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1. Novel loci and biomedical consequences of iron homoeostasis variation

Author

Elias Allara, Steven Bell, Rebecca Smith, Spencer J. Keene, Dipender Gill, Liam Gaziano, Deisy Morselli Gysi, Feiyi Wang, Vinicius Tragante, Amy Mason, Savita Karthikeyan, R. Thomas Lumbers, Emmanuela Bonglack, Willem Ouwehand, David J. Roberts, Joseph Dowsett, Sisse Rye Ostrowski, Margit Hørup Larsen, Henrik Ullum, Ole Birger Pedersen, Søren Brunak, Karina Banasik, Christian Erikstrup, DBDS Genomic Consortium, Jonathan Mitchell, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Domenico Girelli, Mikko Arvas, Jarkko Toivonen, Sophie Molnos, Annette Peters, Ozren Polasek, Igor Rudan, Caroline Hayward, Ciara McDonnell, Nicola Pirastu, James F. Wilson, Katja van den Hurk, Franke Quee, Luigi Ferrucci, Stefania Bandinelli, Toshiko Tanaka, Giorgia Girotto, Maria Pina Concas, Alessandro Pecori, Niek Verweij, Pim van der Harst, Yordi J. van de Vegte, Lambertus A. Kiemeney, Fred C. Sweep, Tessel E. Galesloot, Patrick Sulem, Daniel Gudbjartsson, Egil Ferkingstad, FinnGen Consortium, Luc Djousse, Kelly Cho, Michael Inouye, Stephen Burgess, Beben Benyamin, Konrad Oexle, Dorine Swinkels, Kari Stefansson, Magnus Magnusson, Andrea Ganna, Michael Gaziano, Kerry Ivey, John Danesh, Alexandre Pereira, Angela M. Wood, Adam S. Butterworth, and Emanuele Di Angelantonio

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

Published
2024
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2. A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology

Author

Parsa Akbari, Dragana Vuckovic, Luca Stefanucci, Tao Jiang, Kousik Kundu, Roman Kreuzhuber, Erik L. Bao, Janine H. Collins, Kate Downes, Luigi Grassi, Jose A. Guerrero, Stephen Kaptoge, Julian C. Knight, Stuart Meacham, Jennifer Sambrook, Denis Seyres, Oliver Stegle, Jeffrey M. Verboon, Klaudia Walter, Nicholas A. Watkins, John Danesh, David J. Roberts, Emanuele Di Angelantonio, Vijay G. Sankaran, Mattia Frontini, Stephen Burgess, Taco Kuijpers, James E. Peters, Adam S. Butterworth, Willem H. Ouwehand, Nicole Soranzo, and William J. Astle

Subjects
Science
Abstract

Abstract Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.

Published
2023
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3. Genetically personalised organ-specific metabolic models in health and disease

Author

Carles Foguet, Yu Xu, Scott C. Ritchie, Samuel A. Lambert, Elodie Persyn, Artika P. Nath, Emma E. Davenport, David J. Roberts, Dirk S. Paul, Emanuele Di Angelantonio, John Danesh, Adam S. Butterworth, Christopher Yau, and Michael Inouye

Subjects
Science
Abstract

Here, the authors present a method to build genetically personalised metabolic models across tissues to estimate individualised reaction fluxes. A fluxome-wide association study in UK Biobank identifies fluxes associated with metabolites and coronary artery disease.

Published
2022
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4. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Author

Lingyan Chen, James E. Peters, Bram Prins, Elodie Persyn, Matthew Traylor, Praveen Surendran, Savita Karthikeyan, Ekaterina Yonova-Doing, Emanuele Di Angelantonio, David J. Roberts, Nicholas A. Watkins, Willem H. Ouwehand, John Danesh, Cathryn M. Lewis, Paola G. Bronson, Hugh S. Markus, Stephen Burgess, Adam S. Butterworth, and Joanna M. M. Howson

Subjects
Science
Abstract

Mendelian randomization can be used to mimic the effects of protein-targeting drugs in a population of individuals. Here, the authors have identified potential causal proteins for stroke in a two-sample Mendelian randomization framework, providing potential stroke therapeutic targets.

Published
2022
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5. Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation

Author

Matthew C. Frise, David A. Holdsworth, Andrew W. Johnson, Yu Jin Chung, M. Kate Curtis, Pete J. Cox, Kieran Clarke, Damian J. Tyler, David J. Roberts, Peter J. Ratcliffe, Keith L. Dorrington, and Peter A. Robbins

Subjects
Medicine, Science
Abstract

Abstract Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.

Published
2022
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6. A haemagglutination test for rapid detection of antibodies to SARS-CoV-2

Author

Alain Townsend, Pramila Rijal, Julie Xiao, Tiong Kit Tan, Kuan-Ying A. Huang, Lisa Schimanski, Jiandong Huo, Nimesh Gupta, Rolle Rahikainen, Philippa C. Matthews, Derrick Crook, Sarah Hoosdally, Susanna Dunachie, Eleanor Barnes, Teresa Street, Christopher P. Conlon, John Frater, Carolina V. Arancibia-Cárcamo, Justine Rudkin, Nicole Stoesser, Fredrik Karpe, Matthew Neville, Rutger Ploeg, Marta Oliveira, David J. Roberts, Abigail A. Lamikanra, Hoi Pat Tsang, Abbie Bown, Richard Vipond, Alexander J. Mentzer, Julian C. Knight, Andrew J. Kwok, Gavin R. Screaton, Juthathip Mongkolsapaya, Wanwisa Dejnirattisai, Piyada Supasa, Paul Klenerman, Christina Dold, J. Kenneth Baillie, Shona C. Moore, Peter J. M. Openshaw, Malcolm G. Semple, Lance C. W. Turtle, Mark Ainsworth, Alice Allcock, Sally Beer, Sagida Bibi, Donal Skelly, Lizzy Stafford, Katie Jeffrey, Denise O’Donnell, Elizabeth Clutterbuck, Alexis Espinosa, Maria Mendoza, Dominique Georgiou, Teresa Lockett, Jose Martinez, Elena Perez, Veronica Gallardo Sanchez, Giuseppe Scozzafava, Alberto Sobrinodiaz, Hannah Thraves, and Etienne Joly

Subjects
Science
Abstract

Serological detection of antibodies against SARS-CoV-2 can help establish rates of seroconversion. Here the authors develop a red cell agglutination test to detect antibodies against the receptor binding domain for distribution free of charge to qualified research groups.

Published
2021
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7. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Author

Steven Bell, Andreas S. Rigas, Magnus K. Magnusson, Egil Ferkingstad, Elias Allara, Gyda Bjornsdottir, Anna Ramond, Erik Sørensen, Gisli H. Halldorsson, Dirk S. Paul, Kristoffer S. Burgdorf, Hannes P. Eggertsson, Joanna M. M. Howson, Lise W. Thørner, Snaedis Kristmundsdottir, William J. Astle, Christian Erikstrup, Jon K. Sigurdsson, Dragana Vuckovic, Khoa M. Dinh, Vinicius Tragante, Praveen Surendran, Ole B. Pedersen, Brynjar Vidarsson, Tao Jiang, Helene M. Paarup, Pall T. Onundarson, Parsa Akbari, Kaspar R. Nielsen, Sigrun H. Lund, Kristinn Juliusson, Magnus I. Magnusson, Michael L. Frigge, Asmundur Oddsson, Isleifur Olafsson, Stephen Kaptoge, Henrik Hjalgrim, Gudmundur Runarsson, Angela M. Wood, Ingileif Jonsdottir, Thomas F. Hansen, Olof Sigurdardottir, Hreinn Stefansson, David Rye, DBDS Genomic Consortium, James E. Peters, David Westergaard, Hilma Holm, Nicole Soranzo, Karina Banasik, Gudmar Thorleifsson, Willem H. Ouwehand, Unnur Thorsteinsdottir, David J. Roberts, Patrick Sulem, Adam S. Butterworth, Daniel F. Gudbjartsson, John Danesh, Søren Brunak, Emanuele Di Angelantonio, Henrik Ullum, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

Published
2021
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8. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Author

Matthew S. Buckland, James B. Galloway, Caoimhe Nic Fhogartaigh, Luke Meredith, Nicholas M. Provine, Stuart Bloor, Ane Ogbe, Wioleta M. Zelek, Anna Smielewska, Anna Yakovleva, Tiffeney Mann, Laura Bergamaschi, Lorinda Turner, Frederica Mescia, Erik J. M. Toonen, Carl-Philipp Hackstein, Hossain Delowar Akther, Vinicius Adriano Vieira, Lourdes Ceron-Gutierrez, Jimstan Periselneris, Sorena Kiani-Alikhan, Sofia Grigoriadou, Devan Vaghela, Sara E. Lear, M. Estée Török, William L. Hamilton, Joanne Stockton, Josh Quick, Peter Nelson, Michael Hunter, Tanya I. Coulter, Lisa Devlin, CITIID-NIHR COVID-19 BioResource Collaboration, MRC-Toxicology Unit COVID-19 Consortium, John R. Bradley, Kenneth G. C. Smith, Willem H. Ouwehand, Lise Estcourt, Heli Harvala, David J. Roberts, Ian B. Wilkinson, Nick Screaton, Nicholas Loman, Rainer Doffinger, Paul A. Lyons, B. Paul Morgan, Ian G. Goodfellow, Paul Klenerman, Paul J. Lehner, Nicholas J. Matheson, and James E. D. Thaventhiran

Subjects
Science
Abstract

Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.

Published
2020
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9. Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Author

Maria Didriksen, Muhammad Sulaman Nawaz, Joseph Dowsett, Steven Bell, Christian Erikstrup, Ole B. Pedersen, Erik Sørensen, Poul J. Jennum, Kristoffer S. Burgdorf, Brendan Burchell, Adam S. Butterworth, Nicole Soranzo, David B. Rye, Lynn Marie Trotti, Prabhjyot Saini, Lilja Stefansdottir, Sigurdur H. Magnusson, Gudmar Thorleifsson, Thordur Sigmundsson, Albert P. Sigurdsson, Katja Van Den Hurk, Franke Quee, Michael W. T. Tanck, Willem H. Ouwehand, David J. Roberts, Eric J. Earley, Michael P. Busch, Alan E. Mast, Grier P. Page, John Danesh, Emanuele Di Angelantonio, Hreinn Stefansson, Henrik Ullum, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Didriksen, Nawaz, et al. identify three novel genetic risk variants for restless legs syndrome and confirm 19 out of 20 previously reported variants through a genome-wide association meta-analysis including nearly half a million individuals. Using expression QTL analysis, they also find that a subset of these loci may have a causal effect on nearby gene expression.

Published
2020
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11. Genome-wide analysis identifies molecular systems and 149 genetic loci associated with income

Author

W. David Hill, Neil M. Davies, Stuart J. Ritchie, Nathan G. Skene, Julien Bryois, Steven Bell, Emanuele Di Angelantonio, David J. Roberts, Shen Xueyi, Gail Davies, David C. M. Liewald, David J. Porteous, Caroline Hayward, Adam S. Butterworth, Andrew M. McIntosh, Catharine R. Gale, and Ian J. Deary

Subjects
Science
Abstract

Household income is used as a marker of socioeconomic position, a trait that is associated with better physical and mental health. Here, Hill et al. report a genome-wide association study for household income in the UK and explore its relationship with intelligence in post-GWAS analyses including Mendelian randomization.

Published
2019
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12. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author

Romina Petersen, John J. Lambourne, Biola M. Javierre, Luigi Grassi, Roman Kreuzhuber, Dace Ruklisa, Isabel M. Rosa, Ana R. Tomé, Heather Elding, Johanna P. van Geffen, Tao Jiang, Samantha Farrow, Jonathan Cairns, Abeer M. Al-Subaie, Sofie Ashford, Antony Attwood, Joana Batista, Heleen Bouman, Frances Burden, Fizzah A. Choudry, Laura Clarke, Paul Flicek, Stephen F. Garner, Matthias Haimel, Carly Kempster, Vasileios Ladopoulos, An-Sofie Lenaerts, Paulina M. Materek, Harriet McKinney, Stuart Meacham, Daniel Mead, Magdolna Nagy, Christopher J. Penkett, Augusto Rendon, Denis Seyres, Benjamin Sun, Salih Tuna, Marie-Elise van der Weide, Steven W. Wingett, Joost H. Martens, Oliver Stegle, Sylvia Richardson, Ludovic Vallier, David J. Roberts, Kathleen Freson, Lorenz Wernisch, Hendrik G. Stunnenberg, John Danesh, Peter Fraser, Nicole Soranzo, Adam S. Butterworth, Johan W. Heemskerk, Ernest Turro, Mikhail Spivakov, Willem H. Ouwehand, William J. Astle, Kate Downes, Myrto Kostadima, and Mattia Frontini

Subjects
Science
Abstract

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
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