Guaqueta, Jeser Santiago, Green, Cameron, Grimaldi, David, Hammond, Naomi E, Harvala, Heli, Heralde, Francisco M, Herrick, Jesica, Higgins, Alisa M, Hills, Thomas E, Hines, Jennifer, Holm, Karin, Hoque, Ashraful, Hoste, Eric, Ignacio, Jose M, Ivanov, Alexander V, Janssen, Maike, Jennings, Jeffrey H, Jha, Vivekanand, King, Ruby Anne N, Kjeldsen-Kragh, Jens, Klenerman, Paul, Kotecha, Aditya, Krapp, Fiorella, Labanca, Luciana, Laing, Emma, Landin-Olsson, Mona, Laterre, Pierre-François, Lim, Lyn-Li, Lim, Jodor, Ljungquist, Oskar, Llaca-Díaz, Jorge M, López-Robles, Concepción, López-Cárdenas, Salvador, Lopez-Plaza, Ileana, Lucero, Josephine Anne C, Lundgren, Maria, Macías, Juan, Maganito, Sandy C, Malundo, Anna Flor G, Manrique, Rubén D, Manzini, Paola M, Marcos, Miguel, Marquez, Ignacio, Martínez-Marcos, Francisco Javier, Mata, Ana M, McArthur, Colin J, McQuilten, Zoe K, McVerry, Bryan J, Menon, David K, Meyfroidt, Geert, Mirasol, Ma Angelina L, Misset, Benoît, Molton, James S, Mondragon, Alric V, Monsalve, Diana M, Moradi Choghakabodi, Parastoo, Morpeth, Susan C, Mouncey, Paul R, Moutschen, Michel, Müller-Tidow, Carsten, Murphy, Erin, Najdovski, Tome, Nichol, Alistair D, Nielsen, Henrik, Novak, Richard M, O'Sullivan, Matthew VN, Olalla, Julian, Osibogun, Akin, Osikomaiya, Bodunrin, Oyonarte, Salvador, Pardo-Oviedo, Juan M, Patel, Mahesh C, Paterson, David L, Peña-Perez, Carlos A, Perez-Calatayud, Angel A, Pérez-Alba, Eduardo, Perkina, Anastasia, Perry, Naomi, Pouladzadeh, Mandana, Poyato, Inmaculada, Price, David J, Quero, Anne Kristine H, Rahman, Md M, Rahman, Md S, Ramesh, Mayur, Ramírez-Santana, Carolina, Rasmussen, Magnus, Rees, Megan A, Rego, Eduardo, Roberts, Jason A, Roberts, David J, Rodríguez, Yhojan, Rodríguez-Baño, Jesús, Rogers, Benjamin A, Rojas, Manuel, Romero, Alberto, Rowan, Kathryn M, Saccona, Fabio, Safdarian, Mehdi, Santos, Maria Clariza M, Sasadeusz, Joe, Scozzari, Gitana, Shankar-Hari, Manu, Sharma, Gorav, Snelling, Thomas, Soto, Alonso, Tagayuna, Pedrito Y, Tang, Amy, Tatem, Geneva, Teofili, Luciana, Tong, Steven YC, Turgeon, Alexis F, Veloso, Januario D, Venkatesh, Balasubramanian, Ventura-Enriquez, Yanet, Webb, Steve A, Wiese, Lothar, Wikén, Christian, Wood, Erica M, Yusubalieva, Gaukhar M, Zacharowski, Kai, Zarychanski, Ryan, Khanna, Nina, Moher, David, Goodman, Steven N, Ioannidis, John PA, and Hemkens, Lars G
Subjects: Meta-analysis, Convalescent plasma, Treatment Outcome, SARS-CoV-2, Immunization, Passive, COVID-19, Humans, COVID-19 Serotherapy, 3. Good health, Randomized Controlled Trials as Topic
Abstract: Funder: laura and john arnold foundation, BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

29. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Author: Schormair, Barbara, Zhao, Chen, Bell, Steven, Tilch, Erik, Salminen, Aaro V, Pütz, Benno, Dauvilliers, Yves, Stefani, Ambra, Högl, Birgit, Poewe, Werner, Kemlink, David, Sonka, Karel, Bachmann, Cornelius G, Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H, Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M, Polo, Olli, Fietze, Ingo, Ross, Owen A, Wszolek, Zbigniew, Butterworth, Adam S, Soranzo, Nicole, Ouwehand, Willem H, Roberts, David J, Danesh, John, Allen, Richard P, Earley, Christopher J, Ondo, William G, Xiong, Lan, Montplaisir, Jacques, Gan-Or, Ziv, Perola, Markus, Vodicka, Pavel, Dina, Christian, Franke, Andre, Tittmann, Lukas, Stewart, Alexandre FR, Shah, Svati H, Gieger, Christian, Peters, Annette, Rouleau, Guy A, Berger, Klaus, Oexle, Konrad, Di Angelantonio, Emanuele, Hinds, David A, Müller-Myhsok, Bertram, Winkelmann, Juliane, 23andMe Research Team, and DESIR Study Group
Subjects: DNA-Binding Proteins, Restless Legs Syndrome, European Continental Ancestry Group, Humans, Genetic Predisposition to Disease, Nerve Tissue Proteins, Semaphorins, GPI-Linked Proteins, 3. Good health, Genome-Wide Association Study, Transcription Factors
Abstract: BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

30. Recruitment and representativeness of blood donors in the INTERVAL randomised trial assessing varying inter-donation intervals

Author: Moore, Carmel, Bolton, Thomas, Walker, Matthew, Kaptoge, Stephen, Allen, David, Daynes, Michael, Mehenny, Susan, Sambrook, Jennifer, Watkins, Nicholas A, Miflin, Gail, Di Angelantonio, Emanuele, Ouwehand, Willem H, Roberts, David J, Danesh, John, Thompson, Simon G, Kaptoge, Stephen [0000-0002-1155-4872], Di Angelantonio, Emanuele [0000-0001-8776-6719], Ouwehand, Willem [0000-0002-7744-1790], Danesh, John [0000-0003-1158-6791], Thompson, Simon [0000-0002-5274-7814], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Blood donation, Randomised trial, Generalisability, Time Factors, Adolescent, Research, Health Status, Patient Selection, Medicine (miscellaneous), Blood Donors, Middle Aged, Donor Selection, Young Adult, England, Blood Banks, Humans, Female, Pharmacology (medical), Recruitment, Representativeness, Aged
Abstract: Background The interpretation of trial results can be helped by understanding how generalisable they are to the target population for which inferences are intended. INTERVAL, a large pragmatic randomised trial of blood donors in England, is assessing the effectiveness and safety of reducing inter-donation intervals. The trial recruited mainly from the blood service’s static centres, which collect only about 10 % of whole-blood donations. Hence, the extent to which the trial’s participants are representative of the general blood donor population is uncertain. We compare these groups in detail. Methods We present the CONSORT flowchart from participant invitation to randomisation in INTERVAL. We compare the characteristics of those eligible and consenting to participate in INTERVAL with the general donor population, using the national blood supply ’PULSE’ database for the period of recruitment. We compare the characteristics of specific groups of trial participants recruited from different sources, as well as those who were randomised versus those not randomised. Results From a total of 540,459 invitations, 48,725 donors were eligible and consented to participate in INTERVAL. The proportion of such donors varied from 1–22 % depending on the source of recruitment. The characteristics of those consenting were similar to those of the general population of 1.3 million donors in terms of ethnicity, blood group distribution and recent deferral rates from blood donation due to low haemoglobin. However, INTERVAL participants included more men (50 % versus 44 %), were slightly older (mean age 43.1 versus 42.3 years), included fewer new donors (3 % versus 22 %) and had given more donations over the previous 2 years (mean 3.3 versus 2.2) than the general donor population. Of the consenting participants, 45,263 (93 %) donors were randomised. Compared to those not randomised, the randomised donors showed qualitatively similar differences to those described above. Conclusions There was broad similarity of participants in INTERVAL with the general blood donor population of England, notwithstanding some differences in age, sex and donation history. Any heterogeneity of the trial’s results according to these characteristics will need to be studied to ensure its generalisability to the general donor population. Trial registration Current Controlled Trials ISRCTN24760606. Registered on 25 January 2012. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1579-7) contains supplementary material, which is available to authorized users.
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31. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Turcot, Valérie, Lu, Yingchang, Highland, Heather M, Schurmann, Claudia, Justice, Anne E, Fine, Rebecca S, Bradfield, Jonathan P, Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E, Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E, Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L, Alfred, Tamuno, Feitosa, Mary F, Masca, Nicholas GD, Manning, Alisa K, Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie CY, Reiner, Alex P, Vedantam, Sailaja, Willems, Sara M, Winkler, Thomas W, Abecasis, Gonçalo, Aben, Katja K, Alam, Dewan S, Alharthi, Sameer E, Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W, Auer, Paul L, Balkau, Beverley, Bang, Lia E, Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bots, Michiel L, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H, Broer, Linda, Brumat, Marco, Burt, Amber A, Butterworth, Adam S, Campbell, Peter T, Cappellani, Stefania, Carey, David J, Catamo, Eulalia, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der I, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Cocca, Massimiliano, Collins, Francis S, Cook, James P, Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J, Crosslin, David S, Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul IW, Groot, Mark CH, Mutsert, Renée, Deary, Ian J, Dedoussis, George, Demerath, Ellen W, Heijer, Martin, Hollander, Anneke I, Ruijter, Hester M, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Edwards, Todd L, Ellinghaus, David, Ellinor, Patrick T, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I Sadaf, Faul, Jessica D, Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Ford, Ian, Fornage, Myriam, Franco, Oscar H, Franke, Andre, Franks, Paul W, Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P, Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan FA, Grarup, Niels, Griffiths, Helen L, Grove, Megan L, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B, Hattersley, Andrew T, Have, Christian T, Hayward, Caroline, He, Liang, Heard-Costa, Nancy L, Heath, Andrew C, Heid, Iris M, Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Huang, Paul L, Huffman, Jennifer E, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jansson, Jan-Håkan, Jarvik, Gail P, Jensen, Gorm B, Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E, Jørgensen, Torben, Jukema, J Wouter, Kahali, Bratati, Kahn, René S, Kähönen, Mika, Kamstrup, Pia R, Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A, Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Ethan M, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Liu, Yongmei, Lo, Ken S, Lophatananon, Artitaya, Lotery, Andrew J, Loukola, Anu, Luan, Jian'an, Lubitz, Steven A, Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L, McCarthy, Mark I, McKean-Cowdin, Roberta, Medland, Sarah E, Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L, Moilanen, Leena, Moitry, Marie, Montgomery, Grant W, Mook-Kanamori, Dennis O, Moore, Carmel, Mori, Trevor A, Morris, Andrew D, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Nalls, Mike A, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Nielsen, Sune F, Nikus, Kjell, Njølstad, Pål R, Nordestgaard, Børge G, Nyholt, Dale R, O'Connel, Jeffrey R, O'Donoghue, Michelle L, Olde Loohuis, Loes M, Ophoff, Roel A, Owen, Katharine R, Packard, Chris J, Padmanabhan, Sandosh, Palmer, Colin NA, Palmer, Nicholette D, Pasterkamp, Gerard, Patel, Aniruddh P, Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Person, Thomas N, Peters, Annette, Petersen, Eva RB, Peyser, Patricia A, Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J, Puolijoki, Hannu, Raitakari, Olli T, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Renström, Frida, Rheinberger, Myriam, Ridker, Paul M, Rioux, John D, Rivas, Manuel A, Roberts, David J, Robertson, Neil R, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo P, Shah, Svati H, Sheu, Wayne H-H, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Albert V, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J, Tada, Hayato, Tansey, Katherine E, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P, Uher, Rudolf, Uitterlinden, André G, Uusitupa, Matti, Laan, Sander W, Duijn, Cornelia M, Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V, Varma, Rohit, Velez Edwards, Digna R, Vermeulen, Sita H, Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wang, Yiqin, Ware, Erin B, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Witte, Daniel R, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter, Jerome I, Pospisilik, John A, Rivadeneira, Fernando, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, North, Kari E, Lindgren, Cecilia M, Hirschhorn, Joel N, and Loos, Ruth JF
Subjects: 2. Zero hunger, Adult, Male, Genetic Variation, Proteins, Syndrome, Body Mass Index, Gene Frequency, Animals, Humans, Drosophila, Female, Obesity, Energy Intake, Energy Metabolism
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

32. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018
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32 results on '"Roberts, David J"'

1. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

2. Summary results of the 2014-2015 DARPA Chikungunya challenge

3. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

4. Accelerated waning of the humoral response to COVID-19 vaccines in obesity

5. Cost-effectiveness of alternative minimum recall intervals between whole blood donations

6. Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

7. Highly sensitive lineage discrimination of SARS-CoV-2 variants through allele-specific probe PCR

8. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

9. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

10. Comparison of four methods to measure haemoglobin concentrations in whole blood donors (COMPARE): A diagnostic accuracy study

11. Time-to-death is a potential confounder in observational studies of blood transfusion in severe malaria

12. Accuracy of UK Rapid Test Consortium (UK-RTC) 'AbC-19 Rapid Test' for detection of previous SARS-CoV-2 infection in key workers: test accuracy study

13. The Polygenic and Monogenic Basis of Blood Traits and Diseases

14. Optimal individualized decision rules from a multi-arm trial: A comparison of methods and an application to tailoring inter-donation intervals among blood donors in the UK

15. Development and validation of a universal blood donor genotyping platform: a multinational prospective study

16. January 2020: What lies ahead?

17. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

18. Life in times of<scp>COVID</scp>‐19

19. A catalog of genetic loci associated with kidney function from analyses of a million individuals

20. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

21. Automated Typing of Red Blood Cell and Platelet Antigens from Whole Genome Sequencing

22. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

23. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

24. Clinical iron deficiency disturbs normal human responses to hypoxia

25. Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

26. Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

27. Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income

28. Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

29. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

30. Recruitment and representativeness of blood donors in the INTERVAL randomised trial assessing varying inter-donation intervals

31. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

32. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

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