Author: "John Danesh" / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

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149 results on '"John Danesh"'

1. The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation

Author: Aoife McMahon, Helen Parkinson, Simon Jupp, Laurent Gil, Scott C. Ritchie, Samuel A. Lambert, Jacqueline A. L. MacArthur, Michael Inouye, Yu Xu, Annalisa Buniello, John Danesh, Gad Abraham, and Michael A Chapman
Subjects: Metadata, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Information retrieval, Extramural, Genetics, MEDLINE, Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: We present the Polygenic Score (PGS) Catalog ( https://www.PGSCatalog.org ), an open resource of published scores (including variants, alleles and weights) and consistently curated metadata required for reproducibility and independent applications. The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with a platform for PGS dissemination, research and translation.
Published: 2021

2. A cross-platform approach identifies genetic regulators of human metabolism and health

Author: Kay-Tee Khaw, Angela M. Wood, Julian L. Griffin, Gabi Kastenmüller, Fiona M. Gribble, Adam S. Butterworth, Luca A. Lotta, Verena Zuber, Chen Li, Victoria P W Auyeung, Johannes Raffler, Isobel D. Stewart, Nita G. Forouhi, Jian'an Luan, Nicholas J. Wareham, Claudia Langenberg, Maik Pietzner, Laura B. L. Wittemans, Eleanor Wheeler, Robert A. Scott, Roberto Bonelli, John Danesh, Frank Reimann, Praveen Surendran, Stephen Burgess, Ellie Paige, Clare Oliver-Williams, Albert Koulman, Fumiaki Imamura, Eric B. Fauman, Gregory A. Michelotti, Melanie Bahlo, Eleanor Sanderson, and Emma K. Biggs
Subjects: Nonsynonymous substitution, 0303 health sciences, Mechanism (biology), Genome-wide association study, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy, Mendelian randomization, Genetics, Genetic Pleiotropy, Metabolome, Allelic heterogeneity, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In cross-platform analyses of 174 metabolites, we identify 499 associations (P
Published: 2021

3. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author: Hannah M. Martin, Yi Liu, Tom R. Gaunt, Michael V. Holmes, Matthew R. Nelson, Jie Zheng, Benjamin B. Sun, Stephen Burgess, George Davey Smith, Jamie Robinson, John Danesh, James R Staley, Shan Luo, Robert A. Scott, Pau Erola, Karol Estrada, Dawn M. Waterworth, Gibran Hemani, Benjamin Elsworth, Alex Gutteridge, Valeriia Haberland, Charles Laurin, Heiko Runz, Denis Baird, Venexia M Walker, Tom G. Richardson, Mark R. Hurle, Jimmy Z. Liu, Joseph C. Maranville, Adam S. Butterworth, Philip C Haycock, James Yarmolinsky, Rita Santos, Linda McCarthy, Zheng, Jie [0000-0002-6623-6839], Haberland, Valeriia [0000-0002-3874-0683], Robinson, Jamie [0000-0001-8721-6514], Richardson, Tom G [0000-0002-7918-2040], Elsworth, Benjamin [0000-0001-7328-4233], Sun, Benjamin B [0000-0001-6347-2281], Smith, George Davey [0000-0002-1407-8314], Butterworth, Adam S [0000-0002-6915-9015], Hemani, Gibran [0000-0003-0920-1055], Scott, Robert A [0000-0003-3634-3016], Gaunt, Tom R [0000-0003-0924-3247], and Apollo - University of Cambridge Repository
Subjects: Proteomics, Linkage disequilibrium, Proteome, Genome-wide association study, Computational biology, 030204 cardiovascular system & hematology, Phenome, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Human proteome project, Genetics, Humans, Genetic Predisposition to Disease, health care economics and organizations, Genetic association, 030304 developmental biology, 0303 health sciences, Drug discovery, High-throughput screening, Colocalization, Mendelian Randomization Analysis, Blood Proteins, Phenotype, 3. Good health, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here, we estimated the effects of 1002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium (LD) is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programmes showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of our approach in identifying and prioritising potential therapeutic targets.
Published: 2020

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

Author: Andrew D Beswick, Tõnu Esko, Niki Dimou, Xue Zhong, Jette Bork-Jensen, Petra Schubert, Masato Akiyama, Girish N. Nadkarni, Ruth J. F. Loos, Huijun Qian, Michele K. Evans, Stephen S. Rich, Nicole Soranzo, Henry Völzke, Yongmei Liu, Nicholas A. Watkins, Markus M. Lerch, Richard C. Trembath, Adam S. Butterworth, Erwin P. Bottinger, Jennifer E. Huffman, Bruce M. Psaty, Jingzhong Ding, Michael Preuss, Yoav Ben-Shlomo, Bhavi Trivedi, Yoichiro Kamatani, David A. van Heel, Kjell Nikus, Torben Hansen, Adolfo Correa, Mohsen Ghanbari, Paul L. Auer, Véronique Laplante, Ken Sin Lo, Hua Tang, Peter W.F. Wilson, Paul Elliott, David J. Roberts, Hilary C. Martin, Jean-Claude Tardif, Praveen Surendran, Regina Manansala, Terho Lehtimäki, Emanuele Di Angelantonio, Fotis Koskeridis, Alexander P. Reiner, Mélissa Beaudoin, Vijay G. Sankaran, Benjamin Rodriguez, William J. Astle, Parsa Akbari, Frank J. A. van Rooij, Yun Li, Andreas Greinacher, Abdou Mousas, Andrew D. Johnson, Yukinori Okada, Michael H. Guo, Leo-Pekka Lyytikäinen, Traci M. Bartz, Minhui Chen, Alan B. Zonderman, Niels Grarup, Oluf Pedersen, Kumaraswamynaidu Chitrala, Jeffrey Haessler, Ming-Huei Chen, Cassandra N. Spracklen, Karen L. Mohlke, Guillaume Lettre, Erik L. Bao, Bingshan Li, James S. Floyd, Wei Huang, Ani Manichaikul, John Danesh, Uwe Völker, Allan Linneberg, Evangelos Evangelou, Joanna M. M. Howson, Olli T. Raitakari, Tim Kacprowski, Jean-François Gauchat, Hélène Choquet, Arden Moscati, Saori Sakaue, Mika Kähönen, Linda Broer, Caleb A. Lareau, Qin Qin Huang, Matthias Nauck, Yoshinori Murakami, Charleston W. K. Chiang, VA Million Veteran Program, Nina Mononen, Tao Jiang, Laura M. Raffield, Jerome I. Rotter, Leslie A. Lange, Jonathan D. Rosen, Eric Jorgenson, Savita Karthikeyan, Karen A. Hunt, Nathan Pankratz, Kelly Cho, Masahiro Kanai, Willem H. Ouwehand, Jennifer A. Brody, Koichi Matsuda, Dragana Vuckovic, Epidemiology, and Internal Medicine
Subjects: LOCI, Mutation, Missense, Ethnic group, POLYGENIC RISK SCORES, HUMAN HEMATOPOIESIS, Biology, BIOBANK, phenome-wide association study, Polymorphism, Single Nucleotide, DISEASE, White People, General Biochemistry, Genetics and Molecular Biology, Article, Blood cell, 03 medical and health sciences, SINGLE-CELL, selective sweeps, 0302 clinical medicine, Asian People, parasitic diseases, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, AFRICAN-AMERICANS, 0303 health sciences, interleukin-7, Interleukin-7, genetic architecture, Genetic architecture, TRAIT, HEK293 Cells, Phenotype, medicine.anatomical_structure, fine-mapping, polygenic trait score, lipids (amino acids, peptides, and proteins), FREQUENCY CODING VARIANTS, 030217 neurology & neurosurgery, Genome-Wide Association Study
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

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

Author: Christian Erikstrup, Jon K. Sigurdsson, Dragana Vuckovic, Isleifur Olafsson, Daniel F. Gudbjartsson, Vinicius Tragante, Steven Bell, Stephen Kaptoge, Andreas S. Rigas, Snaedis Kristmundsdottir, Khoa Manh Dinh, Hreinn Stefansson, Helene M. Paarup, Anna Ramond, Kristinn Juliusson, Hannes P. Eggertsson, Pall T. Onundarson, Erik Sørensen, Gudmundur Runarsson, Parsa Akbari, Tao Jiang, Søren Brunak, David J. Roberts, Willem H. Ouwehand, Asmundur Oddsson, Gisli H. Halldorsson, Adam S. Butterworth, James E Peters, Brynjar Vidarsson, Hilma Holm, Magnus I Magnusson, Kari Stefansson, Joanna M. M. Howson, Lise Wegner Thørner, Angela M. Wood, Karina Banasik, Sigrun H. Lund, Henrik Hjalgrim, Olof Sigurdardottir, David Westergaard, Emanuele Di Angelantonio, Unnur Thorsteinsdottir, Henrik Ullum, John Danesh, Gudmar Thorleifsson, Egil Ferkingstad, Michael L. Frigge, Patrick Sulem, Ingileif Jonsdottir, Thomas Hansen, Ole Birger Pedersen, Magnus K. Magnusson, David B. Rye, Dirk S. Paul, Gyda Bjornsdottir, Praveen Surendran, Elias Allara, William J. Astle, Kaspar René Nielsen, Nicole Soranzo, Kristoffer Sølvsten Burgdorf, and United Kingdom Research and Innovation
Subjects: Life Sciences & Biomedicine - Other Topics, 0301 basic medicine, Denmark, Iceland, Medicine (miscellaneous), Transferrin/metabolism, Genome-wide association study, Anemia, Iron-Deficiency/blood, 0302 clinical medicine, Total iron-binding capacity, Risk Factors, Genetics research, Homeostasis, Biology (General), Genetics, education.field_of_study, medicine.diagnostic_test, biology, Anemia, Iron-Deficiency, Transferrin, Iron deficiency, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, TMPRSS6, Iron Overload, Genotype, QH301-705.5, Iron, Population, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Humans, education, Iron/blood, Biology, Science & Technology, Transferrin saturation, Ferritins/blood, DBDS Genomic Consortium, Genetic Variation, medicine.disease, United Kingdom, Ferritin, Iron Overload/blood, 030104 developmental biology, Iron-deficiency anemia, Genetic Loci, Ferritins, biology.protein, Biomarkers/blood, Biomarkers, Genome-Wide Association Study
Abstract: Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation., 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

6. An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript

Author: Elizabeth Selvin, Adam S. Butterworth, Fernando Riveros-Mckay, Nicole Soranzo, Emanuele Di Angelantonio, David J. Roberts, Bing Yu, John Danesh, Inês Barroso, Barroso, Inês [0000-0001-5800-4520], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Endocrinology, Diabetes and Metabolism, Locus (genetics), Genome-wide association study, Receptors, Fc, Biology, Polymorphism, Single Nucleotide, Genetic correlation, Cohort Studies, chemistry.chemical_compound, Gene Frequency, Internal Medicine, Humans, Glycemic, Glycated Hemoglobin, Genetics, Calcium-Binding Proteins, Histocompatibility Antigens Class I, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, Atherosclerosis, United Kingdom, United States, Genetic architecture, Fructosamine, Diabetes Mellitus, Type 2, Gene Expression Regulation, chemistry, Genetic Loci, Expression quantitative trait loci, Female, Glycated hemoglobin, Metabolic Networks and Pathways, Genome-Wide Association Study
Abstract: Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 US White and 2,712 US Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. Here we performed a GWAS on 20,731 European ancestry blood donors, and meta-analysed our results with previous data from US White participants from The Atherosclerosis Risk in Communities (ARIC) study (Nmeta=29,685). We identified a novel association near GCK (rs3757840, betameta=0.0062, MAF=0.49, pmeta=3.66x10-08) and confirmed the association near RCN3 (rs113886122, betameta=0.0134, MAF=0.17, pmeta= 5.71x10-18). Co-localization analysis with whole blood eQTL data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2=7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (p>0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni corrected pFCGRT for downstream functional studies at the established RCN3 locus.
Published: 2021

7. Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

Author: Mohammad Raza, Alison E. Mather, Gilberto Betancor, Ian Merrick, Ben Taylor, Mathew A. Beale, Helen Ward, Samir Dervisevic, Michelle Cronin, Aaron R. Jeffries, Louise Smith, Steven Rudder, Mara K. N. Lawniczak, Sascha Ott, Ashok Dadrah, Luke Bedford, Gabrielle Vernet, Erik M. Volz, Rahul Batra, Johnny Debebe, Caoimhe McKerr, Samantha McGuigan, Oliver Megram, Katie Jones, Mailis Maes, Rebecca Dewar, Emma Swindells, Robert E. Johnson, Myra Hosmillo, Wen C Yew, Vineet Patel, Scott Aj Thurston, Matthew Bashton, Luke B Snell, Lynn Monaghan, David Buck, Gregory R Young, Garren Scott, Louis du Plessis, Sara Kumziene-Summerhayes, David M. Aanensen, Carl Jones, Nadine Holmes, Bernardo Gutierrez, Elizabeth Wastenge, Stavroula F Louka, Dennis Wang, Richard I. Gregory, M. Estée Török, Alistair C. Darby, Ulf Schaefer, Marc Niebel, David Robertson, E. Thomson, Carol Churcher, Patrick C McClure, Scott Elliott, Sarah Jeremiah, Katerina Galai, Matthew W. Loose, Megan Mayhew, Adhyana I K Mahanama, Angeliki Karamani, Naomi R Park, David J. Williams, Lance Turtle, Lucy R. Frost, Alicia Thornton, Jennifier Liddle, M Morgan, Tim Wyatt, Paul W Bird, Chloe Bishop, Esther Robinson, Alasdair MacLean, Inigo Martincorena, Bridget A. Knight, Emma Meader, Thomas R. Connor, Hermione J. Webster, Peter Muir, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Hannah E Bridgewater, David Simpson, Radoslaw Poplawski, Angus I. Best, David Baker, Laura Letchford, Cassie Breen, Yann Bourgeois, Matthew Gemmell, Nikki Smith, Alison Holmes, Iliana Georgana, Christophe Fraser, Natasha Jesudason, Johnathan M Evans, Rachael Stanley, Lesley-Anne Williams, Jessica Lynch, Hannah Lowe, Eleri Wilson-Davies, Paul A. Baker, Alex Makunin, James Bonfield, Helen Adams, Christopher Fearn, Peter J. Diggle, Harry D Wilson, Carmen F. Manso, Nichola Duckworth, D Haw, Anna L. Casey, Audrey Farbos, Sam Haldenby, Vicki Chalker, Roberto Amato, Elen De Lacy, Ben Farr, Eric Witele, Buddhini Samaraweera, G MacIntyre-Cockett, Husam Osman, Jane Greenaway, Justin O'Grady, Sally Forrest, Andrew Nelson, Monika Pusok, A Lloyd, Edward Barton, James W. Harrison, Sophie Palmer, Amanda Symmonds, James Shepherd, Nazreen F. Hadjirin, Stephen L. Michell, Mohammed O Hassan-Ibrahim, Fiona Ashcroft, Daniel Mair, Richard H. Myers, Dianne Irish-Tavares, Hannah C. Howson-Wells, Jacqui Prieto, Christine Sambles, Andrew Hesketh, Alp Aydin, Sónia Gonçalves, Tabitha Mahungu, Tanzina Haque, Nicholas Ellaby, Karen Oliver, Hannah Paul, Joanne Watts, Claire McMurray, Lisa J Levett, Darren Smith, Simon Cottrell, Joanna Warwick-Dugdale, Pinglawathee Madona, Matthew J. Dorman, Lizzie Meadows, Ali R Awan, Leanne M Kermack, Jennifer Hart, Angie Lackenby, Carol Scott, Michael Spencer Chapman, Lucille Rainbow, Kyriaki Nomikou, Julianne R Brown, Juan Ledesma, Adam P Westhorpe, Giri Shankar, Karlie Fallon, Tim J Sloan, Joanne Watkins, Robert Impey, Sue Edwards, Rebecca C H Brown, Robin J Moll, Karla Spellman, Laura Gifford, Jamie Young, Adrienn Angyal, Graham Phillip Taylor, Robin Manley, Gavin Dabrera, Michelle Wantoch, Rachel Williams, David Heyburn, Mirko Menegazzo, Derrick W. Crook, Gaia Nebbia, Rachel Nelson, Elaine O'Toole, Luke Foulser, Katherine L Harper, Fatima Downing, Hassan Hartman, Nathan Moore, Gemma L. Kay, Matthew Wyles, Thanh Le-Viet, Edith Vamos, John Sillitoe, Lesley Shirley, Nicholas J. Loman, Iona Willingham, Elihu Aranday-Cortes, Ian B Vipond, Jeremy Mirza, Alberto C Cerda, Michelle L Michelsen, Steven Riley, Alison Cox, Igor Siveroni, Nadua Bayzid, Shavanthi Rajatileka, Giselda Bucca, Benjamin J Cogger, Tim Boswell, Matthew J. Bull, Stephen Carmichael, Lisa Berry, Frances Bolt, Kylie E. C. Ainslie, Martyn Guest, Sarojini Pandey, Katherine L. Bellis, Shane A. McCarthy, Christopher Ruis, Fei Sang, David Bonsall, Danni Weldon, Alex Alderton, Lee Graham, Amy Trebes, Sally Corden, Adrian W Signell, Tanya Golubchik, Huw Gulliver, Rocio Martinez Nunez, Dinesh Aggarwal, Tanya Curran, Jonathan K. Ball, Sharif Shaaban, Paul Randell, Jillian Durham, Alec Birchley, Matilde Mori, Joana Dias, Katherine A Twohig, Grant Hall, Antony D Hale, Alan McNally, Jonathan D. Edgeworth, Safiah Afifi, Andrew Rambaut, Katherine Smollett, David N. Lee, Tamyo Mbisa, Shahjahan Miah, Steven Rushton, Grace Taylor-Joyce, Hannah M Pymont, Chloe L Fisher, Cordelia Langford, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Kathleen A. Williamson, Anna Price, Holli Carden, Khalil Abudahab, Joanne D. Stockton, Meera Unnikrishnan, Jennifer Collins, Emma Moles-Garcia, Michaela John, Christine Kitchen, Tranprit Saluja, Ian Harrison, Lily Tong, Thomas G. Thompson, Thomas Helmer, Amita Patel, Siona Silveira, Deborah Ashby, Claire M Bewshea, Anita Justice, Brendan A I Payne, Alexander J. Trotter, Nikos Manesis, Katie F. Loveson, Cristina V. Ariani, Wendy Chatterton, Robert J. Munn, Julian A. Hiscox, Robert Beer, Judith Breuer, Caroline E. Walters, Liam Crawford, Ara Darzi, Will P. M. Rowe, Cariad Evans, Matthew Parker, Tammy V Merrill, Louise Aigrain, Joshua Quick, Leigh M Jackson, Samuel M. Nicholls, Jonathan W. Moore, John A Hartley, Graham P. Taylor, Cherian Koshy, Shirelle Burton-Fanning, Sheila Waugh, Catherine Moore, Danielle C. Groves, Peijun Zhang, Sahar Eldirdiri, Derek Fairley, Tim E. A. Peto, Jack Cd Lee, Sharon Glaysher, Liam Prestwood, Hannah Dent, Anita Kenyon, Stephen P. Kidd, Nick Levene, Igor Starinskij, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Laia Fina, Angela Marchbank, Daniel Bradshaw, Marina Escalera Zamudio, Scott Goodwin, Andrew D Beggs, Seema Nickbakhsh, Trevor Robinson, Christina Atchison, David K. Jackson, Kathy Li, Rory Gunson, Sunando Roy, Graham S Cooke, Steven Liggett, Yasmin Chaudhry, Anoop Chauhan, Ben Temperton, Mariateresa de Cesare, Paul E Brown, Li Xu-McCrae, Martin P McHugh, Catherine Ludden, Wendy Smith, Danielle Leek, Divya K. Shah, Judith Heaney, Dominic P. Kwiatkowski, Kate M. Johnson, Robin Howe, Malorie Perry, Tetyana I. Vasylyeva, David F. Bibby, Haowei Wang, Steve Palmer, Nicholas W Machin, Charlotte A Williams, Bree Gatica-Wilcox, Angie Green, John A. Todd, Paul Elliott, Noel Craine, Jeffrey K. J. Cheng, Kate Templeton, Jonathan Hubb, Joshua Maksimovic, Christl A. Donnelly, Monique Andersson, Christopher Holmes, Dimitris Grammatopoulos, Christopher B. Williams, David G Partridge, Aminu S Jahun, Alexander Adams, Marius Cotic, Sarah Essex, Christopher J. Moore, Trudy Workman, Nicola Sheriff, Helen L Lowe, Ewan M. Harrison, Dorota Jamrozy, Rachel Jones, Ellen Higginson, Erwan Acheson, Christopher R. Jones, Oliver G. Pybus, Francesc Coll, Sian Morgan, Paul J. Parsons, Patawee Asamaphan, Veena Raviprakash, Andrew R. Bassett, Declan Bradley, Laura Atkinson, Anthony Underwood, Graciela Sluga, Sally Kay, Ellena Brooks, Oliver Eales, Andrew Whitwham, Surendra Parmar, Angela Cowell, Nicole Pacchiarini, Theocharis Tsoleridis, Jason Coombes, Robert Davies, Flavia Flaviani, Benita Percival, Jenna Nichols, Natasha M. Johnson, Salman Goudarzi, Hibo Asad, Amanda Bradley, Hannah Jones, Chrystala Constantinidou, Georgina M McManus, Minal Patel, Steven Leonard, Rebecca Williams Bmbs, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Amy Ash, John Danesh, Corin Yeats, Claudia Wierzbicki, Kordo Saeed, John Boyes, Michael A. Quail, Sharon J. Peacock, Nabil-Fareed Alikhan, Jon-Paul Keatley, Claudio Fronterre, Garry Scarlett, James McKenna, Thushan I de Silva, Malte L Pinckert, Kate B. Cook, Amy Gaskin, Rajiv Shah, Matthew T. G. Holden, Sophie J Prosolek, Nathaniel Storey, Ryan P George, Lindsay Coupland, Jenifer Mason, Matthew Carlile, Thomas D Stanton, Guy Mollett, Siddharth Mookerjee, Mary Ramsay, Steven Platt, Stephen W Attwood, Susanne Stonehouse, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Mark Whitehead, Catherine Bresner, Stefanie V Lensing, Louissa R Macfarlane-Smith, Colin P. Smith, Wendy Hogsden, Charlotte Nelson, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Samuel Robson, Zoltán Molnár, Emma L. Wise, Sian Ellard, Kim S Smith, Alice Broos, Manjinder Khakh, Kathryn A Jackson, Claire Cormie, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Meera Chand, Debra Padgett, Cassandra S Malone, James V. Price, Themoula Charalampous, Ronan A Lyons, Natalie Groves, Stefan Rooke, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Michelle Lister, Carlos Balcazar, Ana da Silva Filipe, Ben Warne, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Rose K Davidson, Angela Helen Beckett, Ember Hilvers, Kathryn McCluggage, Eileen Gallagher, Charlotte Beaver, Nick Cortes, Alisha Davies, Yusri Taha, Leah Ensell, Emanuela Pelosi, Elias Allara, Cressida Auckland, Eleanor Drury, Richard Eccles, Adela Alcolea-Medina, William L Hamilton, Rich Livett, Rachel Blacow, Margaret Hughes, Sarah François, Melisa Louise Fenton, Liz Ratcliffe, Verity Hill, Stephanie Hutchings, Kathryn Ann Harris, Emma Betteridge, William D. Fuller, Sophia T Girgis, Louise Berry, Gemma Clark, Nicholas M Redshaw, Richard Hopes, Leonardo de Oliveira Martins, Alexander J Keeley, Beth Blane, Wendy S. Barclay, Victoria Wright, Anita Lucaci, Luke R. Green, Fenella D. Halstead, Sarah Wyllie, Iraad F. Bronner, Áine O'Toole, Ravi Gupta, Leanne Kane, Clare M. McCann, Michael R Chapman, David W Eyre, Kelly Bicknell, Aileen G. Rowan, Sara Rey, Shazaad Ahmad, Diana Rajan, S Taylor, Sarah J. O'Brien, Alessandro M Carabelli, Amelia Joseph, Max Whiteley, Riaz Jannoo, Victoria Blakey, Martin D. Curran, David J. Studholme, Harmeet K Gill, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Julian Tang, Clare Pearson, Mark Kristiansen, Miren Iturriza-Gomara, National Institute for Health Research, and UK Research and Innovation
Subjects: Delta, Adult, Male, 2019-20 coronavirus outbreak, COVID-19 Vaccines, Vaccination Coverage, Coronavirus disease 2019 (COVID-19), Adolescent, General Science & Technology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Vaccine Efficacy, Biology, Young Adult, Exponential growth, Ethnicity, Prevalence, Humans, Child, Aged, Family Characteristics, Multidisciplinary, High prevalence, COVID-19 Genomics UK (COG-UK) Consortium11‡, SARS-CoV-2, Age Factors, COVID-19, Middle Aged, Virology, Hospitalization, England, Socioeconomic Factors, COVID-19 Nucleic Acid Testing, Child, Preschool, Female, Self Report
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.
Published: 2021

8. Polygenic basis and biomedical consequences of telomere length variation

Author: Christopher P. Nelson, Veryan Codd, John R Thompson, Crispin Musicha, Tao Jiang, Angela M. Wood, Shilpi Sheth, Charley A. Budgeon, Willem H. Ouwehand, Emanuele Di Angelantonio, Svetlana Stoma, Vasiliki Bountziouka, Matthew Denniff, Peter S. Braund, James Eales, Stephen E. Hamby, Sophie C Warner, Dominika E Nanus, Qingning Wang, Stephen Kaptoge, Chloe Swinfield, Amit Khera, Manolo Papakonstantinou, Nilesh J. Samani, Adam S. Butterworth, John Danesh, Minxian Wang, Elias Allara, Codd, Veryan [0000-0002-9430-8254], Allara, Elias [0000-0002-1634-8330], Braund, Peter S. [0000-0001-8540-5709], Papakonstantinou, Manolo [0000-0003-2664-9046], Wang, Minxian [0000-0002-3753-508X], Khera, Amit V. [0000-0001-6535-5839], Eales, James [0000-0001-6238-5952], Ouwehand, Willem H. [0000-0002-7744-1790], Thompson, John R. [0000-0003-4819-1611], Butterworth, Adam S. [0000-0002-6915-9015], Samani, Nilesh J. [0000-0002-3286-8133], Apollo - University of Cambridge Repository, Braund, Peter S [0000-0001-8540-5709], Khera, Amit V [0000-0001-6535-5839], Ouwehand, Willem H [0000-0002-7744-1790], Thompson, John R [0000-0003-4819-1611], Butterworth, Adam S [0000-0002-6915-9015], Samani, Nilesh J [0000-0002-3286-8133], Kaptoge, Stephen [0000-0002-1155-4872], Ouwehand, Willem [0000-0002-7744-1790], Di Angelantonio, Emanuele [0000-0001-8776-6719], Wood, Angela [0000-0002-7937-304X], Butterworth, Adam [0000-0002-6915-9015], and Danesh, John [0000-0003-1158-6791]
Subjects: Senescence, Multifactorial Inheritance, media_common.quotation_subject, Quantitative Trait Loci, 631/208/205/2138, 45/43, Computational biology, Biology, Genome-wide association studies, Health data, Length variation, Genetics research, Genetics, Humans, media_common, Basis (linear algebra), Genome, Human, Longevity, 692/308/2056, article, Telomere Homeostasis, Mendelian Randomization Analysis, Biobank, Phenotype, Genetic architecture, Telomere, Evolutionary biology, Function (biology), Genome-Wide Association Study
Abstract: Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607)., Funder: Health Data Research UK, Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.
Published: 2021

9. Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Author: Erin Macdonald-Dunlop, Lucija Klarić, Lasse Folkersen, Paul R.H.J. Timmers, Stefan Gustafsson, Jing Hua Zhao, Niclas Eriksson, Anne Richmond, Stefan Enroth, Niklas Mattsson-Carlgren, Daria V. Zhernakova, Anette Kalnapenkis, Martin Magnusson, Eleanor Wheeler, Shih-Jen Hwang, Yan Chen, Andrew P Morris, Bram Prins, Urmo Võsa, Nicholas J. Wareham, John Danesh, Johan Sundstrom, Bruna Gigante, Damiano Baldassarre, Rona J. Strawbridge, Harry Campbell, Ulf Gyllensten, Chen Yao, Daniela Zanetti, Themistocles L. Assimes, Per Eriksson, Daniel Levy, Claudia Langenberg, J. Gustav Smith, Tõnu Esko, Jingyuan Fu, Oskar Hansson, Åsa Johansson, Caroline Hayward, Lars Wallentin, Agneta Siegbahn, Lars Lind, Adam S. Butterworth, Karl Michaëlsson, James E. Peters, Anders Mälarstig, Peter K. Joshi, and James F. Wilson
Subjects: Genetics, medicine.medical_specialty, Genetic epidemiology, Expression quantitative trait loci, DNA methylation, medicine, Medical genetics, Disease, Quantitative trait locus, Biology, medicine.disease, Inflammatory bowel disease, Genetic architecture
Abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
Published: 2021

10. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

Author: Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian Saliba, Katja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta, Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O’Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Áine O’Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Grammatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Anita O. Lucaci, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Sam T. Haldenby, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I.K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Radoslaw Poplawski, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-Summerhayes, Sarah Taylor, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U.G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Dorota Jamrozy, Stephanie Lo, Minal Patel, Verity Hill, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S.Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O’Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A.J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V. Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J. Webster, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O’Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, Rob Johnson, Irina Abnizova, Mozam Ali, Laura Allen, Ralph Anderson, Cristina Ariani, Siobhan Austin-Guest, Sendu Bala, Jeffrey Barrett, Andrew Bassett, Kristina Battleday, James Beal, Mathew Beale, Sam Bellany, Tristram Bellerby, Katie Bellis, Duncan Berger, Matt Berriman, Paul Bevan, Simon Binley, Jason Bishop, Kirsty Blackburn, Nick Boughton, Sam Bowker, Timothy Brendler-Spaeth, Iraad Bronner, Tanya Brooklyn, Sarah Kay Buddenborg, Robert Bush, Catarina Caetano, Alex Cagan, Nicola Carter, Joanna Cartwright, Tiago Carvalho Monteiro, Liz Chapman, Tracey-Jane Chillingworth, Peter Clapham, Richard Clark, Adrian Clarke, Catriona Clarke, Daryl Cole, Elizabeth Cook, Maria Coppola, Linda Cornell, Clare Cornwell, Craig Corton, Abby Crackett, Alison Cranage, Harriet Craven, Sarah Craw, Mark Crawford, Tim Cutts, Monika Dabrowska, Matt Davies, Joseph Dawson, Callum Day, Aiden Densem, Thomas Dibling, Cat Dockree, David Dodd, Sunil Dogga, Matthew Dorman, Gordon Dougan, Martin Dougherty, Alexander Dove, Lucy Drummond, Monika Dudek, Laura Durrant, Elizabeth Easthope, Sabine Eckert, Pete Ellis, Ben Farr, Michael Fenton, Marcella Ferrero, Neil Flack, Howerd Fordham, Grace Forsythe, Matt Francis, Audrey Fraser, Adam Freeman, Anastasia Galvin, Maria Garcia-Casado, Alex Gedny, Sophia Girgis, James Glover, Oliver Gould, Andy Gray, Emma Gray, Coline Griffiths, Yong Gu, Florence Guerin, Will Hamilton, Hannah Hanks, Ewan Harrison, Alexandria Harrott, Edward Harry, Julia Harvison, Paul Heath, Anastasia Hernandez-Koutoucheva, Rhiannon Hobbs, Dave Holland, Sarah Holmes, Gary Hornett, Nicholas Hough, Liz Huckle, Lena Hughes-Hallet, Adam Hunter, Stephen Inglis, Sameena Iqbal, Adam Jackson, David Jackson, Carlos Jimenez Verdejo, Matthew Jones, Kalyan Kallepally, Keely Kay, Jon Keatley, Alan Keith, Alison King, Lucy Kitchin, Matt Kleanthous, Martina Klimekova, Petra Korlevic, Ksenia Krasheninnkova, Greg Lane, Cordelia Langford, Adam Laverack, Katharine Law, Stefanie Lensing, Amanah Lewis-Wade, Jennifer Liddle, Quan Lin, Sarah Lindsay, Sally Linsdell, Rhona Long, Jamie Lovell, Jon Lovell, James Mack, Mark Maddison, Aleksei Makunin, Irfan Mamun, Jenny Mansfield, Neil Marriott, Matt Martin, Matthew Mayho, Jo McClintock, Sandra McHugh, Liz MapcMinn, Carl Meadows, Emily Mobley, Robin Moll, Maria Morra, Leanne Morrow, Kathryn Murie, Sian Nash, Claire Nathwani, Plamena Naydenova, Alexandra Neaverson, Ed Nerou, Jon Nicholson, Tabea Nimz, Guillaume G. Noell, Sarah O’Meara, Valeriu Ohan, Charles Olney, Doug Ormond, Agnes Oszlanczi, Yoke Fei Pang, Barbora Pardubska, Naomi Park, Aaron Parmar, Gaurang Patel, Maggie Payne, Sharon Peacock, Arabella Petersen, Deborah Plowman, Tom Preston, Michael Quail, Richard Rance, Suzannah Rawlings, Nicholas Redshaw, Joe Reynolds, Mark Reynolds, Simon Rice, Matt Richardson, Connor Roberts, Katrina Robinson, Melanie Robinson, David Robinson, Hazel Rogers, Eduardo Martin Rojo, Daljit Roopra, Mark Rose, Luke Rudd, Ramin Sadri, Nicholas Salmon, David Saul, Frank Schwach, Phil Seekings, Alison Simms, Matt Sinnott, Shanthi Sivadasan, Bart Siwek, Dale Sizer, Kenneth Skeldon, Jason Skelton, Joanna Slater-Tunstill, Lisa Sloper, Nathalie Smerdon, Chris Smith, Christen Smith, James Smith, Katie Smith, Michelle Smith, Sean Smith, Tina Smith, Leighton Sneade, Carmen Diaz Soria, Catarina Sousa, Emily Souster, Andrew Sparkes, Michael Spencer-Chapman, Janet Squares, Robert Stanley, Claire Steed, Tim Stickland, Ian Still, Mike Stratton, Michelle Strickland, Allen Swann, Agnieszka Swiatkowska, Neil Sycamore, Emma Swift, Edward Symons, Suzanne Szluha, Emma Taluy, Nunu Tao, Katy Taylor, Sam Taylor, Stacey Thompson, Mark Thompson, Mark Thomson, Nicholas Thomson, Scott Thurston, Dee Toombs, Benjamin Topping, Jaime Tovar-Corona, Daniel Ungureanu, James Uphill, Jana Urbanova, Philip Jansen Van, Valerie Vancollie, Paul Voak, Danielle Walker, Matthew Walker, Matt Waller, Gary Ward, Charlie Weatherhogg, Niki Webb, Alan Wells, Eloise Wells, Luke Westwood, Theo Whipp, Thomas Whiteley, Georgia Whitton, Sara Widaa, Mia Williams, Mark Wilson, Sean Wright, and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Resistance, MC UU 1201412, Plasma protein binding, Antibodies, Viral, medicine.disease_cause, MR/R024758/1, 0302 clinical medicine, Recurrence, Chlorocebus aethiops, deletion, Biology (General), Receptor, Phylogeny, Infectivity, Mutation, biology, infectivity, MC_UU_12014/12, C500, C700, UKRI, MRC, Antibody Escape, Spike Glycoprotein, Coronavirus, antibody escape, Antibody, Protein Binding, QH301-705.5, Sars-cov-2, Alpha (ethology), Article, General Biochemistry, Genetics and Molecular Biology, Virus, Cell Line, resistance, Deletion, 03 medical and health sciences, spike mutation, medicine, Alpha Variant, Animals, Humans, neutralizing antibodies, B.1.1.7, Vero Cells, Pandemics, Immune Evasion, SARS-CoV-2, Biochemistry, Genetics and Molecular Biology(all), COVID-19, MR/P008801/1, Antibodies, Neutralizing, Virology, body regions, HEK293 Cells, 030104 developmental biology, Alpha variant, Spike Mutation, biology.protein, Vero cell, Neutralizing Antibodies, 030217 neurology & neurosurgery
Abstract: We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted., Graphical abstract, Meng et al. report that the SARS-CoV-2 spike ΔH69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires ΔH69/V70 for efficient cell entry and cell-cell fusion activity.
Published: 2021

11. Accuracy of four lateral flow immunoassays for anti SARS-CoV-2 antibodies: a head-to-head comparative study

Author: Tim Brooks, Ranya Mulchandani, A E Ades, Sian Taylor-Phillips, Keith R Perry, David H. Wyllie, Matthew Hickman, Hayley E Jones, Isabel Oliver, Stephen Kaptoge, Emanuele Di Angelantonio, Andre Charlett, Nastassya L Chandra, Edsab-Home Study Investigators, John Danesh, Compare study investigators, Justin Shute, Kaptoge, Stephen [0000-0002-1155-4872], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], and Apollo - University of Cambridge Repository
Subjects: education.field_of_study, biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Population, Context (language use), EDSAB-HOME investigators, Confidence interval, Sample size determination, COMPARE study investigators, Statistics, biology.protein, False positive paradox, Seroprevalence, Medicine, Antibody, education, business
Abstract: BackgroundSARS-CoV-2 antibody tests are used for population surveillance and might have a future role in individual risk assessment. Lateral flow immunoassays (LFIAs) can deliver results rapidly and at scale, but have widely varying accuracy.MethodsIn a laboratory setting, we performed head-to-head comparisons of four LFIAs: the Rapid Test Consortium’s AbC-19™Rapid Test, OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19 Rapid Test Cassette, and Biomerica COVID-19 IgG/IgM Rapid Test. We analysed blood samples from 2,847 key workers and 1,995 pre-pandemic blood donors with all four devices.FindingsWe observed a clear trade-off between sensitivity and specificity: the IgG band of the SureScreen device and the AbC-19™device had higher specificities but OrientGene and Biomerica higher sensitivities. Based on analysis of pre-pandemic samples, SureScreen IgG band had the highest specificity (98.9%, 95% confidence interval 98.3 to 99.3%), which translated to the highest positive predictive value across any pre-test probability: for example, 95.1% (95%CI 92.6, 96.8%) at 20% pre-test probability. All four devices showed higher sensitivity at higher antibody concentrations (“spectrum effects”), but the extent of this varied by device.InterpretationThe estimates of sensitivity and specificity can be used to adjust for test error rates when using these devices to estimate the prevalence of antibody. If tests were used to determine whether an individual has SARS-CoV-2 antibodies, in an example scenario in which 20% of individuals have antibodies we estimate around 5% of positive results on the most specific device would be false positives.FundingPublic Health England.Research in contextEvidence before this studyWe searched for evidence on the accuracy of the four devices compared in this study: OrientGene COVID IgG/IgM Rapid Test Cassette, SureScreen COVID-19™ Rapid Test Cassette, Biomerica COVID-19 IgG/IgM Rapid Test and the UK Rapid Test Consortium’s AbC-19™ Rapid Test. We searched Ovid MEDLINE (In-Process & Other Non-Indexed Citations and Daily), PubMed, MedRxiv/BioRxiv and Google Scholar from January 2020 to 16thJanuary 2021. Search terms included device names AND ((SARS-CoV-2) OR (covid)). Of 303 records assessed, data were extracted from 24 studies: 18 reporting on the accuracy of the OrientGene device, 7 SureScreen, 2 AbC-19™ and 1 Biomerica. Only three studies compared the accuracy of two or more of the four devices. With the exception of our previous report on the accuracy of the AbC-19™ device, which the current manuscript builds upon, sample size ranged from 7 to 684. For details, see Supplementary Materials.The largest study compared OrientGene, SureScreen and Biomerica. SureScreen was estimated to have the highest specificity (99.8%, 95% CI 98.9 to 100%) and OrientGene the highest sensitivity (92.6%), but with uncertainty about the latter result due to small sample sizes. The other two comparative studies were small (n = 65, n = 67) and therefore provide very uncertain results.We previously observed spectrum effects for the AbC-19™ device, such that sensitivity is upwardly biased if estimated only from PCR-confirmed cases. The vast majority of previous studies estimated sensitivity in this way.Added value of this studyWe performed a large scale (n = 4,842), head-to-head laboratory-based evaluation and comparison of four lateral flow devices, which were selected for evaluation by the UK Department of Health and Social Care’s New Tests Advisory Group, on the basis of a survey of test and performance data available. We evaluated the performance of diagnosis based on both IgG and IgM bands, and the IgG band alone. We found a clear trade-off between sensitivity and specificity across devices, with the SureScreen and AbC-19™ devices being more specific and OrientGene and Biomerica more sensitive. Based on analysis of 1,995 pre-pandemic blood samples, we are 99% confident that SureScreen (IgG band reading) has the highest specificity of the four devices (98.9%, 95% CI 98.3, 99.3%).We found evidence that all four devices have reduced sensitivity at lower antibody indices, i.e. spectrum effects. However, the extent of this varies by device and appears to be less for other devices than for AbC-19.Our estimates of sensitivity and specificity are likely to be higher than would be observed in real use of these devices, as they were based on majority readings of three trained laboratory personnel.Implications of all the available evidenceWhen used in epidemiological studies of antibody prevalence, the estimates of sensitivity and specificity provided in this study can be used to adjust for test errors. Increased precision in error rates will translate to increased precision in seroprevalence estimates. If lateral flow devices were used for individual risk assessment, devices with maximum specificity would be preferable. However, if, for an example, 20% of the tested population had antibodies, we estimate that around 1 in 20 positive results on the most specific device would be incorrect.
Published: 2021

12. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author: Phuwanat Sakornsakolpat, James F. Wilson, María Soler Artigas, Beate Stubbe, Nicholas J. Wareham, James D. Crapo, Victoria E. Jackson, Eleftheria Zeggini, Olga G. Troyanskaya, Medea Imboden, A. Mesut Erzurumluoglu, Adam S. Butterworth, Carl A. Melbourne, Ian Sayers, Lars Lind, Stefan Weiss, Margaret M. Parker, Timmers Prhj, Edwin K. Silverman, John C. Whittaker, Ian P. Hall, Ozren Polasek, Mika Kähönen, Katherine A. Fawcett, Anna Hansell, Liming Li, David J. Porteous, Louise V. Wain, Robert A. Scott, Richard Packer, Richard J. Allen, Robin G Walters, Anna L. Guyatt, Terho Lehtimäki, Nicole Probst-Hensch, Shona M. Kerr, Christian Gieger, Matthias Wielscher, Rajesh Rawal, Jing Hua Zhao, John E. Hokanson, Holger Schulz, Nicola F. Reeve, Claudia Langenberg, Ke Hao, Corry-Anke Brandsma, Megan L. Paynton, Vitart, Dmitry Prokopenko, Jennie Hui, Eugene R. Bleecker, Ma'en Obeidat, John Danesh, Ralf Ewert, Benjamin B. Sun, Frank Dudbridge, Jian Zhou, Brian D. Hobbs, Blair H. Smith, Don D. Sin, Dawn L. DeMeo, Joseph C. Maranville, Ida Surakka, Alison Catherine Murray, Nicholas Locantore, Katherine A. Kentistou, Terri H. Beaty, Igor Rudan, Kuang Lin, Amund Gulsvik, Ian J. Deary, Ruth Tal-Singer, Kijoung Song, David C. Nickle, Michael H. Cho, Jian'an Luan, Joshua D. Hoffman, Georg Homuth, Zhengming Chen, Dandi Qiao, Heiko Runz, Per Bakke, Chiara Batini, Caroline Hayward, Stefan Karrasch, Alan James, Andrew P. Morris, Prescott G. Woodruff, Laura M Yerges Armstrong, David Sparrow, Ulf Gyllensten, James P. Cook, Jonathan Marten, Olli T. Raitakari, Nick Shrine, Deborah A. Meyers, Tobin, Ruth Boxall, Marjo-Riitta Järvelin, David P. Strachan, Sarah E. Harris, Philippe Joubert, Stefan Enroth, Xingnan Li, van den Berge M, Anubha Mahajan, Yohan Bossé, Peter K. Joshi, Shrine, Nick [0000-0003-3641-4371], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Sakornsakolpat, Phuwanat [0000-0002-4308-0974], Obeidat, Ma'en [0000-0002-5443-2752], Weiss, Stefan [0000-0002-3553-4315], Kentistou, Katherine A [0000-0002-5816-664X], Sun, Benjamin B [0000-0001-6347-2281], Enroth, Stefan [0000-0002-5056-9137], Vitart, Veronique [0000-0002-4991-3797], Allen, Richard J [0000-0002-8450-3056], Beaty, Terri H [0000-0002-7644-1705], Bossé, Yohan [0000-0002-3067-3711], Joshi, Peter K [0000-0002-6361-5059], Mahajan, Anubha [0000-0001-5585-3420], Murray, Alison [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Sayers, Ian [0000-0001-5601-5410], Smith, Blair H [0000-0002-5362-9430], Tal-Singer, Ruth [0000-0002-5275-8062], Timmers, Paul RHJ [0000-0002-5197-1267], Troyanskaya, Olga G [0000-0002-5676-5737], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Zeggini, Eleftheria [0000-0003-4238-659X], Hayward, Caroline [0000-0002-9405-9550], Morris, Andrew P [0000-0002-6805-6014], Butterworth, Adam S [0000-0002-6915-9015], Walters, Robin G [0000-0002-9179-0321], Cho, Michael H [0000-0002-4907-1657], Strachan, David P [0000-0001-7854-1366], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Groningen Research Institute for Asthma and COPD (GRIAC), UNIVERSITY OF OULU, and Commission of the European Communities
Subjects: Male, Smoking/genetics, LOCI, Genome-wide association study, VARIANTS, Bioinformatics, Genome-wide association studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GWAS, GENOME-WIDE ASSOCIATION, HERITABILITY, COPD, Lung, 11 Medical and Health Sciences, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Genetic Predisposition to Disease/genetics, Smoking, 1184 Genetics, developmental biology, physiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, 3. Good health, medicine.anatomical_structure, Meta-analysis, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Understanding Society Scientific Group, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Aged, Respiratory tract diseases, Science & Technology, Case-control study, Lung/physiopathology, 06 Biological Sciences, medicine.disease, Pulmonary Disease, Chronic Obstructive/genetics, respiratory tract diseases, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.
Published: 2019

13. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author: Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology
Subjects: Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.
Published: 2022

14. DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes

Author: Danish Saleheen, Nilesh J. Samani, Seyedeh M. Zekavat, Ruth McPherson, Sekar Kathiresan, Diego Ardissino, James G. Wilson, Heribert Schunkert, Amit Khera, Connor A. Emdin, Namrata Gupta, Matthew J. Bown, John Danesh, Mark Chaffin, Pradeep Natarajan, Stacey Gabriel, Jeanette Erdmann, Mary E. Haas, Hugh Watkins, Usman Baber, Roberto Elosua, Alexander G. Bick, Krishna G. Aragam, Derek Klarin, and Akihiro Nomura
Subjects: 0301 basic medicine, medicine.medical_specialty, Diabetis, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, Odds ratio, Type 2 diabetes, Activin receptor, Biology, Lower risk, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Genetic predisposition, Receptor
Abstract: A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes. This work was funded by the National Institutes of Health (R01 HL127564 to S.K.), which had no involvement in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, and approval of the manuscript. This project was also conducted using the Type 2 Diabetes Knowledge Portal resource which is funded by the Accelerating Medicines Partnership. REGICOR study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research andTechnology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). NJS is supported by the British Heart Foundation and is a NIHR Senior Investigator. The Munich MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02).This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Vascular Biology (ATVB) Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010-2012 Area 1–Strategic Programmes– Diabetes Page 30 of 53 30 Regione Emilia-Romagna. Funding for the exome-sequencing project (ESP) was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. Exome sequencing in ATVB, PROCARDIS, Ottawa, PROMIS, Southern German Myocardial Infarction Study, and the Jackson Heart Study was supported by 5U54HG003067 (to Dr. Gabriel).
Published: 2018

15. Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Author: Barbara Thorand, Lars Lind, Anne Richmond, Artemis Papadaki, Erola Pairo-Castineira, Oskar Hansson, Andreas Göteson, Dirk S. Paul, Nicola Pirastu, Eleanor Wheeler, Stefan Enroth, Chen Yao, Karsten Suhre, John Danesh, Daniel Levy, Lucija Klaric, Tõnu Esko, Jingyuan Fu, Shih-Jen Hwang, Daniela Zanetti, Themistocles L. Assimes, James F. Wilson, Niclas Eriksson, Nicholas J. Wareham, Karl Michaëlsson, Caroline Hayward, Stefan Gustafsson, Daria V. Zhernakova, Anders Mälarstig, Peter K. Joshi, Martin Magnusson, Christian Gieger, John R. Petrie, Claudia Langenberg, Rona J Strawbridge, Christian Herder, James E. Peters, Åsa K. Hedman, Erin Macdonald-Dunlop, Arianna Landini, Bram Prins, Mikael Landén, J Kenneth Baillie, Niklas Mattsson-Carlgren, Harry Campbell, Johan Sundström, Charles Kooperberg, Jack Gisby, Yan Chen, Leonid Padyukov, Lars Wallentin, Paul R. H. J. Timmers, Alexander P. Reiner, Adam S. Butterworth, Agneta Siegbahn, Lasse Folkersen, Alex Tokolyi, Bruna Gigante, J. Gustav Smith, Mark Walker, Urmo Võsa, Ulf Gyllensten, Marisa D Muckian, Åsa Johansson, Anette Kalnapenkis, Andrew P. Morris, Elodie Persyn, and Jing Hua Zhao
Subjects: Exon, Mediator, Apoptosis, Alternative splicing, Immunology, Locus (genetics), macromolecular substances, Biology, Quantitative trait locus, Receptor, Cytokine receptor, Article
Abstract: Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at theFASlocus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
Published: 2021

16. Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates

Author: Nicholas J. Timpson, David J. Roberts, Nicholas A. Watkins, George Davey Smith, Nicole Soranzo, Joshua A. Bell, Lucy J Goudswaard, Adam S. Butterworth, Ingeborg Hers, Willem H. Ouwehand, Klaudia Walter, Laura J Corbin, David A. Hughes, John Danesh, and Emanuele Di Angelantonio
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Proteome, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, Genome-wide association study, Disease, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Sex hormone-binding globulin, Internal medicine, Surveys and Questionnaires, Medicine, Humans, Prospective Studies, Adiposity, Nutrition and Dietetics, biology, business.industry, Leptin, Confounding, Mendelian Randomization Analysis, Middle Aged, Blood proteins, 030104 developmental biology, biology.protein, Observational study, Female, business, Body mass index
Abstract: Background Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. Methods We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. Results Observationally, BMI was associated with 1576 proteins (P −5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48–0.79, P = 1.6 × 10−15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46–0.83, P = 6.7 × 10−12) and SHBG (−0.45 SD per SD BMI, 95% CI −0.65 to −0.25, P = 1.4 × 10−5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
Published: 2021

17. Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Author: Erik Volz, Verity Hill, John T. McCrone, Anna Price, David Jorgensen, Áine O’Toole, Joel Southgate, Robert Johnson, Ben Jackson, Fabricia F. Nascimento, Sara M. Rey, Samuel M. Nicholls, Rachel M. Colquhoun, Ana da Silva Filipe, James Shepherd, David J. Pascall, Rajiv Shah, Natasha Jesudason, Kathy Li, Ruth Jarrett, Nicole Pacchiarini, Matthew Bull, Lily Geidelberg, Igor Siveroni, Ian Goodfellow, Nicholas J. Loman, Oliver G. Pybus, David L. Robertson, Emma C. Thomson, Andrew Rambaut, Thomas R. Connor, Cherian Koshy, Emma Wise, Nick Cortes, Jessica Lynch, Stephen Kidd, Matilde Mori, Derek J. Fairley, Tanya Curran, James P. McKenna, Helen Adams, Christophe Fraser, Tanya Golubchik, David Bonsall, Catrin Moore, Sarah L. Caddy, Fahad A. Khokhar, Michelle Wantoch, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Michaela John, Robert Beer, Safiah Afifi, Sian Morgan, Angela Marchbank, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Trudy Workman, William Fuller, Catherine Bresner, Luke B. Snell, Themoula Charalampous, Gaia Nebbia, Rahul Batra, Jonathan Edgeworth, Samuel C. Robson, Angela Beckett, Katie F. Loveson, David M. Aanensen, Anthony P. Underwood, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, Gemma Clark, Wendy Smith, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Paul Bird, Thomas Helmer, Karlie Fallon, Christopher Holmes, Julian Tang, Veena Raviprakash, Sharon Campbell, Nicola Sheriff, Matthew W. Loose, Nadine Holmes, Christopher Moore, Matthew Carlile, Victoria Wright, Fei Sang, Johnny Debebe, Francesc Coll, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Theresa Feltwell, Charlotte J. Houldcroft, Sahar Eldirdiri, Anita Kenyon, Thomas Davis, Oliver Pybus, Louis du Plessis, Alex Zarebski, Jayna Raghwani, Moritz Kraemer, Sarah Francois, Stephen Attwood, Tetyana Vasylyeva, M. Estee Torok, William L. Hamilton, Ian G. Goodfellow, Grant Hall, Aminu S. Jahun, Yasmin Chaudhry, Myra Hosmillo, Malte L. Pinckert, Iliana Georgana, Anna Yakovleva, Luke W. Meredith, Samuel Moses, Hannah Lowe, Felicity Ryan, Chloe L. Fisher, Ali R. Awan, John Boyes, Judith Breuer, Kathryn Ann Harris, Julianne Rose Brown, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adela Alcolea-Medina, Nathan Moore, Nicholas Cortes, Rebecca Williams, Michael R. Chapman, Lisa J. Levett, Judith Heaney, Darren L. Smith, Matthew Bashton, Gregory R. Young, John Allan, Joshua Loh, Paul A. Randell, Alison Cox, Pinglawathee Madona, Alison Holmes, Frances Bolt, James Price, Siddharth Mookerjee, Aileen Rowan, Graham P. Taylor, Manon Ragonnet-Cronin, Rob Johnson, Olivia Boyd, Erik M. Volz, Kirstyn Brunker, Katherine L. Smollett, Joshua Quick, Claire McMurray, Joanne Stockton, Sam Nicholls, Will Rowe, Radoslaw Poplawski, Rocio T. Martinez-Nunez, Jenifer Mason, Trevor I. Robinson, Elaine O'Toole, Joanne Watts, Cassie Breen, Angela Cowell, Catherine Ludden, Graciela Sluga, Nicholas W. Machin, Shazaad S.Y. Ahmad, Ryan P. George, Fenella Halstead, Venkat Sivaprakasam, James G. Shepherd, Patawee Asamaphan, Marc O. Niebel, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yasmin A. Parr, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Igor Starinskij, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Joshua B. Singer, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Yusri Taha, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Jennifer Collins, Gary Eltringham, Kate E. Templeton, Martin P. McHugh, Rebecca Dewar, Elizabeth Wastenge, Samir Dervisevic, Rachael Stanley, Reenesh Prakash, Claire Stuart, Ngozi Elumogo, Dheeraj K. Sethi, Emma J. Meader, Lindsay J. Coupland, Will Potter, Clive Graham, Edward Barton, Debra Padgett, Garren Scott, Emma Swindells, Jane Greenaway, Andrew Nelson, Wen C. Yew, Paola C. Resende Silva, Monique Andersson, Robert Shaw, Timothy Peto, Anita Justice, David Eyre, Derrick Crooke, Sarah Hoosdally, Tim J. Sloan, Nichola Duckworth, Sarah Walsh, Anoop J. Chauhan, Sharon Glaysher, Kelly Bicknell, Sarah Wyllie, Ethan Butcher, Scott Elliott, Allyson Lloyd, Robert Impey, Nick Levene, Lynn Monaghan, Declan T. Bradley, Elias Allara, Clare Pearson, Peter Muir, Ian B. Vipond, Richard Hopes, Hannah M. Pymont, Stephanie Hutchings, Martin D. Curran, Surendra Parmar, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Meera Chand, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Alicia Thornton, Richard Myers, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Ian Harrison, Hassan Hartman, Nikos Manesis, Vineet Patel, Chloe Bishop, Vicki Chalker, Husam Osman, Andrew Bosworth, Esther Robinson, Matthew T.G. Holden, Sharif Shaaban, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Giri Shankar, Hannah Jones, Hibo Asad, Jason Coombes, Joanne Watkins, Johnathan M. Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Michelle Cronin, Noel Craine, Rachel Jones, Robin Howe, Sally Corden, Sara Rey, Sara Kumziene-Summerhayes, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Justin O’Grady, Andrew J. Page, John Wain, Mark A. Webber, Alison E. Mather, David J. Baker, Steven Rudder, Muhammad Yasir, Nicholas M. Thomson, Alp Aydin, Ana P. Tedim, Gemma L. Kay, Alexander J. Trotter, Rachel A.J. Gilroy, Nabil-Fareed Alikhan, Leonardo de Oliveira Martins, Thanh Le-Viet, Lizzie Meadows, Anastasia Kolyva, Maria Diaz, Andrew Bell, Ana Victoria Gutierrez, Ian G. Charles, Evelien M. Adriaenssens, Robert A. Kingsley, Anna Casey, David A. Simpson, Zoltan Molnar, Thomas Thompson, Erwan Acheson, Jane A.H. Masoli, Bridget A. Knight, Andrew Hattersley, Sian Ellard, Cressida Auckland, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Yann Bourgeois, Garry P. Scarlett, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Steven Liggett, Paul Baker, Sarah Essex, Ronan A. Lyons, Laura G. Caller, Sergi Castellano, Rachel J. Williams, Mark Kristiansen, Sunando Roy, Charlotte A. Williams, Patricia L. Dyal, Helena J. Tutill, Yasmin N. Panchbhaya, Leysa M. Forrest, Paola Niola, Jacqueline Findlay, Tony T. Brooks, Artemis Gavriil, Lamia Mestek-Boukhibar, Sam Weeks, Sarojini Pandey, Lisa Berry, Katie Jones, Alex Richter, Andrew Beggs, Colin P. Smith, Giselda Bucca, Andrew R. Hesketh, Ewan M. Harrison, Sharon J. Peacock, Sophie Palmer, Carol M. Churcher, Katherine L. Bellis, Sophia T. Girgis, Plamena Naydenova, Beth Blane, Sushmita Sridhar, Chris Ruis, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Leanne M. Kermack, Nazreen F. Hadjirin, Dinesh Aggarwal, Luke Griffith, Tracey Swingler, Rose K. Davidson, Thomas Williams, Carlos E. Balcazar, Michael D. Gallagher, Áine O'Toole, Stefan Rooke, Rachel Colquhoun, Jordan Ashworth, J.T. McCrone, Emily Scher, Xiaoyu Yu, Kathleen A. Williamson, Thomas D. Stanton, Stephen L. Michell, Claire M. Bewshea, Ben Temperton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Aaron R. Jeffries, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Miren Iturriza-Gomara, Kathryn A. Jackson, Anita O. Lucaci, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Lance Turtle, Sam T. Haldenby, Richard Gregory, Matthew Gemmell, Dominic Kwiatkowski, Thushan I. de Silva, Nikki Smith, Adrienn Angyal, Benjamin B. Lindsey, Danielle C. Groves, Luke R. Green, Dennis Wang, Timothy M. Freeman, Matthew D. Parker, Alexander J. Keeley, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Matthew Wyles, Chrystala Constantinidou, Meera Unnikrishnan, Sascha Ott, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Richard Stark, Laura Baxter, Mohammad T. Alam, Paul E. Brown, Patrick C. McClure, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Dimitris Grammatopoulos, David Buck, John A. Todd, Angie Green, Amy Trebes, George MacIntyre-Cockett, Mariateresa de Cesare, Cordelia Langford, Alex Alderton, Roberto Amato, Sonia Goncalves, David K. Jackson, Ian Johnston, John Sillitoe, Steve Palmer, Mara Lawniczak, Matt Berriman, John Danesh, Rich Livett, Lesley Shirley, Ben Farr, Mike Quail, Scott Thurston, Naomi Park, Emma Betteridge, Danni Weldon, Scott Goodwin, Rachel Nelson, Charlotte Beaver, Laura Letchford, David A. Jackson, Luke Foulser, Liz McMinn, Liam Prestwood, Sally Kay, Leanne Kane, Matthew J. Dorman, Inigo Martincorena, Christoph Puethe, Jon-Paul Keatley, Gerry Tonkin-Hill, Christen Smith, Dorota Jamrozy, Mathew A. Beale, Minal Patel, Cristina Ariani, Michael Spencer-Chapman, Eleanor Drury, Stephanie Lo, Shavanthi Rajatileka, Carol Scott, Keith James, Sarah K. Buddenborg, Duncan J. Berger, Gaurang Patel, Maria V. Garcia-Casado, Thomas Dibling, Samantha McGuigan, Hazel A. Rogers, Adam D. Hunter, Emily Souster, Alexandra S. Neaverson, Medical Research Council (MRC), Pascall, David [0000-0002-7543-0860], and Apollo - University of Cambridge Repository
Subjects: Genome, Genetic analysis, 0302 clinical medicine, Clade, 11 Medical and Health Sciences, Genetics, 0303 health sciences, education.field_of_study, Phylogenetic tree, Virulence, C500, COG-UK Consortium, C700, Transmissibility (vibration), 3. Good health, founder effect, Spike Glycoprotein, Coronavirus, epidemiology, Viral load, Population, Glycine, B100, Genomics, Genome, Viral, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, evolution, Humans, education, 030304 developmental biology, Aspartic Acid, Whole Genome Sequencing, Biochemistry, Genetics and Molecular Biology(all), SARS-CoV-2, COVID-19, spike, The COVID-19 Genomics UK Consortium, A300, 06 Biological Sciences, United Kingdom, Amino Acid Substitution, Evolutionary biology, Mutation, Biological dispersal, 030217 neurology & neurosurgery, Founder effect, Developmental Biology
Abstract: Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant., Graphical Abstract, Highlights • Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage • Phylodynamic analyses do not show significantly different growth of D614G clusters • There is no association of D614G replacement with greater severity of infection • The D614G replacement is associated with higher viral loads and younger patient age, Analysis of the spread and frequency of SARS-CoV-2 D614G in the United Kingdom suggests a selective advantage for this strain that is associated with higher viral loads in younger patients but not higher COVID-19 clinical severity or mortality.
Published: 2021

18. Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Author: Marju Orho-Melander, Humberto García-Ortiz, Xueling Sim, Amp-T D-Genes, Cheol Joo Park, Gina M. Peloso, Jason Flannick, Brian Tomlinson, Hyun Min Kang, Emilio J. Cordova, Stephen S. Rich, Richard A. Gibbs, Angélica Martínez-Hernández, Lorena Orozco, Harsha Doddapaneni, Lisa R. Yanek, Jiwon Lee, Namrata Gupta, Valeriya Lyssenko, Sohee Han, James B. Meigs, Bong-Jo Kim, Bruce M. Psaty, Leslie S. Emery, Kerrin S. Small, Pradeep Natarajan, May E. Montasser, Christian Gieger, Sharon L.R. Kardia, Sarah C. Nelson, Craig L. Hanis, Heikki A. Koistinen, María Elena González-Villalpando, Edmund Chan, Michael Y. Tsai, Benjamin Glaser, Thomas Meitinger, Matthew J. Bown, Mariaelisa Graff, John Danesh, Sekar Kathiresan, Tiinamaija Tuomi, Ramachandran S. Vasan, Gil Atzmon, Alyna T. Khan, Diego Ardissino, Yii-Der Ida Chen, David Zhang, Rob M. van Dam, Wendy S. Post, Barry I. Freedman, D. C. Rao, Michael Preuss, Donna M. Lehman, L. Adrienne Cupples, Colin N. A. Palmer, Claudia H. T. Tam, Hortensia Moreno-Macías, Markku Laakso, Peter Dornbos, Teresa Tusié-Luna, Stella Aslibekyan, Marguerite R. Irvin, Daniel J. Rader, Jee-Young Moon, Eimear E. Kenny, Lisa W. Martin, Jennifer A. Brody, Amit Khera, Erwin P. Bottinger, Sarah E. Graham, Myriam Fornage, Ruth McPherson, Nancy L. Heard-Costa, Michael Boehnke, Clicerio Gonzalez, Ryan W. Kim, Yi-Cheng Chang, Peter M. Nilsson, Yik Ying Teo, Robert Sladek, Cristen J. Willer, Fei Fei Wang, Donna K. Arnett, Mark Chaffin, Karine A. Viaud Martinez, Alanna C. Morrison, Leslie A. Lange, Ravindranath Duggirala, Donna M. Muzny, Kent D. Taylor, Niels Grarup, Soren Germer, Patricia A. Peyser, Brian E. Cade, Lewis C. Becker, Steven A. Lubitz, Nicholette D. Palmer, Susan K. Dutcher, Ronald C.W. Ma, Xuenan Mi, Xiuqing Guo, Hugh Watkins, Eric Boerwinkle, Qibin Qi, Johanna Kuusisto, Christie M. Ballantyne, Tanika N. Kelly, Rajiv Chowdhury, Elvia Mendoza-Caamal, Wing-Yee So, Tien Yin Wong, Torben Hansen, Cecilia Contreras-Cubas, Jeong-Sun Seo, Mi Yeong Hwang, Daekwan Seo, Dajiang J. Liu, Cristina Revilla-Monsalve, Paul S. de Vries, Daniel R. Witte, Yi-Jen Hung, Olle Melander, Karen L. Mohlke, Lucinda Antonacci-Fulton, Francisco Barajas-Olmos, Soo Heon Kwak, Daniel E. Weeks, Claudia Schurmann, Ginger A. Metcalf, Young-Jin Kim, Adrienne M. Stilp, Lori L. Bonnycastle, John Blangero, Ralph A. DeFronzo, Donald W. Bowden, Rasika A. Mathias, Oluf Pedersen, Rozenn N. Lemaitre, Stephen T. McGarvey, Heribert Schunkert, Jaakko Tuomilehto, Farook Thameem, Valentin Fuster, Joshua C. Bis, George Hindy, Allan Linneberg, James G. Wilson, Kyong Soo Park, Sergio A. Islas-Andrade, Ching-Yu Cheng, Won Jung Choi, Minxian X. Wang, Xuzhi Wang, Adolfo Correa, Jai G. Broome, Gail P. Jarvik, Alexander P. Reiner, E. Shyong Tai, Juyoung Lee, Mark I. McCarthy, Nilesh J. Samani, Susan Redline, Carlos A. Aguilar-Salinas, Jerome I. Rotter, Ma. Eugenia Garay-Sevilla, Jiang He, Patrick T. Ellinor, Joseph Park, Joanne E. Curran, Nir Barzilai, Federico Centeno-Cruz, Seonwook Lee, Lawrence F. Bielak, Jianjun Liu, Charles Kooperberg, Juan M. Peralta, Jose C. Florez, Leif Groop, Noël P. Burtt, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, and Ruth J. F. Loos
Subjects: Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, DNA sequencing, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, SNP, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Published: 2020

19. Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases

Author: Rachael A Lawson, Adam S. Butterworth, Emanuele Di Angelantonio, Klaudia Walter, Joanna M M Howson, Lixin Li, Caroline H. Williams-Gray, Ekaterina Yonova-Doing, Zoe J. Golder, Marta Camacho, Aurora Gomez-Duran, Peter M. Rothwell, Kousik Kundu, Na Cai, Maik Pietzner, Nicholas J. Wareham, John Danesh, Annette I. Burgess, Willem H. Ouwehand, Oliver Stegle, Marc Jan Bonder, Claudia Calabrese, Claudia Langenberg, Nicole Soranzo, Nicholas A. Watkins, Patrick F. Chinnery, David J. Roberts, Isobel D. Stewart, Medical Research Council (UK), Engineering and Physical Sciences Research Council (UK), Economic and Social Research Council (UK), Department of Health & Social Care (UK), Wellcome Trust, University of Cambridge, European Commission, NIHR Biomedical Research Centre (UK), Cai, Na, Gómez-Durán, Aurora, Kundu, Kousik, Burgess, Annette I., Calabrese, Claudia, Camacho, Marta, Lawson, Rachael A., Williams-Gray, Caroline H., Di Angelantonio, Emanuele, Butterworth, Adam S., Pietzner, Maik, Wareham, Nicholas J., Langenberg, Claudia, Danesh, John, Walter, Klaudia, Rothwell, Peter M., Howson, Joanna M. M., Stegle, Oliver, Chinnery, Patrick F., Soranzo, Nicole, Cai, Na [0000-0001-7496-2075], Gómez-Durán, Aurora [0000-0002-5895-6860], Kundu, Kousik [0000-0002-1019-8351], Burgess, Annette I. [0000-0003-3442-8083], Calabrese, Claudia [0000-0002-8941-2620], Camacho, Marta [0000-0002-1490-5703], Lawson, Rachael A. [0000-0003-2608-8285], Williams-Gray, Caroline H. [0000-0002-2648-9743], Di Angelantonio, Emanuele [0000-0001-8776-6719], Butterworth, Adam S. [0000-0002-6915-9015], Pietzner, Maik [0000-0003-3437-9963], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Danesh, John [0000-0003-1158-6791], Walter, Klaudia [0000-0003-4448-0301], Rothwell, Peter M. [0000-0001-9739-9211], Howson, Joanna M. M. [0000-0001-7618-0050], Stegle, Oliver [0000-0002-8818-7193], Chinnery, Patrick F. [0000-0002-7065-6617], Soranzo, Nicole [0000-0003-1095-3852], Burgess, Annette I [0000-0003-3442-8083], Lawson, Rachael A [0000-0003-2608-8285], Butterworth, Adam S [0000-0002-6915-9015], Wareham, Nick J [0000-0003-1422-2993], Howson, Joanna MM [0000-0001-7618-0050], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository
Subjects: Male, Mitochondrial DNA, education, Cell, Blood Donors, Disease, Biology, Cytoplasmic hybrid, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Risk Factors, medicine, Humans, Age of Onset, health care economics and organizations, 030304 developmental biology, Genetics, 0303 health sciences, N-Formylmethionine, General Medicine, Middle Aged, United Kingdom, 3. Good health, Mitochondria, Cytosol, Proteostasis, medicine.anatomical_structure, Haplotypes, Cardiovascular Diseases, Female, 030217 neurology & neurosurgery, Biomarkers, Human mitochondrial DNA haplogroup, Follow-Up Studies
Abstract: 47 p.-11 fig., Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis., This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. N.C. is supported by an EBI–Sanger Postdoctoral Fellowship. A.G.-D. receives funding from the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust. E.Y.-D. was funded by the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme. J.M.M.H. was funded by the NIHR Cambridge BRC (BRC-1215-20014)*. P.F.C.is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Evelyn Trust and the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. C.H.W.-G. is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and by the Cambridge Centre for Parkinson-Plus. N.S. is supported by the Wellcome Trust(grant number 098051 until 30 September 2016 and 206194 from 1 October 2016),the Cambridge BHF Centre of Research Excellence (RE/18/1/34212) and the NIHR Cambridge Biomedical Research Centre Biomedical Resources Grant, University of Cambridge, Cardiovascular Theme (RG64226). J.D. holds a British Heart Foundation Professorship and an NIHR Senior Investigator Award*. R.A.L. is supported by grants from Parkinson’s UK. Sequencing of INTERVAL samples was supported by the Wellcome Trust (grant number 206194). Metabolon metabolomics assays were funded by the NIHR BioResource, the Wellcome Trust (grant number 206194) and the NIHR Cambridge BRC (BRC-1215-20014)*. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). SomaLogic assays were funded by Merck and the NIHR Cambridge BRC (BRC-1215-20014)*. ICICLE-PD was funded by Parkinson’s UK (J-0802, G-1301, G-1507) and the Lockhart Parkinson’s Disease Research Fund and supported by the NIHR Newcastle Biomedical Research Unit and the NIHR Cambridge Biomedical Research Centre (146281). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). Genetic work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372.
Published: 2020

20. Genome-wide analysis of blood lipid metabolites in over 5,000 South Asians reveals biological insights at cardiometabolic disease loci

Author: Unzila Ishtiaq, Dirk S. Paul, Zoubia Hina, Philippe M. Frossard, Danish Saleheen, Eric B. Fauman, Syed Nadeem Hasan Rizvi, Rachel M. Y. Ong, Nadeem Hayat Mallick, Syed Zahed Rasheed, Eric L. Harshfield, Angela M. Wood, Taniya Sattar, John Danesh, Fazal-ur-Rehman Memon, David Stacey, Shahid Abbas, Zameer-ul-Asar, Anis Memon, Zia Yaqub, Imran Saleem, Asif Rasheed, Albert Koulman, Anjum Jalal, M. Ishaq, Tahir Saghir, Adam S. Butterworth, Daniel Ziemek, Julian L. Griffin, and Nadeem Qamar
Subjects: Genetics, education.field_of_study, South asia, Population, Lipidomics, Blood lipids, Disease, Lipidome, Biology, education, Gene, Genetic architecture
Abstract: BackgroundGenetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.MethodsWe characterised the genetic architecture of the human blood lipidome in 5,662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.ResultsWe identified 359 genetic associations with 255 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 616 genetic associations with 326 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.ConclusionsOur findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.
Published: 2020

21. Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease

Author: Diego Ardissino, Daniel J. Rader, Heribert Schunkert, Jeanette Erdmann, Danish Saleheen, Masa-aki Kawashiri, Hugh Watkins, Stacey Gabriel, Nilesh J. Samani, Akihiro Nomura, Namrata Gupta, Ruth McPherson, Pradeep Natarajan, Hong-Hee Won, Sekar Kathiresan, Svati H. Shah, Matthew J. Bown, John Danesh, Gina M. Peloso, Hayato Tada, Adolfo Correa, Roberto Elosua, Amit Khera, Connor A. Emdin, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Heterozygote, Lipoproteins, prevalence, Hypercholesterolemia, Coronary Artery Disease, 030204 cardiovascular system & hematology, Gastroenterology, Lipid Metabolism, Inborn Errors, Coronary artery disease, lipids, 03 medical and health sciences, Biliary excretion, symbols.namesake, 0302 clinical medicine, Loss of Function Mutation, Risk Factors, Internal medicine, medicine, Odds Ratio, Humans, ATP Binding Cassette Transporter, Subfamily G, Member 5, Gene, biology, business.industry, ATP Binding Cassette Transporter, Subfamily G, Member 8, pedigree, Phytosterols, General Medicine, Odds ratio, Cholesterol, LDL, Middle Aged, medicine.disease, Sitosterols, 3. Good health, Intestinal Diseases, 030104 developmental biology, Case-Control Studies, Mendelian inheritance, symbols, ABCG5, biology.protein, lipids (amino acids, peptides, and proteins), Female, business, Sitosterolemia
Abstract: Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in theABCG5orABCG8genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8—as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.Methods:We first recruited 9 sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency ABCG5orABCG8.Results:In sitosterolemia families, 7 pedigrees harbored causative LoF variants inABCG5and 2 pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8was ≈0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35];P=1.1×10−6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35];P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.Conclusions:Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
Published: 2020

22. Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study

Author: Maciej Tomaszewski, Adam S. Butterworth, Christian Herder, Alessia Fornoni, Shaza B. Zaghlool, Mohamed A. Elhadad, John Danesh, John Dormer, Haifa Maalmi, Pamela R. Matias-Garcia, Jana Nano, Willem H Ouwehand, Annette Peters, Dennis O. Mook-Kanamori, Qi Guo, Karsten Suhre, Christian Gieger, Kristian Hveem, Fadi J. Charchar, Juliane Winkelmann, Pascal Schlosser, Marco Prunotto, James Eales, Emanuele Di Angelantonio, Xiaoguang Xu, Anna Köttgen, Rory P. Wilson, Agnese Petrera, Stefanie M. Hauck, Nicholas A. Watkins, Alexander Teumer, Melanie Waldenberger, Johannes Graumann, Christian Jonasson, Wolfgang Koenig, David J. Roberts, and Sapna Sharma
Subjects: 0301 basic medicine, Kidney, Melanoma inhibitory activity, Renal function, General Medicine, 030204 cardiovascular system & hematology, Biology, Bioinformatics, medicine.disease, Blood proteins, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Nephrology, Meta-analysis, Mendelian randomization, Proteome, medicine, Clinical Epidemiology, Kidney disease
Abstract: Background Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. Methods A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . Results Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. Conclusions In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.
Published: 2020

23. Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

Author: Tõnu Esko, Lars Wallentin, Andrew D. Bretherick, Adam S. Butterworth, Jesper R. Gådin, Anders Hamsten, Anders Mälarstig, Gunnar Engström, Johan Ärnlöv, Andres Ingason, Céline Fernandez, Jian Yang, Peter M. Nilsson, George Davey-Smith, Weidong Zhang, Agneta Siegbahn, Lasse Folkersen, Thibaud Boutin, Michael V. Holmes, Lars Lind, Julie Lee, Erik Ingelsson, James F. Wilson, Olle Melander, Eric B. Fauman, Lude Franke, Amira Quazi, John Danesh, Ozren Polasek, Niclas Ericsson, Sarah E. Bergen, Mika Ala-Korpela, Andrew J. Schork, Marketa Sjögren, Seung Hoan Choi, Jan Nilsson, Åsa K Hedman, Cecilia M. Lindgren, Bram P. Prins, Daria V. Zhernakova, Yang Wu, Karl Michaëlsson, James E. Peters, Andrew P. Morris, Marju Orho-Melander, Stefan Enroth, Reedik Mägi, Stefan Gustafsson, Mikael Landén, Martin Magnusson, Qin Wang, Steven A. Lubitz, Johan Sundström, Federico De Masi, Jingyuan Fu, Rasmus Wernersson, Thomas Werge, Praveen Surendran, Tom Palmer, Paul W. Franks, Caroline Hayward, Daniel Hvidberg Hansen, Ulf Gyllensten, Vilmantas Giedraitis, Ljubica Perisic Matic, Urmo Võsa, Åsa Johansson, Alexandra Zhernakova, Bianca E. Suur, Karen Page, Gustav Smith, Erik Pålsson, Ting Qi, Harm-Jan Westra, Michael W. Nagle, Erin Macdonald-Dunlop, Annique Claringbould, Peter K. Joshi, Sölve Elmståhl, Anettne Kalnapenkis, Yan Chen, Chris Haley, and Jeremy D. Gale
Subjects: Drug, 0303 health sciences, media_common.quotation_subject, Drug target, Disease, Computational biology, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Precision medicine, 3. Good health, 03 medical and health sciences, Human health, 0302 clinical medicine, Mendelian randomization, Gene, 030304 developmental biology, media_common
Abstract: Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping usingtrans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.
Published: 2020
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24. Elucidating mechanisms of genetic cross-disease associations: an integrative approach implicates protein C as a causal pathway in arterial and venous diseases

Author: Lingyan Chen, Neda Farahi, Daniel J. Schneider, Nebojsa Janjic, John Danesh, Weihong Tang, Joanna M. M. Howson, Dirk S. Paul, Nathan Pankratz, Charlotte Summers, Maria Sabater-Lleal, David Stacey, Kate Downes, Paul S. de Vries, James E. Peters, Edwin R. Chilvers, Amy D. Gelinas, Stephen MacDonald, Nicholas L. Smith, Amy M. Mason, Harriett McKinney, James S. Pankow, Jonathan Langdown, Stephen Burgess, and Saonli Basu
Subjects: 0303 health sciences, Endothelial protein C receptor, Factor VII, Locus (genetics), Disease, 030204 cardiovascular system & hematology, Biology, PROCR Gene, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Immunology, Mendelian randomization, medicine, Allele, Protein C, 030304 developmental biology, medicine.drug
Abstract: Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in thePROCRgene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found thatPROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte–endothelial cell adhesion, a marker for vascular inflammation. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting thatPROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations.
Published: 2020
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25. The influence of rare variants in circulating metabolic biomarkers

Author: Nicole Soranzo, Eleftheria Zeggini, Emanuele Di Angelantonio, Interval Study, Kousik Kundu, Adam S. Butterworth, Fernando Riveros-Mckay, Willem H. Ouwehand, Clare Oliver-Williams, Klaudia Walter, Inês Barroso, Eleanor Wheeler, John Danesh, Savita Karthikeyan, David J. Roberts, Riveros-Mckay, Fernando [0000-0002-6671-1177], Oliver-Williams, Clare [0000-0002-3573-2426], Karthikeyan, Savita [0000-0002-4798-5746], Walter, Klaudia [0000-0003-4448-0301], Kundu, Kousik [0000-0002-1019-8351], Ouwehand, Willem H [0000-0002-7744-1790], Wheeler, Eleanor [0000-0002-8616-6444], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, and Ouwehand, Willem H. [0000-0002-7744-1790]
Subjects: Male, Cancer Research, Apolipoprotein B, Metabolite, Genome-wide association study, Disease, QH426-470, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Mathematical and Statistical Techniques, Drug Metabolism, Medicine and Health Sciences, Genetics (clinical), 0303 health sciences, Statistics, Genomics, Metaanalysis, Pyruvate dehydrogenase complex, Phenotype, Lipids, 3. Good health, Cholesterol, Cardiovascular Diseases, Physical Sciences, Lipoprotein disorder, Female, lipids (amino acids, peptides, and proteins), Research Article, medicine.medical_specialty, Lipoproteins, Computational biology, Biology, Research and Analysis Methods, 03 medical and health sciences, Internal medicine, medicine, Genome-Wide Association Studies, Genetics, Humans, Pharmacokinetics, Statistical Methods, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Triglycerides, 030304 developmental biology, Pharmacology, Genetic Variation, Biology and Life Sciences, Computational Biology, Proteins, Human Genetics, Metabolism, Cholesterol, LDL, Genome Analysis, Lipid Metabolism, Endocrinology, chemistry, biology.protein, Drug metabolism, 030217 neurology & neurosurgery, Biomarkers, Mathematics, Lipoprotein, Genome-Wide Association Study
Abstract: Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p, Author summary Cardiovascular diseases (CVD) are the number one cause of death globally. Various metabolic biomarkers including lipid and lipoprotein particles have been implicated as risk factors for the development of CVD. Understanding how these biomarkers are regulated can lead to increased understanding of CVD aetiology and the potential identification of drug targets. Here we take advantage of high resolution measurements on a large cohort of 7,142 healthy blood donors with whole-exome and whole-genome sequencing data to explore the influence of rare variation on circulating metabolic biomarker levels. Using a novel approach leveraging the information gained from various measurements on the same participants we are able to identify a novel biological pathway involved in the regulation of intermediate-density and low-density lipoproteins as well as circulating cholesterol, confirm various established gene associations and identify potential novel gene associations that merit further replication. This work highlights the advantages that can be gained by combining high resolution genotypic and phenotypic measurements in one large cohort.
Published: 2020

26. Correction: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition

Author: Pauli Ohukainen, Michael V. Holmes, Clare Oliver-Williams, Qin Wang, Elias Allara, Adam S. Butterworth, John Danesh, Veikko Salomaa, Mika Kähönen, Therese Tillin, Terho Lehtimäki, George Davey Smith, Olga Anufrieva, Jorma Viikari, Emanuele Di Angelantonio, Alun D. Hughes, Marjo-Riitta Järvelin, Mika Ala-Korpela, Johannes Kettunen, Nish Chaturvedi, Markus Perola, and Olli T. Raitakari
Subjects: Adult, Male, Adolescent, QH301-705.5, Lipoproteins, Coronary Disease, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Young Adult, Cholesterylester transfer protein, Humans, Biology (General), Alleles, Triglycerides, Apolipoproteins B, General Immunology and Microbiology, biology, General Neuroscience, Correction, Genetic Variation, Cholesterol, LDL, Middle Aged, Cholesterol Ester Transfer Proteins, Biochemistry, HMG-CoA reductase, biology.protein, Female, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, General Agricultural and Biological Sciences, Lipoprotein, Follow-Up Studies
Abstract: Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
Published: 2020

27. Learning polygenic scores for human blood cell traits

Author: Yu Xu, Dragana Vuckovic, Michael Inouye, Adam S. Butterworth, Scott C. Ritchie, Nicole Soranzo, David J. Roberts, Tao Jiang, Willem H. Ouwehand, Jason Grealey, Emanuele Di Angelantonio, Parsa Akbari, and John Danesh
Subjects: Genetics, 0303 health sciences, Human blood, Cell, Univariate, Biology, 3. Good health, Blood cell, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Trait, Disease prevention, 030217 neurology & neurosurgery, Selection (genetic algorithm), 030304 developmental biology, Genetic association
Abstract: Polygenic scores (PGSs) for blood cell traits can be constructed using summary statistics from genome-wide association studies. As the selection of variants and the modelling of their interactions in PGSs may be limited by univariate analysis, therefore, such a conventional method may yield sub-optional performance. This study evaluated the relative effectiveness of four machine learning and deep learning methods, as well as a univariate method, in the construction of PGSs for 26 blood cell traits, using data from UK Biobank (n=~400,000) and INTERVAL (n=~40,000). Our results showed that learning methods can improve PGSs construction for nearly every blood cell trait considered, with this superiority explained by the ability of machine learning methods to capture interactions among variants. This study also demonstrated that populations can be well stratified by the PGSs of these blood cell traits, even for traits that exhibit large differences between ages and sexes, suggesting potential for disease prevention. As our study found genetic correlations between the PGSs for blood cell traits and PGSs for several common human diseases (recapitulating well-known associations between the blood cell traits themselves and certain diseases), it suggests that blood cell traits may be indicators or/and mediators for a variety of common disorders via shared genetic variants and functional pathways.
Published: 2020

28. Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Author: Fumiaki Imamura, Maik Pietzner, Fiona M. Gribble, Robert A. Scott, John Danesh, Clare Oliver-Williams, Julian L. Griffin, Roberto Bonelli, Frank Reimann, Isobel D. Stewart, Stephen Burgess, Kay-Tee Khaw, Luca A. Lotta, Adam S. Butterworth, Eric B. Fauman, Melanie Bahlo, Angela M. Wood, Nita G. Forouhi, Emma K. Biggs, Gabi Kastenm uumlller, Johannes Raffler, Praveen Surendran, Chen Li, Victoria P W Auyeung, Verena Zuber, Nicholas J. Wareham, Eleanor Sanderson, Gregory A. Michelotti, Laura B. L. Wittemans, Claudia Langenberg, and Albert Koulman
Subjects: 2. Zero hunger, 0303 health sciences, Metabolite, Metabolism, Computational biology, Biology, Small molecule, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, Human health, 0302 clinical medicine, chemistry, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p-10) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10-30)]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.
Published: 2020
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29. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Jean-Claude Tardif, Kelly Cho, Adolfo Correa, Na Cai, Koichi Matsuda, Paul L. Auer, Ken Sin Lo, Jennifer A. Brody, Dragana Vuckovic, Oluf Pedersen, Eric Jorgenson, Cassandra N. Spracklen, Jennifer E. Huffman, Stefan Weiss, Tim Kacprowski, Nicholas A. Watkins, Yoichiro Kamatani, Michele K. Evans, John Danesh, Masahiro Kanai, Karyn Megy, Kumaraswamy Naidu Chitrala, Michael H. Guo, James S. Floyd, Savita Karthikeyan, Ani Manichaikul, Petra Schubert, Vijay G. Sankaran, Torben Hansen, Traci M. Bartz, Laura M. Raffield, Regina Manansala, Parsa Akbari, Scott C. Ritchie, Ruth J. F. Loos, Manuel Tardaguila, Willem H. Ouwehand, Peter W.F. Wilson, Emanuele Di Angelantonio, Abdou Mousas, Jeffrey Haessler, Yoav Ben-Shlomo, Benjamin Rodriguez, Karen L. Mohlke, Girish N. Nadkarni, Oliver Stegle, Paul Elliott, Erwin P. Bottinger, Nathan Pankratz, Hélène Choquet, Julian C. Knight, Niels Grarup, Niki Dimou, Leslie A. Lange, Stephan B. Felix, William J. Astle, Jerome I. Rotter, Frank J. A. van Rooij, Andreas Greinacher, Yongmei Liu, Tao Jiang, Michael Inouye, Ming-Huei Chen, Jingzhong Ding, Uwe Völker, Huijun Qian, Henry Völzke, Alan B. Zonderman, Evangelos Evangelou, Wei Huang, Jonathan D. Rosen, Christopher J. Penkett, Michel Georges, Kousik Kundu, Mohsen Ghanbari, Hannes Ponstingl, Adam S. Butterworth, Joanna M. M. Howson, Praveen Surendran, Terho Lehtimäki, Allan Linneberg, Emilie M. Wigdor, Michael Preuss, Olli T. Raitakari, Arden Moscati, Yukinori Okada, Yoshinori Murakami, Guillaume Lettre, Leo-Pekka Lyytikäinen, Hua Tang, Caleb A. Lareau, David J. Roberts, Saori Sakaue, Mika Kähönen, Alexander P. Reiner, VA Million Veteran Program, Fotis Koskeridis, Nina Mononen, Linda Broer, Kjell Nikus, Andrew D. Johnson, Patrick K. Albers, Stephen B. Watt, Erik L. Bao, Yun Li, Klaudia Walter, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Andrew D Beswick, Tõnu Esko, Jette Bork-Jensen, and Masato Akiyama
Subjects: Genetics, Gene regulatory network, Oxygen transport, Genome-wide association study, Biology, Genetic architecture, Blood cell, symbols.namesake, medicine.anatomical_structure, medicine, Mendelian inheritance, symbols, Allele, Allele frequency
Abstract: SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum 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 cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Published: 2020
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30. Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

Author: Stephen Kaptoge, Jeffrey M. Verboon, Jennifer G. Sambrook, Emanuele Di Angelantonio, Tao Jiang, William J. Astle, Louisa Mayer, Taco W. Kuijpers, Janine Collins, Vijay G. Sankaran, Michel Georges, Nicholas A. Watkins, Julian C. Knight, Kousik Kundu, Roman Kreuzhuber, Kate Downes, Adam S. Butterworth, Stephen Burgess, David J. Roberts, Luigi Grassi, Stuart Meacham, Dragana Vuckovic, Denis Seyres, Jose A. Guerrero, Parsa Akbari, Mattia Frontini, Nicole Soranzo, Willem H. Ouwehand, Klaudia Walter, Erik L. Bao, John Danesh, Oliver Stegle, and James E. Peters
Subjects: 0303 health sciences, Cell type, education.field_of_study, Multiple sclerosis, Population, Genome-wide association study, Computational biology, Disease, Biology, medicine.disease, Phenotype, 3. Good health, Blood cell, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Epigenetics, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SUMMARYThousands of genetic associations with phenotypes of blood cells are known, but few are with phenotypes relevant to cell function. We performed GWAS of 63 flow-cytometry phenotypes, including measures of cell granularity, nucleic acid content, and reactivity, in 39,656 participants in the INTERVAL study, identifying 2,172 variant-trait associations. These include associations mediated by functional cellular structures such as secretory granules, implicated in vascular, thrombotic, inflammatory and neoplastic diseases. By integrating our results with epigenetic data and with signals from molecular abundance/disease GWAS, we infer the hematopoietic origins of population phenotypic variation and identify the transcription factor FOG2 as a regulator of plateletα-granularity. We show how flow cytometry genetics can suggest cell types mediating complex disease risk and suggest efficacious drug targets, presenting Daclizumab/Vedolizumab in autoimmune disease as positive controls. Finally, we add to existing evidence supporting IL7/IL7-R as drug targets for multiple sclerosis.
Published: 2020
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31. Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition

Author: Qin Wang, Marjo-Riitta Järvelin, Terho Lehtimäki, Veikko Salomaa, Michael V. Holmes, Mika Ala-Korpela, Clare Oliver-Williams, Emanuele Di Angelantonio, Therese Tillin, Adam S. Butterworth, Elias Allara, Mika Kähönen, Johannes Kettunen, Nish Chaturvedi, George Davey Smith, Pauli Ohukainen, Markus Perola, John Danesh, Olli T. Raitakari, Jorma Viikari, Alun D. Hughes, Olga Anufrieva, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, University of Helsinki, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, Holmes, Michael V [0000-0001-6617-0879], Allara, Elias [0000-0002-1634-8330], Ohukainen, Pauli [0000-0002-0919-7204], Oliver-Williams, Clare [0000-0002-3573-2426], Hughes, Alun D [0000-0001-5432-5271], Salomaa, Veikko [0000-0001-7563-5324], Järvelin, Marjo-Riitta [0000-0002-2149-0630], Davey Smith, George [0000-0002-1407-8314], Butterworth, Adam S [0000-0002-6915-9015], Ala-Korpela, Mika [0000-0001-5905-1206], Apollo - University of Cambridge Repository, UNIVERSITY OF OULU, Holmes, Michael V. [0000-0001-6617-0879], Hughes, Alun D. [0000-0001-5432-5271], and Butterworth, Adam S. [0000-0002-6915-9015]
Subjects: Life Sciences & Biomedicine - Other Topics, Male, 0301 basic medicine, Very low-density lipoprotein, Apolipoprotein B, LOCI, Coronary Disease, Biochemistry, Vascular Medicine, DISEASE, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Medicine and Health Sciences, Coronary Heart Disease, EPIDEMIOLOGY, Biology (General), Genetics of disease, 11 Medical and Health Sciences, education.field_of_study, biology, PLASMA, General Neuroscience, CARDIOVASCULAR RISK, Middle Aged, Lipids, Coronary heart disease, Cholesterol, HMG-CoA reductase, Female, lipids (amino acids, peptides, and proteins), General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Research Article, Adult, Biochemistry & Molecular Biology, medicine.medical_specialty, Adolescent, Biolääketieteet - Biomedicine, QH301-705.5, Lipoproteins, Population, Cardiology, General Biochemistry, Genetics and Molecular Biology, LDL, Young Adult, 03 medical and health sciences, MAGNETIC-RESONANCE METABOLOMICS, 07 Agricultural and Veterinary Sciences, Internal medicine, Cholesterylester transfer protein, REVEALS, medicine, Genetics, Humans, GENOME-WIDE ASSOCIATION, education, Biology, Triglycerides, Alleles, Apolipoproteins B, Science & Technology, General Immunology and Microbiology, Triglyceride, Genetic Variation, Biology and Life Sciences, Proteins, Cholesterol, LDL, 06 Biological Sciences, Cholesterol Ester Transfer Proteins, Medical risk factors, 030104 developmental biology, Endocrinology, Apolipoproteins, chemistry, Genetic Loci, Medical Risk Factors, Genetics of Disease, biology.protein, COHORT PROFILE, 1182 Biochemistry, cell and molecular biology, Hydroxymethylglutaryl CoA Reductases, 3111 Biomedicine, Hydroxymethylglutaryl-CoA Reductase Inhibitors, 030217 neurology & neurosurgery, Follow-Up Studies, Developmental Biology, Lipoprotein
Abstract: Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (−0.02 SD LDL defined by particle size; 95% CI: −0.10 to 0.05 for CETP versus −0.24 SD, 95% CI −0.30 to −0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18–1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies., Inhibition of cholesteryl ester transfer protein does not affect size-specific low-density lipoprotein cholesterol, but may lower coronary heart disease risk by lowering cholesterol concentrations in other apolipoprotein-B containing atherogenic lipoproteins, and by lowering triglyceride content of high-density lipoprotein particles.
Published: 2020
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32. Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Author: Ming-Huei Chen, Laura M. Raffield, Abdou Mousas, Saori Sakaue, Jennifer E. Huffman, Tao Jiang, Parsa Akbari, Dragana Vuckovic, Erik L. Bao, Arden Moscati, Xue Zhong, Regina Manansala, Véronique Laplante, Minhui Chen, Ken Sin Lo, Huijun Qian, Caleb A. Lareau, Mélissa Beaudoin, Masato Akiyama, Traci M. Bartz, Yoav Ben-Shlomo, Andrew Beswick, Jette Bork-Jensen, Erwin P. Bottinger, Jennifer A. Brody, Frank J.A. van Rooij, Kumaraswamynaidu Chitrala, Kelly Cho, Hélène Choquet, Adolfo Correa, John Danesh, Emanuele Di Angelantonio, Niki Dimou, Jingzhong Ding, Paul Elliott, Tõnu Esko, Michele K. Evans, James S. Floyd, Linda Broer, Niels Grarup, Michael H. Guo, Andreas Greinacher, Jeff Haessler, Torben Hansen, Joanna M. M. Howson, Wei Huang, Eric Jorgenson, Tim Kacprowski, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Savita Karthikeyan, Fotis Koskeridis, Leslie A. Lange, Terho Lehtimäki, Markus M. Lerch, Allan Linneberg, Yongmei Liu, Leo-Pekka Lyytikäinen, Ani Manichaikul, Koichi Matsuda, Karen L. Mohlke, Nina Mononen, Yoshinori Murakami, Girish N. Nadkarni, Matthias Nauck, Kjell Nikus, Willem H. Ouwehand, Nathan Pankratz, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Olli T. Raitakari, David J. Roberts, Stephen S. Rich, Benjamin A.T. Rodriguez, Jonathan D. Rosen, Jerome I. Rotter, Petra Schubert, Cassandra N. Spracklen, Praveen Surendran, Hua Tang, Jean-Claude Tardif, Mohsen Ghanbari, Uwe Völker, Henry Völzke, Nicholas A. Watkins, Alan B. Zonderman, VA Million Veteran Program, Peter W.F. Wilson, Yun Li, Adam S. Butterworth, Jean-François Gauchat, Charleston W.K. Chiang, Bingshan Li, Ruth J.F. Loos, William J. Astle, Evangelos Evangelou, Vijay G. Sankaran, Yukinori Okada, Nicole Soranzo, Andrew D. Johnson, Alexander P. Reiner, Paul L. Auer, and Guillaume Lettre
Subjects: Blood cell, Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Ethnic group, Genome-wide association study, Biology, 030304 developmental biology
Abstract: SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 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 EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact 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

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

Author: Augusto Rendon, John M. Jongerius, Nicholas A. Watkins, Kim Brügger, Nicholas Gleadall, Daniel Duarte, Tiffany C. Timmer, Sara Trompeter, Matthew R. Walker, Jennifer G. Sambrook, David J. Roberts, Christopher J. Penkett, Carolin M. Sauer, Nieke van der Bolt, Barbera Veldhuisen, Shane Grimsley, Colin Brown, Adam S. Butterworth, Michael J. Sweeting, Salih Tuna, Emanuele Di Angelantonio, John Ord, Karyn Megy, Jessie S Luken, C. Ellen van der Schoot, Ilenia Simeoni, Gail Miflin, William J. Lane, Nicole Thornton, Ram Varma, William J. Astle, Connie M. Westhoff, Christopher S. Nelson, Katja van den Hurk, Jeremy Gollub, Kathleen Stirrups, Willem H. Ouwehand, Femmeke J. Prinsze, Alexander T. Dilthey, John Danesh, Public and occupational health, Graduate School, AII - Inflammatory diseases, APH - Methodology, and Landsteiner Laboratory
Subjects: medicine.medical_specialty, Blood transfusion, Genotype, medicine.medical_treatment, Concordance, Blood Donors, Human leukocyte antigen, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Isoantibodies, medicine, Humans, Blood Transfusion, Prospective Studies, Typing, Genotyping, biology, Transfusion Medicine, business.industry, Transfusion medicine, Hematology, Biobank, Immunology, biology.protein, Antibody, business, 030215 immunology
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

34. Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length

Author: Joris Deelen, Antonia Trichopoulou, Sara Hägg, Kim Overvad, Elisabete Weiderpass, Iryna O. Fedko, Rudolf Kaaks, Nicola D. Kerrison, Kirsi H. Pietiläinen, Ida Surakka, Veikko Salomaa, Svetlana Stoma, Jaakko Kaprio, Alessandra Allione, Cornelia M. van Duijn, Nicholas G. Martin, Veryan Codd, Olle Melander, Nilesh J. Samani, Josine E. Verhoeven, Anne Tjønneland, Natalia Pervjakova, Domenico Palli, Adam S. Butterworth, Nicholas J. Wareham, María Dolores Chirlaque, P. Eline Slagboom, Massimo Mangino, Pascal P. Arp, Christopher P. Nelson, Brenda W.J.H. Penninx, Jessica L. Buxton, Pietro Ferrari, Tao Jiang, Iiris Hovatta, Taylor K. Loe, N. Charlotte Onland-Moret, Salvatore Panico, Peter Jones, Heiner Boeing, Timothy J. Key, Luca A. Lotta, Miguel Rodríguez-Barranco, Diana van Heemst, Chen Li, Robert A. Scott, Sarah E. Medland, Giuseppe Matullo, Alexessander Couto Alves, Rosario Tumino, Jouke-Jan Hottenga, Ken K. Ong, Vittorio Krogh, Gonneke Willemsen, Andres Metspalu, Eva Albrecht, Elina Sillanpää, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Reedik Mägi, Eros Lazzerini Denchi, Peter M. Nilsson, André G. Uitterlinden, Antonio Agudo, Yuri Milaneschi, Ashley van der Spek, Alessia Russo, Linda Broer, Federico Canzian, Marian Beekman, Grant W. Montgomery, Sophie C Warner, Guy Fagherazzi, Markus Perola, Alexandra I. F. Blakemore, Marjo-Riitta Järvelin, Robert Karlsson, Tim D. Spector, Paul W. Franks, H. Eka D. Suchiman, Claudia Langenberg, Liher Imaz, Nancy L. Pedersen, Scott D. Gordon, Stephen E. Hamby, J. Ramón Quirós, Yvonne T. van der Schouw, Concha Moreno, Christian Gieger, Pekka Jousilahti, Dorret I. Boomsma, Marc J. Gunter, Benjamin Miraglio, Gianluca Severi, John Danesh, UNIVERSITY OF OULU, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, APH - Methodology, Sociology and Social Gerontology, Li, Chen [0000-0002-6423-6325], Ong, Kenneth [0000-0003-4689-7530], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Abdominal Center, Department of Medicine, Endokrinologian yksikkö, Clinicum, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, HUS Helsinki and Uusimaa Hospital District, Department of Psychology and Logopedics, Genetics, SLEEPWELL Research Program, Department of Public Health, Mind and Matter, Internal Medicine, and Epidemiology
Subjects: Netherlands Twin Register (NTR), Limfomes, LOCI, Genome-wide association study, Disease, VARIANTS, DISEASE, 0302 clinical medicine, Leukocytes, telomere length, GWAS, Genetics(clinical), Càncer, Mendelian randomisation, Thyroid cancer, Genetics (clinical), 11 Medical and Health Sciences, Cancer, Genetics, Genetics & Heredity, RISK, 0303 health sciences, Telòmer, age-related disease, biological aging, Humans, Nucleotides, Genome-Wide Association Study, Telomere, meta-analyysi, genomiikka, Genomics, CANCER, 3. Good health, 030220 oncology & carcinogenesis, MENDELIAN RANDOMIZATION, Medical genetics, Biomarker (medicine), HEART, Lymphomas, Life Sciences & Biomedicine, Medical Genetics, medicine.medical_specialty, GENES, DATABASE, Age-related Disease, Biological Aging, Mendelian Randomisation, Telomere Length, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Journal Article, 030304 developmental biology, Medicinsk genetik, Science & Technology, 06 Biological Sciences, medicine.disease, Genòmica, ikääntyminen, 1182 Biochemistry, cell and molecular biology, telomeerit, biological
Abstract: Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Published: 2020

35. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Author: Tom Palmer, Lars Lind, George Davey Smith, Ting Qi, Michael W. Nagle, Paul W. Franks, Bram P. Prins, Julie Lee, Jingyuan Fu, Niclas Eriksson, Peter K. Joshi, Chris Haley, Ljubica Perisic Matic, Jeremy D. Gale, Mika Ala-Korpela, Michael V. Holmes, Urmo Võsa, Adam S. Butterworth, Eric B. Fauman, Anette Kalnapenkis, Reedik Mägi, Åsa Johansson, James F. Wilson, Mikael Landén, Gunnar Engström, Johan Ärnlöv, Anders Hamsten, Ozren Polasek, Andres Ingason, Andrew J. Schork, Agneta Siegbahn, Lasse Folkersen, Qin Wang, Andrew P. Morris, Johan Sundström, Daria V. Zhernakova, Olle Melander, Erik Ingelsson, Federico De Masi, Lude Franke, James E. Peters, Alexandra Zhernakova, Seung Hoan Choi, Rasmus Wernersson, Thibaud Boutin, Karl Michaëlsson, Stefan Gustafsson, Bianca E. Suur, Karen Page, Yang Wu, Caroline Hayward, Marketa Sjögren, Cecilia M. Lindgren, Stefan Enroth, Tõnu Esko, Amira Quazi, John Danesh, Anders Mälarstig, Daniel Hvidberg Hansen, Åsa K Hedman, Jan Nilsson, Ulf Gyllensten, Vilmantas Giedraitis, J. Gustav Smith, Martin Magnusson, Marju Orho-Melander, Steven A. Lubitz, Erin Macdonald-Dunlop, Thomas Werge, Praveen Surendran, Yan Chen, Céline Fernandez, Weidong Zhang, Lars Wallentin, Andrew D. Bretherick, Jian Yang, Peter M. Nilsson, Jesper R. Gådin, Annique Claringbould, Sölve Elmståhl, Sarah E Bergen, Harm-Jan Westra, Erik Pålsson, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), United Kingdom Research and Innovation, Folkersen, Lasse [0000-0003-0708-9530], Hansen, Daniel Hvidberg [0000-0003-3285-605X], Wu, Yang [0000-0002-0128-7280], Eriksson, Niclas [0000-0002-2152-4343], Bretherick, Andrew D [0000-0001-9258-3140], Enroth, Stefan [0000-0002-5056-9137], Lee, Julie [0000-0001-6090-6718], Ala-Korpela, Mika [0000-0001-5905-1206], Claringbould, Annique [0000-0002-9201-6557], Davey Smith, George [0000-0002-1407-8314], Fauman, Eric [0000-0002-9739-0249], Fernandez, Celine [0000-0003-1290-4982], Franke, Lude [0000-0002-5159-8802], Franks, Paul W [0000-0002-0520-7604], Giedraitis, Vilmantas [0000-0003-3423-2021], Haley, Chris [0000-0002-9811-0210], Johansson, Åsa [0000-0002-2915-4498], Lubitz, Steven [0000-0002-9599-4866], Palmer, Tom [0000-0003-4655-4511], Macdonald-Dunlop, Erin [0000-0001-6569-6086], Magnusson, Martin [0000-0003-1710-5936], Michaelsson, Karl [0000-0003-2815-1217], Nagle, Michael W [0000-0002-4677-7582], Nilsson, Peter M [0000-0002-5652-8459], Nilsson, Jan [0000-0002-9752-7479], Prins, Bram [0000-0001-5774-034X], Sundström, Johan [0000-0003-2247-8454], Werge, Thomas [0000-0003-1829-0766], Westra, Harm-Jan [0000-0001-7038-567X], Fu, Jingyuan [0000-0001-5578-1236], Esko, Tõnu [0000-0003-1982-6569], Hayward, Caroline [0000-0002-9405-9550], Landen, Mikael [0000-0002-4496-6451], Butterworth, Adam S [0000-0002-6915-9015], Holmes, Michael V [0000-0001-6617-0879], Ingelsson, Erik [0000-0003-2256-6972], Mälarstig, Anders [0000-0003-2608-1358], Apollo - University of Cambridge Repository, and 30387078 - Magnusson, P. Martin
Subjects: Proteomics, Proteome, Endocrinology, Diabetes and Metabolism, Asthma, ATP Binding Cassette Transporter 1, Cardiovascular System, Chromosome Mapping, Drug Delivery Systems, Gene Knockdown Techniques, Genome-Wide Association Study, Genomics, Humans, Inflammatory Bowel Diseases, Interleukin-1 Receptor-Like 1 Protein, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Mendelian Randomization Analysis, Protein-Serine-Threonine Kinases, Quantitative Trait Loci, Receptors, CCR2, Receptors, CCR5, Genome-wide association study, 030204 cardiovascular system & hematology, Chemokine receptor, 0302 clinical medicine, RECEPTOR ANTAGONIST, GWAS, Cardiac and Cardiovascular Systems, 0303 health sciences, Molecular medicine, 3. Good health, Medical genetics, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, Computational biology, Biology, Protein Serine-Threonine Kinases, Article, 03 medical and health sciences, Endocrinology & Metabolism, Physiology (medical), Mendelian randomization, Internal Medicine, medicine, 030304 developmental biology, Science & Technology, Cell Biology, GENE, ANTIBODY
Abstract: Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
Published: 2020
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36. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease

Author: Tuomo Kiiskinen, Matthew J. Bown, Sekar Kathiresan, James G. Wilson, John Danesh, Heribert Schunkert, Krishna G. Aragam, Joshua C. Denny, Million Veteran Program, Diego Ardissino, Danish Saleheen, Marina Serper, Julie A. Lynch, Marijana Vujkovic, Usman Baber, Alexander G. Bick, George Hindy, Amit Khera, Nilesh J. Samani, Connor A. Emdin, Mark J. Daly, Hugh Watkins, Ruth McPherson, Aki S. Havulinna, QiPing Feng, Scott M. Damrauer, Namrata Gupta, Derek Klarin, Roberto Elosua, Juha Karjalainen, Philip S Tsao, B F Voight, Josep M. Mercader, Craig L. Hanis, Kyong-Mi Chang, Mark Chaffin, Wei-Qi Wei, David E. Kaplan, Stacey Gabriel, Lan Jiang, Jeanette Erdmann, Mary E. Haas, Institute for Molecular Medicine Finland, University of Helsinki, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, Emdin, Connor A. [0000-0003-2337-1229], Haas, Mary E. [0000-0002-2816-9268], Khera, Amit V. [0000-0001-6535-5839], Chaffin, Mark [0000-0002-1234-5562], Klarin, Derek [0000-0002-4636-5780], Jiang, Lan [0000-0002-2583-3661], Wei, Wei-Qi [0000-0003-4985-056X], Feng, Qiping [0000-0002-6213-793X], Havulinna, Aki [0000-0002-4787-8959], Kiiskinen, Tuomo [0000-0002-6306-8227], Bick, Alexander [0000-0001-5824-9595], Ardissino, Diego [0000-0003-0410-3528], Schunkert, Heribert [0000-0001-6428-3001], McPherson, Ruth [0000-0002-9087-6107], Erdmann, Jeanette [0000-0002-4486-6231], Chang, Kyong-Mi [0000-0001-6811-9364], Vujkovic, Marijana [0000-0003-4924-5714], Voight, Ben [0000-0002-6205-9994], Damrauer, Scott [0000-0001-8009-1632], Lynch, Julie [0000-0003-0108-2127], Kaplan, David [0000-0002-3839-336X], Serper, Marina [0000-0003-4899-2160], Tsao, Philip [0000-0001-7274-9318], Mercader, Josep [0000-0001-8494-3660], Hanis, Craig [0000-0002-4880-5348], Denny, Joshua [0000-0002-3049-7332], Apollo - University of Cambridge Repository, Emdin, Connor A [0000-0003-2337-1229], Haas, Mary E [0000-0002-2816-9268], and Khera, Amit V [0000-0001-6535-5839]
Subjects: Liver Cirrhosis, Male, Cancer Research, Cirrhosis, Datasets as Topic, PROTEIN, Coronary Artery Disease, QH426-470, Fetge -- Malalties, Biochemistry, Vascular Medicine, Liver disease, chemistry.chemical_compound, 0302 clinical medicine, Sociology, ANGPTL3, Consortia, Liver Cirrhosis, Alcoholic, Loss of Function Mutation, Psychology, Coronary Heart Disease, CONFERS SUSCEPTIBILITY, Genetics (clinical), 0303 health sciences, Liver Diseases, Homozygote, Fatty liver, 1184 Genetics, developmental biology, physiology, Middle Aged, Lipids, Addicts, 3. Good health, Cholesterol, Liver, Alkaline phosphatase, Female, Oxidoreductases, ENZYMES, Colesterol, Research Article, medicine.medical_specialty, Cirrosi hepàtica, Cardiology, Mutation, Missense, Addiction, Gastroenterology and Hepatology, Biology, Social sciences, TM6SF2, Mitochondrial Proteins, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alcoholics, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, PNPLA3, 030304 developmental biology, Medicine and health sciences, Biology and life sciences, MORTALITY, Correction, Cholesterol, LDL, medicine.disease, RISK LOCI, Mitochondrial amidoxime reducing component 1, Fatty Liver, Endocrinology, YIELD, chemistry, Alanine transaminase, Genetic Loci, biology.protein, 3111 Biomedicine, Proteïnes, 030217 neurology & neurosurgery
Abstract: Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis., Author summary Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease.
Published: 2020

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

Author: Nicholas A. Watkins, Julian C. Knight, William J. Astle, Stephan B. Felix, Petra Schubert, Andreas Greinacher, Laura M. Raffield, Guillaume Lettre, Leslie A. Lange, Erwin P. Bottinger, Jonathan D. Rosen, Frank J. A. van Rooij, Tim Kacprowski, Hua Tang, Regina Manansala, Manuel Tardaguila, Mohsen Ghanbari, Tao Jiang, Torben Hansen, Abdou Mousas, Adam S. Butterworth, Yoav Ben-Shlomo, Praveen Surendran, Terho Lehtimäki, Peter W.F. Wilson, Parsa Akbari, Hélène Choquet, Niels Grarup, Girish N. Nadkarni, Jean-Claude Tardif, Jennifer E. Huffman, Dragana Vuckovic, Ruth J. F. Loos, Karyn Megy, Emilie M. Wigdor, Michael Preuss, Alan B. Zonderman, Yukinori Okada, Oluf Pedersen, Arden Moscati, Leo-Pekka Lyytikäinen, Masahiro Kanai, Wei Huang, Andrew D Beswick, Stephen B. Watt, Erik L. Bao, Allan Linneberg, Paul Elliott, Eric Jorgenson, Tõnu Esko, Michael H. Guo, VA Million Veteran Program, Saori Sakaue, Mika Kähönen, Olli T. Raitakari, Stefan Weiss, Traci M. Bartz, Nina Mononen, Jette Bork-Jensen, Willem H. Ouwehand, Linda Broer, John Danesh, Masato Akiyama, James S. Floyd, Scott C. Ritchie, Kjell Nikus, Paul L. Auer, Emanuele Di Angelantonio, Ken Sin Lo, Kelly Cho, Uwe Völker, Ming-Huei Chen, Evangelos Evangelou, David J. Roberts, Na Cai, Benjamin Rodriguez, Savita Karthikeyan, Yoichiro Kamatani, Michael Inouye, Yoshinori Murakami, Yongmei Liu, Alexander P. Reiner, Koichi Matsuda, Jingzhong Ding, Kumaraswamy Naidu Chitrala, Niki Dimou, Andrew D. Johnson, Nathan Pankratz, Jeffrey Haessler, Vijay G. Sankaran, Oliver Stegle, Qi Guo, Karen L. Mohlke, Jennifer A. Brody, Michele K. Evans, Fotios Koskeridis, Cassandra N. Spracklen, Jerome I. Rotter, Ani Manichaikul, Patrick K. Albers, Caleb A. Lareau, Michel Georges, Hannes Ponstingl, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Yun Li, Klaudia Walter, Huijun Qian, Henry Völzke, Christopher J. Penkett, J. M. M. Howson, Kousik Kundu, Epidemiology, and Internal Medicine
Subjects: Gene regulatory network, LOCI, EFFICIENT, Genome-wide association study, VARIANTS, Blood cell, 0302 clinical medicine, RARE, genetics, 11 Medical and Health Sciences, 0303 health sciences, rare diseases, Biobank, ddc, medicine.anatomical_structure, fine-mapping, VA Million Veteran Program, symbols, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, UK Biobank, polygenic risk, rare disease, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GENETIC ARCHITECTURE, 03 medical and health sciences, symbols.namesake, splicing, blood, medicine, CELL, Allele, GENOME-WIDE ASSOCIATION, COMMON, 030304 developmental biology, Science & Technology, COMPLEX, Oxygen transport, Cell Biology, 06 Biological Sciences, Genetic architecture, hematopoiesis, INTERROGATION, Mendelian inheritance, chromatin, omnigenic, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Summary 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., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.
Published: 2020
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38. Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

Author: Stephen Burgess, Anna C. Calkin, Jonathan Marten, Scott C. Ritchie, Amit Khera, Sohail Zahid, Shu Mei Teo, Sekar Kathiresan, Gad Abraham, Mark Chaffin, Brian G. Drew, Nicole Soranzo, Yingying Liu, Petar Scepanovic, Michael Inouye, Adam S. Butterworth, Samuel A. Lambert, and John Danesh
Subjects: Genetics, 0303 health sciences, Druggability, Mendelian Randomization Analysis, Disease, Type 2 diabetes, 030204 cardiovascular system & hematology, Biology, medicine.disease, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Proteome, Genetic variation, medicine, 030304 developmental biology, Genetic association
Abstract: Polygenic risk scores (PRSs) capture the polygenic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects individual9s disease risk, affording a new opportunity to identify downstream molecular pathways involved in disease pathogenesis. We performed an integrative analysis to characterise associations of PRSs of five cardiometabolic diseases with 3,442 plasma proteins in 3,175 healthy individuals. Through polygenic association scans we identified 48 plasma proteins whose levels were associated with PRSs for coronary artery disease (CAD), chronic kidney disease (CKD), or type 2 diabetes (T2D). This approach identified both well-known disease-associated proteins as well as those with previously no known link to these diseases. We found that PRSs to protein associations were largely truly polygenic; independent of single loci and genomic regions expected to have strong effects on protein levels. Our integrative analysis and laboratory experiments revealed a role for polygenic effects on several well-known disease proteins and identified several promising novel targets for follow-up studies, including genes which through Mendelian randomization analysis displayed causal evidence for effects on disease risk. Mouse studies highlighted specific tissues and phenotypes for PRS-associated human proteins. We found that implicated genes were responsive to dietary intervention in mice and showed strong evidence of druggability in humans, consistent with PRS-associated proteins having therapeutic potential. Overall, our study provides a framework for polygenic association studies, and demonstrates the power of polygenic scores to unravel novel disease biology.
Published: 2019

39. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis

Author: Marijana, Vujkovic, Jacob M, Keaton, Julie A, Lynch, Donald R, Miller, Jin, Zhou, Catherine, Tcheandjieu, Jennifer E, Huffman, Themistocles L, Assimes, Kimberly, Lorenz, Xiang, Zhu, Austin T, Hilliard, Renae L, Judy, Jie, Huang, Kyung M, Lee, Derek, Klarin, Saiju, Pyarajan, John, Danesh, Olle, Melander, Asif, Rasheed, Nadeem H, Mallick, Shahid, Hameed, Irshad H, Qureshi, Muhammad Naeem, Afzal, Uzma, Malik, Anjum, Jalal, Shahid, Abbas, Xin, Sheng, Long, Gao, Klaus H, Kaestner, Katalin, Susztak, Yan V, Sun, Scott L, DuVall, Kelly, Cho, Jennifer S, Lee, J Michael, Gaziano, Lawrence S, Phillips, James B, Meigs, Peter D, Reaven, Peter W, Wilson, Todd L, Edwards, Daniel J, Rader, Scott M, Damrauer, Christopher J, O'Donnell, Philip S, Tsao, Kyong-Mi, Chang, Benjamin F, Voight, and Sumitra, Muralidhar
Subjects: Oncology, Male, medicine.medical_specialty, endocrine system diseases, Type 2 diabetes, Disease, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Genetics, medicine, Genetic predisposition, Humans, Hypoglycemic Agents, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genetic association, 0303 health sciences, Chromosomes, Human, X, nutritional and metabolic diseases, medicine.disease, Black or African American, Europe, Diabetes Mellitus, Type 2, Meta-analysis, Medical genetics, Female, 030217 neurology & neurosurgery, Diabetic Angiopathies, Kidney disease
Abstract: We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
Published: 2019

40. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling

Author: Matthew J. Bown, John Danesh, Pradeep Natarajan, Seyedeh M. Zekavat, Jeanette Erdmann, Namrata Gupta, Mary E. Haas, Amit Khera, Connor A. Emdin, Nathan O. Stitziel, Danish Saleheen, Diego Ardissino, Usman Baber, Derek Klarin, Padhraig Gormley, Ruth McPherson, Akihiro Nomura, Roberto Elosua, Aarno Palotie, Hugh Watkins, Stacey Gabriel, Krishna G. Aragam, Heribert Schunkert, Sekar Kathiresan, James G. Wilson, Nilesh J. Samani, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Nitric Oxide Synthase Type III, Blood Pressure, Coronary Disease, 030204 cardiovascular system & hematology, Nitric Oxide, medicine.disease_cause, Bioinformatics, Polymorphism, Single Nucleotide, Nitric oxide, Peripheral Arterial Disease, 03 medical and health sciences, chemistry.chemical_compound, Soluble Guanylyl Cyclase, 0302 clinical medicine, cardiovascular disease, Risk Factors, Physiology (medical), medicine, Genetic predisposition, Humans, genetics, Genetic Predisposition to Disease, Platelet activation, Genetic Association Studies, Mutation, biology, nitric oxide synthase, business.industry, Protective Factors, Cell biology, Stroke, Nitric oxide synthase, Phenotype, 030104 developmental biology, chemistry, biology.protein, Signal transduction, Cardiology and Cardiovascular Medicine, Soluble guanylyl cyclase, business, Signal Transduction
Abstract: Background: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. Methods: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [ NOS3 ] and Guanylate Cyclase 1, Soluble, Alpha 3 [ GUCY1A3 ]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3 ) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). Results: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P =5.5*10 –26 ], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P =0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P =0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P =5.6*10 –5 ) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P =0.01). Conclusions: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.
Published: 2018

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

Author: Christopher L. Bowlus, Sören Mucha, Piotr Milkiewicz, Jennifer G. Sambrook, Michael P. Manns, Peter R. Durie, Daniel J. Gaffney, Catalina Coltescu, Konstantinos N. Lazaridis, David Ellinghaus, Daniel Gotthardt, George F. Mells, Espen Melum, Joseph A. Odin, Mattias Laudes, Cisca Wijmenga, Kris V. Kowdley, Annarosa Floreani, Tejas S. Shah, Richard Sandford, Erik M. Schlicht, Kirsten Muri Boberg, Javier Gutierrez-Achury, Felix Braun, Martina Sterneck, Carl A. Anderson, Tom H. Karlsen, Andre Franke, Velimir A. Luketic, Brijesh Srivastava, Aliya Gulamhusein, Elizabeth C. Goode, Kelly Spiess, Gunnar Jacobs, Olivier Chazouillères, Wolfgang Lieb, Tobias Müller, Andreas Teufel, Trine Folseraas, Roger W. Chapman, Hanns-Ulrich Marschall, David J. Roberts, Christoph Schramm, Sun-Gou Ji, Albert Parés, Mariza de Andrade, Stefan Schreiber, Elizabeth J. Atkinson, Kimmo Kontula, Pietro Invernizzi, Simon M. Rushbrook, Luke Jostins, Carmel Moore, Naga Chalasani, Jimmy Z. Liu, Brian D. Juran, Willem H. Ouwehand, Graeme J.M. Alexander, John E. Eaton, Gideon M. Hirschfield, Natsuhiko Kumasaka, Martti Färkkilä, Annika Bergquist, Kapil B. Chopra, John Danesh, Bertus Eksteen, Tobias J. Weismüller, Rinse K. Weersma, Ulrich Beuers, Severine Vermeire, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, and Universitat de Barcelona
Subjects: 0301 basic medicine, Genome-wide association study, VARIANTS, Bioinformatics, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Risk Factors, Gastroenterologia, education.field_of_study, digestive, oral, and skin physiology, REGIONS, Ulcerative colitis, Inflamació, 3. Good health, Malalties inflamatòries intestinals, ULCERATIVE-COLITIS, 030211 gastroenterology & hepatology, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, Cholangitis, Sclerosing, Locus (genetics), Biology, Inflammatory bowel diseases, digestive system, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, 03 medical and health sciences, Internal medicine, REVEALS, Genetics, medicine, SNP, Humans, RNA, Messenger, Allele, TRANSCRIPTOME, education, METAANALYSIS, Alleles, Adaptor Proteins, Signal Transducing, Inflammation, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, 030104 developmental biology, PSORIATIC-ARTHRITIS, Colitis, Ulcerative, Genome-Wide Association Study
Abstract: Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 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 (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P
Published: 2016

42. Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease

Author: Diego Ardissino, Daniel J. Rader, Gina M. Peloso, Hayato Tada, Masa-aki Kawashiri, Heribert Schunkert, Matthew J. Bown, Svati H. Shah, Stacey Gabriel, John Danesh, Ruth McPherson, Pradeep Natarajan, Danish Saleheen, Nilesh J. Samani, Adolfo Correa, Akihiro Nomura, Jeanette Erdmann, Amit Khera, Connor A. Emdin, Roberto Elosua, Sekar Kathiresan, Namrata Gupta, Hong-Hee Won, and Hugh Watkins
Subjects: medicine.medical_specialty, Blood lipids, Pedigree chart, ABCG8, 030204 cardiovascular system & hematology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, medicine, 030304 developmental biology, 0303 health sciences, biology, business.industry, Odds ratio, medicine.disease, 3. Good health, Minor allele frequency, Endocrinology, ABCG5, biology.protein, Mendelian inheritance, symbols, lipids (amino acids, peptides, and proteins), business, Sitosterolemia
Abstract: BackgroundFamilial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency – homozygous loss-of-function (LoF) variants — in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.MethodsWe first recruited nine sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% inABCG5orABCG8.ResultsIn sitosterolemia families, seven pedigrees harbored causative LoF variants inABCG5and two pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8were approximately 0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1×10−6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.ConclusionsAlthough familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.
Published: 2019
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43. Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease

Author: John Danesh, Joseph B. Leader, David J. Carey, Danish Saleheen, Frederick E. Dewey, Ruth McPherson, Tanya M. Teslovich, Jaume Marrugat, Amit Khera, Diego Ardissino, Mark Chaffin, Heribert Schunkert, Akihiro Nomura, Jeanette Erdmann, Masa-aki Kawashiri, Hugh Watkins, Shane A. McCarthy, Nilesh J. Samani, Atsushi Nohara, Aris Baras, Hong-Hee Won, H. Lester Kirchner, Sekar Kathiresan, James G. Wilson, Gina M. Peloso, Hayato Tada, Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: Male, Apolipoprotein B, Coronary Disease, 030204 cardiovascular system & hematology, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, Japan, Risk Factors, genetics, 030212 general & internal medicine, triglycerides, Mutation, biology, Genetic disorder, hypobetalipoproteinemia, General Medicine, Middle Aged, 3. Good health, ddc, Pedigree, Female, lipids (amino acids, peptides, and proteins), Adult, medicine.medical_specialty, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, Genetic variation, medicine, Humans, human, Gene, Aged, Apolipoproteins B, business.industry, Cholesterol, Case-control study, cholesterol, Genetic Variation, Cholesterol, LDL, medicine.disease, Endocrinology, chemistry, Case-Control Studies, biology.protein, Hypobetalipoproteinemia, business
Abstract: Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD. Dr Peloso is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number K01HL125751. Dr Nomura was supported by the Yoshida Scholarship Foundation. Dr Khera is supported by an institutional grant from the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard (BroadIgnite), a K08 from the National Human Genome Research Institute (K08HG010155), and a Junior Faculty Award from the National Lipid Association. Dr Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the NHLBI. Funding for the EOMI study (Exome Sequencing Project Early-Onset Myocardial Infarction) was provided by grants RC2 HL103010 (HeartGO, Heart Grand Opportunity), RC2 HL102923 (LungGO, Lung Grand Opportunity), and RC2 HL102924 (WHISP) from the NHLBI. Exome sequencing was performed through grants RC2 HL102925 (BroadGO, Broad Grand Opportunity) and RC2 HL102926 (SeattleGO, Seattle Grand Opportunity) from the NHLBI. Exome sequencing in ATVB (Italian Atherosclerosis, Thrombosis, and Vascular Biology), the PROCARDIS study (Precocious Coronary Artery Disease), the OHS (Ottawa Heart Study), PROMIS (Pakistan Risk of Myocardial Infarction Study), South German MI study (South German Myocardial Infarction), and the JHS (Jackson Heart Study) was supported by grant 5U54HG003067 from the National Institutes of Health. Fieldwork, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, European Union (EU) Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012–279233). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. REGICOR study (Registre Gironí del COR [Gerona Heart Registry]) was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester (Leicester Myocardial Infarction) cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The South MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces and SFB 1123. The ATVB study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010–2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. The authors would like to thank the MyCode Community Health Initiative participants for their permission to utilize their health and genomics information in the DiscovEHR (DiscovEHR partnership of the Regeneron Genetics Center and Geisinger Health System) collaboration. The DiscovEHR study was funded, in part, by the Regeneron Genetics Center.
Published: 2019

44. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Author: Tuomo Kiiskinen, Jeanette Erdmann, Diego Ardissino, Mary E. Haas, Krishna G. Aragam, Amit Khera, Connor A. Emdin, Sekar Kathiresan, Mark J. Daly, QiPing Feng, James G. Wilson, Aki S. Havulinna, Roberto Elosua, Danish Saleheen, Nilesh J. Samani, Usman Baber, Lan Jiang, Mark Chaffin, Joshua C. Denny, Namrata Gupta, Wei-Qi Wei, Alexander G. Bick, Stacey Gabriel, Ruth McPherson, Heribert Schunkert, Matthew J. Bown, John Danesh, Juha Karjalainen, and Hugh Watkins
Subjects: 0303 health sciences, medicine.medical_specialty, Cirrhosis, biology, Cholesterol, Fatty liver, medicine.disease, Mitochondrial amidoxime reducing component 1, 03 medical and health sciences, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, Endocrinology, chemistry, Alanine transaminase, 030220 oncology & carcinogenesis, Internal medicine, medicine, biology.protein, Alkaline phosphatase, Missense mutation, 030304 developmental biology
Abstract: Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10−8). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (−0.012 SD, 1.4*10−8), alkaline phosphatase (−0.019 SD, 6.6*10−9), total cholesterol (−0.037 SD, p=1*10−18) and LDL cholesterol (−0.035 SD, p=7.3*10−16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.
Published: 2019
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45. Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease

Author: Adam S. Butterworth, Deepak L. Bhatt, Alberico L. Catapano, Angela M. Wood, Chris J. Packard, Ulrich Laufs, Marc S. Sabatine, Stephen J. Nicholls, John J.P. Kastelein, Clare Oliver-Williams, John Danesh, Kausik K. Ray, Brian A. Ference, Henry N. Ginsberg, M. John Chapman, Emanuele Di Angelantonio, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Oliver-Williams, Clare [0000-0002-3573-2426], Wood, Angela [0000-0002-7937-304X], Butterworth, Adam [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
Subjects: Male, Apolipoprotein B, Blood lipids, Coronary Disease, SECONDARY PREVENTION, THERAPY, 01 natural sciences, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Loss of Function Mutation, Risk Factors, Receptors, Receptors, LDL/genetics, WIDE ASSOCIATION, 030212 general & internal medicine, Prospective Studies, 11 Medical and Health Sciences, Original Investigation, biology, General Medicine, Middle Aged, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, Low-density lipoprotein, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Metabolic Networks and Pathways, medicine.medical_specialty, INHIBITION, LDL/genetics, Lower risk, 03 medical and health sciences, Medicine, General & Internal, Coronary Disease/blood, General & Internal Medicine, Internal medicine, medicine, Humans, Lipoprotein Lipase/genetics, Genetic Predisposition to Disease, 0101 mathematics, CARDIOVASCULAR EVENTS, METAANALYSIS, Triglycerides, Apolipoproteins B, GEMFIBROZIL, Science & Technology, DENSITY-LIPOPROTEIN-CHOLESTEROL, Triglyceride, business.industry, 010102 general mathematics, Genetic Variation, Cholesterol, LDL, Odds ratio, Mendelian Randomization Analysis, Apolipoproteins B/blood, REDUCTION, Lipoprotein Lipase, ATHEROSCLEROSIS, Receptors, LDL, chemistry, Case-Control Studies, biology.protein, business, Lipoprotein
Abstract: Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD) - defined as coronary death, myocardial infarction, or coronary revascularization - per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654783 participants, including 91129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10 -1363 ) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P =.04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10 -465 ) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P =.04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10 -38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10 -46 , respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P =.19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P =.19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10 -20 ). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
Published: 2019

46. Genetic effects on promoter usage are highly context-specific and contribute to complex traits

Author: Julia Rodrigues, Daniel J. Gaffney, Dirk S. Paul, Kaur Alasoo, John Danesh, Daniel F. Freitag, Alasoo, Kaur [0000-0002-1761-8881], Paul, Dirk S [0000-0002-8230-0116], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, RNA-Seq, Exon, computational biology, 0302 clinical medicine, Transcription (biology), genetics, Biology (General), Promoter Regions, Genetic, Genetics, 0303 health sciences, General Neuroscience, systems biology, General Medicine, macrophages, RNA splicing, Trait, Medicine, Female, transcription, Research Article, Computational and Systems Biology, QH301-705.5, Science, Systems biology, Quantitative Trait Loci, Genomics, Computational biology, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, splicing, 03 medical and health sciences, Quantitative Trait, Heritable, Genetic variation, genomics, Humans, human, RNA, Messenger, 030304 developmental biology, General Immunology and Microbiology, Genetics and Genomics, Promoter, Genetic architecture, 030104 developmental biology, Gene Expression Regulation, RNA-seq, 030217 neurology & neurosurgery
Abstract: Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3ʹ end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3ʹ end usage. We found that promoters, splicing and 3ʹ ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner., eLife digest Genes contain all instructions needed to build an organism in form of DNA. Humans share around 99.5% of DNA, but it is the remaining 0.5% that contain the small genetic variations that make us unique. Subtle differences in genes can, for example, influence the color of our hair or eyes. To build gene products, such as proteins, DNA first needs to be transcribed into RNA. Some genetic variants can affect how a gene is transcribed into an RNA molecule, for example by making it be transcribed too much or too little, which can lead to diseases. These variants can also influence where the transcription begins through a process called promoter usage. This can lead to shorter or longer RNAs, which can have different biological impacts. With current research methods it is difficult to detect changes in the latter kind of alteration. As a result, it is harder to distinguish these from other types of changes. Now, Alasoo et al. wanted to find out what proportion of genetic variants that alter traits influence promoter usage, compared to other changes. To do so, a new computational method was developed to directly measure how genetic variants influence different parts of the RNA, such as promoters, middle sections and ends. The method was then applied to datasets of human immune cells. The experiments revealed that genetic variants often influence promoter usage. Many of the effects could only be found when cells are exposed to external stimuli, such as bacteria. The results highlight that to discover genes responsible for human traits and disease we need to consider all the possible ways genetic differences between individuals could alter the gene products. Large published datasets could be reanalyzed using this method to identify new genes that could be implicated in human health and disease, potentially leading to new treatment options in future.
Published: 2019

47. Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation

Author: Wieland Kiess, Josée Dupuis, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, George Dedoussis, Frida Renström, Carolina Medina-Gomez, Tamara B. Harris, Cramer Christensen, Audrey Y. Chu, Nicola L. Beer, Emil V. R. Appel, Niels Grarup, Fredrik Karpe, Mark I. McCarthy, Yuning Chen, Veikko Salomaa, Sylvain Sebert, Richard A. Jensen, Joel N. Hirschhorn, Lars Lind, Jocelyn E. Manning Fox, Caroline Hayward, Patrick E. MacDonald, Matti Uusitupa, Stavroula Kanoni, Carola Marzi, Kenneth Rice, Leslie A. Lange, Ken Sin Lo, Jennifer L. Asimit, Nisa M. Maruthur, Leonard Lipovich, James S. Floyd, Rona J. Strawbridge, Magdalena Zoledziewska, Anne Raimondo, Robert Sladek, Alexandra I. F. Blakemore, Hugoline G. de Haan, Danish Saleheen, Ji Chen, Neil Robertson, Ching-Yu Cheng, Heiner Boeing, Min A. Jhun, Marjo-Riitta Järvelin, Anubha Mahajan, Rainer Rauramaa, Satu Männistö, Paul M. Ridker, Ivan Brandslund, Hester M. den Ruijter, Tien Yin Wong, Alison D. Murray, Jaakko Tuomilehto, Xueling Sim, Igor Rudan, Martijn van de Bunt, Jin Li, Marit E. Jørgensen, Marie-France Hivert, Archie Campbell, Salman M. Tajuddin, Pekka Jousilahti, Lawrence F. Bielak, Juan P. Fernandez, Eleanor Wheeler, Alan B. Zonderman, Anne Clark, Lori L. Bonnycastle, Kurt Lohman, Peter Kovacs, Jung-Jin Lee, Jennifer Wessel, Wesam A Alhejily, Gerard Pasterkamp, John M. Starr, Ping An, Matthias Blüher, Jian'an Luan, Hanieh Yeghootkar, Jakob Stokholm, Michael Roden, Blair H. Smith, Johanna Jakobsdottir, Franco Giulianini, Andrianos M. Yiorkas, Hidetoshi Kitajima, Michael A. Province, Aliki-Eleni Farmaki, Kerrin S. Small, Juha Saltevo, Robert A. Scott, Alena Stančáková, Gaëlle Marenne, Asif Rasheed, Ruth J. F. Loos, David J. Porteous, Cecilia M. Lindgren, Inês Barroso, Gail Davies, Anna L. Gloyn, Shuai Wang, Paul Redmond, Xiuqing Guo, Ele Ferrannini, Mariaelisa Graff, Cornelia M. van Duijn, Juha Auvinen, David R. Weir, Kay-Tee Kaw, Tarunveer S. Ahluwalia, Olov Rolandsson, Wei Zhao, Paul Elliott, Torben Hansen, Abbas Dehghan, Bram P. Prins, Michiel L. Bots, Alison Pattie, Jun Liu, Gonçalo R. Abecasis, Maria Karaleftheri, Claudia Langenberg, Jan-Håkan Jansson, Marja Vääräsmäki, James S. Pankow, Rebecca S. Fine, Jaana Lindström, Ozren Polasek, Vinicius Tragante, Soren K. Thomsen, Jana K. Rundle, Najaf Amin, Saima Afaq, Jennifer A. Smith, Anne U. Jackson, Eirini Marouli, Weihua Zhang, Tim D. Spector, Paul W. Franks, Serena Sanna, Mark J. Caulfield, Heikki A. Koistinen, Jaspal S. Kooner, Tea Skaaby, Francis S. Collins, Eva Rabing Brix Petersen, Arfan Ikram, Sander W. van der Laan, Johanna Kuusisto, Jette Bork-Jensen, Daniel I. Chasman, Michele K. Evans, Emmanouil Tsafantakis, A. I. Tarasov, Ian J. Deary, Hans Bisgaard, Dennis O. Mook-Kanamori, Helen R. Warren, Kent D. Taylor, Andrew D. Morris, Eleftheria Zeggini, Sharon L.R. Kardia, Emma Ahlqvist, Gert J. de Borst, Torben Jørgensen, Antonella Mulas, Man Li, Betina H. Thuesen, Yuan Shi, Timo A. Lakka, Jie Yao, Tapani Ebeling, Natasha H. J. Ng, Sai Chen, Leena Kinnunen, Antje Körner, Klaus Bønnelykke, Lorraine Southam, Anette P. Gjesing, Ilonca Vaartjes, Heather M. Highland, Göran Hallmans, Anke Tönjes, Markku Laakso, Lenore J. Launer, Josef Coresh, Oscar H. Franco, Yongmei Liu, Beverley Balkau, Leena Moilanen, Karl-Heinz Herzig, James G. Wilson, Jennifer A. Brody, Renée de Mutsert, Alisa K. Manning, Anne E. Justice, Matthias B. Schulze, Sandosh Padmanabhan, Jose C. Florez, Shuang Feng, Heather M. Stringham, Bruce M. Psaty, Erwin P. Bottinger, Hannu Puolijoki, Vilmundur Gudnason, Leif Groop, Nicholas J. Wareham, Karina Meidtner, Andrew P. Morris, Taulant Muka, Benoit Hastoy, Panos Deloukas, Pirjo Komulainen, Ayse Demirkan, Francesco Cucca, Stefan Gustafsson, Eric Boerwinkle, Patrik Rorsman, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Allan Linneberg, Tiinamaija Tuomi, Dan E. Arking, Steve Franks, Jonathan Marten, Mark Walker, Ruifang Li-Gao, Kai Savonen, Michael Stumvoll, Andreas Fritsche, E-Shyong Tai, Mark O. Goodarzi, Matt J. Neville, Oluf Pedersen, Eero Kajantie, Ching-Ti Liu, Michael Boehnke, Aaron Leong, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, John C. Chambers, John Danesh, Sirkka Keinänen-Kiukaanniemi, Giorgio Pistis, Karen L. Mohlke, Folkert W. Asselbergs, James B. Meigs, Tibor V. Varga, Erica L. Kleinbrink, Andrew T. Hattersley, Nathan A. Bihlmeyer, Harald Grallert, Albert V. Smith, Konstantin Strauch, Jerome I. Rotter, and Frits R. Rosendaal
Subjects: medicine.medical_specialty, G6PC2, pathways, Adipose tissue, Type 2 diabetes, Biology, effector transcript, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, 0502 economics and business, medicine, Glucose homeostasis, genetics, 050207 economics, 030304 developmental biology, Glycemic, 0303 health sciences, 050208 finance, Pancreatic islets, 05 social sciences, tissue, Genomics, medicine.disease, Endocrinology, medicine.anatomical_structure, chemistry, glycemic traits, Glycated hemoglobin, type 2 diabetes, 030217 neurology & neurosurgery
Abstract: SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
Published: 2019

48. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author: Tobias Hermle, Holger Kirsten, Karsten B. Sieber, Aiko P. J. de Vries, Su Chi Lim, Peter Kovacs, Charumathi Sabanayagam, Carl D. Langefeld, Bernhard K. Krämer, Kent D. Taylor, Janine F. Felix, Belen Ponte, Markus Loeffler, Mary F. Feitosa, Kai-Uwe Eckardt, Jianjun Liu, Katalin Dittrich, Charlene A. Wong, Uwe Völker, Adriana M. Hung, Thomas Meitinger, Anubha Mahajan, Anselm Hoppmann, Erik Ingelsson, Martin H. de Borst, Oscar H. Franco, Niek Verweij, Kai-Uwe Saum, Vilmundur Gudnason, Bram P. Prins, Carsten A. Böger, Terho Lehtimäki, Andrew A. Hicks, Todd L. Edwards, Olivier Devuyst, Peter P. Pramstaller, Katrin Horn, Leslie A. Lange, Johanne Tremblay, Jin-Fang Chai, Sahar Ghasemi, Kjell Nikus, Tanja Poulain, Massimiliano Cocca, Anna Köttgen, Eric Boerwinkle, Barry I. Freedman, Miao-Ling Chee, Man Li, Stephan J. L. Bakker, Tamara B. Harris, Albert V. Smith, Ton J. Rabelink, Dennis O. Mook-Kanamori, Iris M. Heid, Jasmin Divers, Chaolong Wang, Kathleen A. Ryan, Pavel Hamet, Silke Szymczak, Shih-Jen Hwang, Hauke Thomsen, Rainer Rettig, Ayush Giri, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Cristian Pattaro, Andrej Teren, Valencia Hui Xian Foo, Myriam Rheinberger, Audrey Y. Chu, Barbara McMullen, Franziska Grundner-Culemann, Masayuki Yasuda, Murielle Bochud, Martin Gögele, Anke Tönjes, Jeannette Lee, Adrienne Tin, Kevin Ho, Konstantin Strauch, Josef Coresh, Renée de Mutsert, Sandra Freitag-Wolf, Gardar Sveinbjornsson, Yizhe Xu, Katalin Susztak, Tien Yin Wong, Mary L. Biggs, Isleifur Olafsson, Qiong Yang, Antje Körner, Chengxiang Qiu, E-Shyong Tai, Martina Müller-Nurasyid, Ben Schöttker, Jeffrey O' Connell, Mengmeng Chen, Daniel F. Gudbjartsson, Dermot F. Reilly, Vincent W. V. Jaddoe, Damia Noce, Pim van der Harst, Sanaz Sedaghat, Chiea Chuen Khor, Adam S. Butterworth, Mathias Gorski, Robert J. Carroll, James G. Wilson, Johan Ärnlöv, Christa Meisinger, Kenneth Rice, Bettina Jung, Christian M. Shaffer, Unnur Thorsteinsdottir, Matthias Nauck, Shreeram Akilesh, Mika Kähönen, Johanna Jakobsdottir, Melanie Waldenberger, Ralph Burkhardt, Daniela Baptista, John Danesh, Benjamin B. Sun, Karlhans Endlich, Holly Kramer, Frauke Degenhardt, Wolfgang Lieb, Kari Stefansson, Joachim Thiery, Lars Lind, Nicholette D. Palmer, Sarah A. Pendergrass, Suzanne Vogelezang, Peter J. van der Most, Afshin Parsa, Markus Scholz, Florian Kronenberg, Joseph C. Maranville, Laura M. Raffield, Hermann Brenner, Wieland Kiess, Anna I. Podgornaia, Yuan Shi, Tanguy Corre, Miao-Li Chee, Deborah Mascalzoni, Bamidele O. Tayo, Navya Shilpa Josyula, Ching-Yu Cheng, Lea Gerstner, Nisha Bansal, Jerome I. Rotter, Alexander Teumer, Vilmantas Giedraitis, Raymond Noordam, Ron T. Gansevoort, Lihua Wang, Andrew P. Morris, Bruce M. Psaty, Boting Ning, Zhi Yu, Christian Fuchsberger, Matthias Wuttke, Heiko Runz, Annette Peters, Yih Chung Tham, James P. Cook, Yong Li, Chris H. L. Thio, Hilma Holm, Alessandro De Grandi, Jonathan Marten, André G. Uitterlinden, Andre Franke, Nicholas Y. Q. Tan, Otis D. Wilson, Georg Ehret, Cecilia M. Lindgren, Josyf C. Mychaleckyj, Wolfgang Koenig, Harold Snieder, Michael Stumvoll, Kozeta Miliku, M. Arfan Ikram, Teresa Nutile, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Teumer, Alexander [0000-0002-8309-094X], Li, Yong [0000-0003-2651-8791], Wuttke, Matthias [0000-0003-3420-5082], Giri, Ayush [0000-0002-7786-4670], Qiu, Chengxiang [0000-0002-6346-8669], Kirsten, Holger [0000-0002-3126-7950], Tin, Adrienne [0000-0002-4207-5866], Feitosa, Mary F. [0000-0002-0933-2410], Chai, Jin-Fang [0000-0003-3770-1137], Cocca, Massimiliano [0000-0002-1127-7596], Gorski, Mathias [0000-0002-9103-5860], Horn, Katrin [0000-0002-5307-6936], Li, Man [0000-0002-3839-0281], Marten, Jonathan [0000-0001-6916-2014], van der Most, Peter J. [0000-0001-8450-3518], Burkhardt, Ralph [0000-0003-1924-1202], Coresh, Josef [0000-0002-4598-0669], de Borst, Martin H. [0000-0002-4127-8733], Ehret, Georg [0000-0002-5730-0675], Endlich, Karlhans [0000-0001-6052-6061], Felix, Janine F. [0000-0002-9801-5774], Franke, Andre [0000-0003-1530-5811], Freedman, Barry I. [0000-0003-0275-5530], Freitag-Wolf, Sandra [0000-0002-1069-7740], Giedraitis, Vilmantas [0000-0003-3423-2021], Grundner-Culemann, Franziska [0000-0001-9649-281X], Gudnason, Vilmundur [0000-0001-5696-0084], Hicks, Andrew A. [0000-0001-6320-0411], Ikram, M. Arfan [0000-0003-0372-8585], Ingelsson, Erik [0000-0003-2256-6972], Jaddoe, Vincent W. V. [0000-0003-2939-0041], Josyula, Navya Shilpa [0000-0003-2782-8812], Khor, Chiea-Chuen [0000-0002-1128-4729], Koenig, Wolfgang [0000-0002-2064-9603], Kovacs, Peter [0000-0002-0290-5423], Kronenberg, Florian [0000-0003-2229-1120], Lindgren, Cecilia M. [0000-0002-4903-9374], Liu, Jianjun [0000-0002-3255-3019], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Mahajan, Anubha [0000-0001-5585-3420], Mascalzoni, Deborah [0000-0003-4156-1464], Miliku, Kozeta [0000-0002-9614-7191], Müller-Nurasyid, Martina [0000-0003-3793-5910], Mychaleckyj, Josyf C. [0000-0003-2595-0005], Palmer, Nicholette D. [0000-0001-8883-2511], Poulain, Tanja [0000-0003-3825-5829], Raffield, Laura M. [0000-0002-7892-193X], Rice, Kenneth M. [0000-0002-3071-7278], Rivadeneira, Fernando [0000-0001-9435-9441], Sabanayagam, Charumathi [0000-0002-4042-4719], Smith, Albert V. [0000-0003-1942-5845], Sun, Benjamin B. [0000-0001-6347-2281], Szymczak, Silke [0000-0002-8897-9035], Taylor, Kent D. [0000-0002-2756-4370], Thio, Chris H. L. [0000-0003-2623-7172], Uitterlinden, André G. [0000-0002-7276-3387], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Völker, Uwe [0000-0002-5689-3448], Wang, Chaolong [0000-0003-3945-1012], Yang, Qiong [0000-0002-3658-1375], Devuyst, Olivier [0000-0003-3744-4767], Edwards, Todd L. [0000-0003-4318-6119], Ho, Kevin [0000-0002-3054-8697], Morris, Andrew P. [0000-0002-6805-6014], Pendergrass, Sarah A. [0000-0002-0565-6522], Rotter, Jerome I. [0000-0001-7191-1723], Stefansson, Kari [0000-0003-1676-864X], Susztak, Katalin [0000-0002-1005-3726], Scholz, Markus [0000-0002-4059-1779], Butterworth, Adam S. [0000-0002-6915-9015], Hung, Adriana M. [0000-0002-3203-1608], Pattaro, Cristian [0000-0002-4119-0109], Köttgen, Anna [0000-0002-4671-3714], Apollo - University of Cambridge Repository, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Feitosa, Mary F [0000-0002-0933-2410], van der Most, Peter J [0000-0001-8450-3518], de Borst, Martin H [0000-0002-4127-8733], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jaddoe, Vincent WV [0000-0003-2939-0041], Lindgren, Cecilia M [0000-0002-4903-9374], Mychaleckyj, Josyf C [0000-0003-2595-0005], Palmer, Nicholette D [0000-0001-8883-2511], Raffield, Laura M [0000-0002-7892-193X], Rice, Kenneth M [0000-0002-3071-7278], Smith, Albert V [0000-0003-1942-5845], Sun, Benjamin B [0000-0001-6347-2281], Taylor, Kent D [0000-0002-2756-4370], Thio, Chris HL [0000-0003-2623-7172], Uitterlinden, André G [0000-0002-7276-3387], Edwards, Todd L [0000-0003-4318-6119], Morris, Andrew P [0000-0002-6805-6014], Pendergrass, Sarah A [0000-0002-0565-6522], Rotter, Jerome I [0000-0001-7191-1723], Butterworth, Adam S [0000-0002-6915-9015], and Hung, Adriana M [0000-0002-3203-1608]
Subjects: 0301 basic medicine, Drosophila melanogaster/genetics, Diabetes Mellitus/genetics, LD SCORE REGRESSION, 030232 urology & nephrology, 45/43, General Physics and Astronomy, Genome-wide association study, BLOOD-PRESSURE, Bioinformatics, GLOMERULAR-FILTRATION-RATE, Genome-wide association studies, Diabetes mellitus genetics, 0302 clinical medicine, Creatinine/urine, Risk Factors, Genome-wide, Phenomics, lcsh:Science, ddc:616, Regulation of gene expression, RISK, Gene knockdown, Kidney diseases, Multidisciplinary, HERITABILITY, Albuminuria/genetics, article, Chromosome Mapping, Kidney disease, ddc, 3. Good health, Drosophila melanogaster, Creatinine, Nýrnasjúkdómar, 692/4022/1585, Slit diaphragm, Medical genetics, medicine.symptom, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, Science, 631/208/205/2138, 610 Medicine & health, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Meta-Analysis as Topic, 360 Social problems & social services, Diabetes Mellitus, medicine, Animals, Humans, Albuminuria, Genetic Predisposition to Disease, ddc:610, EXCRETION RATE, CARDIOVASCULAR EVENTS, Genetic association, Medicinsk genetik, TRANS-EQTLS, KIDNEY-DISEASE, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, COLLABORATIVE METAANALYSIS, lcsh:Q, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein)., Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria., Competing interests: Karsten B. Sieber is full-time employee of GlaxoSmithKline. Gardar Sveinbjornsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are full-time employees of deCODE genetics, Amgen Inc. John Danesh is member of the Novartis Cardiovascular and Metabolic Advisory Board, received grant support from Novartis. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Wolfgang Koenig received modest consultation fees for advisory board meetings from Amgen, DalCor, Kowa, Novartis, Pfizer and Sanofi, and modest personal fees for lectures from Amgen, AstraZeneca, Novartis, Pfizer and Sanofi. Anna I. Podgornaia and Dermot F. Reilly are employees of Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA. Kevin Ho disclosed a research and financial relationship with Sanofi-Genzyme. Bruce M. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Markus Scholz: Consultancy of and grant support from Merck Serono not related to this project. Adam S. Butterworth received grants from MSD, Pfizer, Novartis, Biogen and Bioverativ and personal fees from Novartis. Anna Köttgen received grant support from Gruenenthal not related to this project. The other authors declare no competing interests.
Published: 2019
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49. Author response: Genetic effects on promoter usage are highly context-specific and contribute to complex traits

Author: Dirk S. Paul, Kaur Alasoo, John Danesh, Daniel F. Freitag, Daniel J. Gaffney, and Julia Rodrigues
Subjects: Evolutionary biology, Context specific, Biology
Published: 2018

50. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations

Author: Adam S. Butterworth, Mihir A Kamat, Praveen Surendran, Robin Young, Stephen Burgess, James R Staley, John Danesh, James A. Blackshaw, Blackshaw, James [0000-0002-0343-0319], Surendran, Praveen [0000-0002-4911-6077], Burgess, Stephen [0000-0001-5365-8760], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Statistics and Probability, Linkage disequilibrium, Genotype, Databases and Ontologies, Genome-wide association study, Computational biology, Phenome, Biology, Biochemistry, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Humans, 1000 Genomes Project, Molecular Biology, Gene, Genetic Association Studies, 030304 developmental biology, Genetic association, 0303 health sciences, Genome, Phenotype, Applications Notes, 3. Good health, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, 030217 neurology & neurosurgery, Software, Genome-Wide Association Study
Abstract: Summary PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates ‘phenome scans’, where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner (‘PhenoScanner V2’), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. Availability and implementation PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.
Published: 2018

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