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

Author

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

Subjects
Science
Abstract

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

Published
2023
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2. South Asian medical cohorts reveal strong founder effects and high rates of homozygosity

Author

Jeffrey D. Wall, J. Fah Sathirapongsasuti, Ravi Gupta, Asif Rasheed, Radha Venkatesan, Saurabh Belsare, Ramesh Menon, Sameer Phalke, Anuradha Mittal, John Fang, Deepak Tanneeru, Manjari Deshmukh, Akshi Bassi, Jacqueline Robinson, Ruchi Chaudhary, Sakthivel Murugan, Zameer ul-Asar, Imran Saleem, Unzila Ishtiaq, Areej Fatima, Saqib Shafi Sheikh, Shahid Hameed, Mohammad Ishaq, Syed Zahed Rasheed, Fazal-ur-Rehman Memon, Anjum Jalal, Shahid Abbas, Philippe Frossard, Christian Fuchsberger, Lukas Forer, Sebastian Schoenherr, Qixin Bei, Tushar Bhangale, Jennifer Tom, Santosh Gopi Krishna Gadde, Priya B V, Naveen Kumar Naik, Minxian Wang, Pui-Yan Kwok, Amit V. Khera, B. R. Lakshmi, Adam S. Butterworth, Rajiv Chowdhury, John Danesh, Emanuele di Angelantonio, Aliya Naheed, Vinay Goyal, Rukmini M. Kandadai, Hrishikesh Kumar, Rupam Borgohain, Adreesh Mukherjee, Pettarusp M. Wadia, Ravi Yadav, Soaham Desai, Niraj Kumar, Atanu Biswas, Pramod Kumar Pal, Uday B. Muthane, Shymal K. Das, Vedam L. Ramprasad, Prashanth L. Kukkle, Somasekar Seshagiri, Sekar Kathiresan, Arkasubhra Ghosh, V. Mohan, Danish Saleheen, Eric W. Stawiski, and Andrew S. Peterson

Subjects
Science
Abstract

Abstract The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.

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

Author

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

Subjects
Science
Abstract

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

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

Author

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

Subjects
Science
Abstract

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

Published
2022
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5. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

David Stacey, Lingyan Chen, Paulina J. Stanczyk, Joanna M. M. Howson, Amy M. Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E. Peters, Saonli Basu, James S. Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S. de Vries, Nicholas L. Smith, CHARGE Hemostasis Working Group, Amy D. Gelinas, Daniel J. Schneider, Nebojsa Janjic, Nilesh J. Samani, Shu Ye, Charlotte Summers, Edwin R. Chilvers, John Danesh, and Dirk S. Paul

Subjects
Science
Abstract

Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.

Published
2022
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6. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Eva Gonçalves Serra, Tobias Schwerd, Loukas Moutsianas, Athena Cavounidis, Laura Fachal, Sumeet Pandey, Jochen Kammermeier, Nicholas M. Croft, Carsten Posovszky, Astor Rodrigues, Richard K. Russell, Farah Barakat, Marcus K. H. Auth, Robert Heuschkel, Matthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon P. Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly C. Gilmour, Andrzej Wedrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem Ouwehand, David Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Mohammad Karaminejadranjbar, Ahmed Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M. Griffiths, COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Scott B. Snapper, Neil Shah, Aleixo M. Muise, David C. Wilson, Holm H. Uhlig, and Carl A. Anderson

Subjects
Science
Abstract

Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

Published
2020
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7. Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke

Author

Gad Abraham, Rainer Malik, Ekaterina Yonova-Doing, Agus Salim, Tingting Wang, John Danesh, Adam S. Butterworth, Joanna M. M. Howson, Michael Inouye, and Martin Dichgans

Subjects
Science
Abstract

Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.

Published
2019
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8. Publisher Correction: Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

David Stacey, Lingyan Chen, Paulina J. Stanczyk, Joanna M. M. Howson, Amy M. Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E. Peters, Saonli Basu, James S. Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S. de Vries, Nicholas L. Smith, CHARGE Hemostasis Working Group, Amy D. Gelinas, Daniel J. Schneider, Nebojsa Janjic, Nilesh J. Samani, Shu Ye, Charlotte Summers, Edwin R. Chilvers, John Danesh, and Dirk S. Paul

Subjects
Science
Published
2022
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9. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, and Anna Köttgen

Subjects
Science
Abstract

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

Published
2019
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10. Assessing the causal association of glycine with risk of cardio-metabolic diseases

Author

Laura B. L. Wittemans, Luca A. Lotta, Clare Oliver-Williams, Isobel D. Stewart, Praveen Surendran, Savita Karthikeyan, Felix R. Day, Albert Koulman, Fumiaki Imamura, Lingyao Zeng, Jeanette Erdmann, Heribert Schunkert, Kay-Tee Khaw, Julian L. Griffin, Nita G. Forouhi, Robert A. Scott, Angela M. Wood, Stephen Burgess, Joanna M. M. Howson, John Danesh, Nicholas J. Wareham, Adam S. Butterworth, and Claudia Langenberg

Subjects
Science
Abstract

Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.

Published
2019
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11. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Author

Eva Gonçalves Serra, Tobias Schwerd, Loukas Moutsianas, Athena Cavounidis, Laura Fachal, Sumeet Pandey, Jochen Kammermeier, Nicholas M. Croft, Carsten Posovszky, Astor Rodrigues, Richard K. Russell, Farah Barakat, Marcus K. H. Auth, Robert Heuschkel, Matthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon P. Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly C. Gilmour, Andrzej Wedrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem Ouwehand, David Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Eli M Carrami, Ahmed Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M. Griffiths, COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Scott B. Snapper, Neil Shah, Aleixo M. Muise, David C. Wilson, Holm H. Uhlig, and Carl A. Anderson

Subjects
Science
Published
2022
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12. Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author

Arthur Gilly, Daniel Suveges, Karoline Kuchenbaecker, Martin Pollard, Lorraine Southam, Konstantinos Hatzikotoulas, Aliki-Eleni Farmaki, Thea Bjornland, Ryan Waples, Emil V. R. Appel, Elisabetta Casalone, Giorgio Melloni, Britt Kilian, Nigel W. Rayner, Ioanna Ntalla, Kousik Kundu, Klaudia Walter, John Danesh, Adam Butterworth, Inês Barroso, Emmanouil Tsafantakis, George Dedoussis, Ida Moltke, and Eleftheria Zeggini

Subjects
Science
Abstract

Rare genetic variants can contribute to complex traits but this contribution is not well understood. Here, the authors analyse deep whole genome sequencing data across 1457 individuals from an isolated Greek population and find association of rare variant burdens with cardiometabolic traits.

Published
2018
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13. Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Author

Chen Yao, George Chen, Ci Song, Joshua Keefe, Michael Mendelson, Tianxiao Huan, Benjamin B. Sun, Annika Laser, Joseph C. Maranville, Hongsheng Wu, Jennifer E. Ho, Paul Courchesne, Asya Lyass, Martin G. Larson, Christian Gieger, Johannes Graumann, Andrew D. Johnson, John Danesh, Heiko Runz, Shih-Jen Hwang, Chunyu Liu, Adam S. Butterworth, Karsten Suhre, and Daniel Levy

Subjects
Science
Abstract

Genetic variation can influence levels of disease-related plasma proteins and, thus, contribute to the pathogenesis of complex diseases. Here, the authors perform genome-wide QTL analysis for 71 plasma proteins to identify causal proteins for coronary heart disease and provide a molecular QTL browser.

Published
2018
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14. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author

Connor A. Emdin, Amit V. Khera, Mark Chaffin, Derek Klarin, Pradeep Natarajan, Krishna Aragam, Mary Haas, Alexander Bick, Seyedeh M. Zekavat, Akihiro Nomura, Diego Ardissino, James G. Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J. Bown, Nilesh J. Samani, Usman Baber, Jeanette Erdmann, Namrata Gupta, John Danesh, Daniel Chasman, Paul Ridker, Joshua Denny, Lisa Bastarache, Judith H. Lichtman, Gail D’Onofrio, Jennifer Mattera, John A. Spertus, Wayne H.-H. Sheu, Kent D. Taylor, Bruce M. Psaty, Stephen S. Rich, Wendy Post, Jerome I. Rotter, Yii-Der Ida Chen, Harlan Krumholz, Danish Saleheen, Stacey Gabriel, and Sekar Kathiresan

Subjects
Science
Abstract

Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

Published
2018
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15. Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Author

Laura J. Corbin, Vanessa Y. Tan, David A. Hughes, Kaitlin H. Wade, Dirk S. Paul, Katherine E. Tansey, Frances Butcher, Frank Dudbridge, Joanna M. Howson, Momodou W. Jallow, Catherine John, Nathalie Kingston, Cecilia M. Lindgren, Michael O’Donavan, Stephen O’Rahilly, Michael J. Owen, Colin N. A. Palmer, Ewan R. Pearson, Robert A. Scott, David A. van Heel, John Whittaker, Tim Frayling, Martin D. Tobin, Louise V. Wain, George Davey Smith, David M. Evans, Fredrik Karpe, Mark I. McCarthy, John Danesh, Paul W. Franks, and Nicholas J. Timpson

Subjects
Science
Abstract

Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.

Published
2018
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16. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Xia Jiang, Paul F. O’Reilly, Hugues Aschard, Yi-Hsiang Hsu, J. Brent Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, Diane Berry, Bryan Kestenbaum, Jusheng Zheng, Jianan Luan, Eleni Sofianopoulou, Elizabeth A. Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. Econs, Henri Wallaschofski, Henry Völzke, Ang Zhou, Chris Power, Mark I. McCarthy, Erin D. Michos, Eric Boerwinkle, Stephanie J. Weinstein, Neal D. Freedman, Wen-Yi Huang, Natasja M. Van Schoor, Nathalie van der Velde, Lisette C. P. G. M. de Groot, Anke Enneman, L. Adrienne Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching-Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan G. Eriksson, M. Kyla Shea, Denise K. Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt K. Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, Eline Slagboom, Joris Deelen, Diana van Heemst, Marcus E. Kleber, Winfried März, Ian H. de Boer, Alexis C. Wood, Jerome I. Rotter, Stephen S. Rich, Cassianne Robinson-Cohen, Martin den Heijer, Marjo-Riitta Jarvelin, Alana Cavadino, Peter K. Joshi, James F. Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M. Carola Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira, Linda Broer, Lina Zgaga, Harry Campbell, Evropi Theodoratou, Susan M. Farrington, Maria Timofeeva, Malcolm G. Dunlop, Ana M. Valdes, Emmi Tikkanen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Mika Kähönen, Olli T. Raitakari, Vera Mikkilä, M. Arfan Ikram, Naveed Sattar, J. Wouter Jukema, Nicholas J. Wareham, Claudia Langenberg, Nita G. Forouhi, Thomas E. Gundersen, Kay-Tee Khaw, Adam S. Butterworth, John Danesh, Timothy Spector, Thomas J. Wang, Elina Hyppönen, Peter Kraft, and Douglas P. Kiel

Subjects
Science
Abstract

Vitamin D deficiency is associated with multiple human pathologic conditions. In a genome-wide association study of 79,366 individuals, Jiang et al. replicate four and identify two new genetic loci for serum levels of 25-hydroxyvitamin D and find evidence for a shared genetic basis with autoimmune diseases.

Published
2018
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17. Platelet function is modified by common sequence variation in megakaryocyte super enhancers

Author

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

Subjects
Science
Abstract

Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.

Published
2017
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18. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

Author

Minako Imamura, Atsushi Takahashi, Toshimasa Yamauchi, Kazuo Hara, Kazuki Yasuda, Niels Grarup, Wei Zhao, Xu Wang, Alicia Huerta-Chagoya, Cheng Hu, Sanghoon Moon, Jirong Long, Soo Heon Kwak, Asif Rasheed, Richa Saxena, Ronald C. W. Ma, Yukinori Okada, Minoru Iwata, Jun Hosoe, Nobuhiro Shojima, Minaka Iwasaki, Hayato Fujita, Ken Suzuki, John Danesh, Torben Jørgensen, Marit E. Jørgensen, Daniel R. Witte, Ivan Brandslund, Cramer Christensen, Torben Hansen, Josep M. Mercader, Jason Flannick, Hortensia Moreno-Macías, Noël P. Burtt, Rong Zhang, Young Jin Kim, Wei Zheng, Jai Rup Singh, Claudia H. T. Tam, Hiroshi Hirose, Hiroshi Maegawa, Chikako Ito, Kohei Kaku, Hirotaka Watada, Yasushi Tanaka, Kazuyuki Tobe, Ryuzo Kawamori, Michiaki Kubo, Yoon Shin Cho, Juliana C. N. Chan, Dharambir Sanghera, Philippe Frossard, Kyong Soo Park, Xiao-Ou Shu, Bong-Jo Kim, Jose C. Florez, Teresa Tusié-Luna, Weiping Jia, E Shyong Tai, Oluf Pedersen, Danish Saleheen, Shiro Maeda, and Takashi Kadowaki

Subjects
Science
Abstract

Here, Imamuraet al. conduct meta-analysis of genome-wide association studies to identify novel susceptibility loci for type 2 diabetes (T2D) in the Japanese population. By doing so, this study shows that both ethnicity-specific and ethnically-shared genetic loci can contribute to T2D risk.

Published
2016
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20. Author Correction: Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author

Arthur Gilly, Daniel Suveges, Karoline Kuchenbaecker, Martin Pollard, Lorraine Southam, Konstantinos Hatzikotoulas, Aliki-Eleni Farmaki, Thea Bjornland, Ryan Waples, Emil V. R. Appel, Elisabetta Casalone, Giorgio Melloni, Britt Kilian, Nigel W. Rayner, Ioanna Ntalla, Kousik Kundu, Klaudia Walter, John Danesh, Adam Butterworth, Inês Barroso, Emmanouil Tsafantakis, George Dedoussis, Ida Moltke, and Eleftheria Zeggini

Subjects
Science
Abstract

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items “rare” and “common” were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

Published
2018
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21. Author Correction: Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Author

Chen Yao, George Chen, Ci Song, Joshua Keefe, Michael Mendelson, Tianxiao Huan, Benjamin B. Sun, Annika Laser, Joseph C. Maranville, Hongsheng Wu, Jennifer E. Ho, Paul Courchesne, Asya Lyass, Martin G. Larson, Christian Gieger, Johannes Graumann, Andrew D. Johnson, John Danesh, Heiko Runz, Shih-Jen Hwang, Chunyu Liu, Adam S. Butterworth, Karsten Suhre, and Daniel Levy

Subjects
Science
Abstract

In the originally published version of this Article, financial support was not fully acknowledged. The sentence “KS was supported by the ‘Biomedical Research Program’ funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation” has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

Published
2018
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22. Author Correction: Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke

Author

Tingting Wang, Rainer Malik, Agus Salim, Ekaterina Yonova-Doing, Martin Dichgans, Michael Inouye, John Danesh, Gad Abraham, Adam S. Butterworth, and Joanna M. M. Howson

Subjects
medicine.medical_specialty, Multidisciplinary, Framingham Risk Score, business.industry, Science, General Physics and Astronomy, Genome-wide association study, General Chemistry, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Internal medicine, Ischaemic stroke, medicine, lcsh:Q, ddc:500, Personalized medicine, lcsh:Science, business, Clinical risk factor, Stroke
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

23. Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke

Author

Tingting Wang, Agus Salim, Gad Abraham, Joanna M. M. Howson, John Danesh, Adam S. Butterworth, Michael Inouye, Rainer Malik, Martin Dichgans, Ekaterina Yonova-Doing, Butterworth, Adam S [0000-0002-6915-9015], Howson, Joanna MM [0000-0001-7618-0050], Dichgans, Martin [0000-0002-0654-387X], Apollo - University of Cambridge Repository, Butterworth, Adam S. [0000-0002-6915-9015], Howson, Joanna M. M. [0000-0001-7618-0050], and Howson, Joanna M M [0000-0001-7618-0050]

Subjects
0301 basic medicine, Male, General Physics and Astronomy, Datasets as Topic, Blood Pressure, Disease, Comorbidity, epidemiology [United Kingdom], Genome-wide association studies, Body Mass Index, Brain Ischemia, 692/617/375/534, 0302 clinical medicine, epidemiology [Smoking], Family history, lcsh:Science, Medical History Taking, Stroke, 2. Zero hunger, 0303 health sciences, Multidisciplinary, Framingham Risk Score, methods [Genomics], Hazard ratio, Smoking, Genomics, Middle Aged, 3. Good health, Predictive value of tests, Female, ddc:500, Risk assessment, 692/499, medicine.medical_specialty, Science, 631/208/205/2138, 631/208/212/2166, genetics [Brain Ischemia], Polymorphism, Single Nucleotide, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 38/43, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, epidemiology [Brain Ischemia], Humans, Genetic Predisposition to Disease, cardiovascular diseases, Risk factor, Author Correction, 030304 developmental biology, Aged, business.industry, fungi, General Chemistry, Guideline, medicine.disease, Personalized medicine, United Kingdom, methods [Risk Assessment], 030104 developmental biology, Blood pressure, Risk factors, lcsh:Q, business, Body mass index, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Recent genome-wide association studies in stroke have enabled the generation of genomic risk scores (GRS) but their predictive power has been modest compared to established stroke risk factors. Here, using a meta-scoring approach, we develop a metaGRS for ischaemic stroke (IS) and analyse this score in the UK Biobank (n = 395,393; 3075 IS events by age 75). The metaGRS hazard ratio for IS (1.26, 95% CI 1.22–1.31 per metaGRS standard deviation) doubles that of a previous GRS, identifying a subset of individuals at monogenic levels of risk: the top 0.25% of metaGRS have three-fold risk of IS. The metaGRS is similarly or more predictive compared to several risk factors, such as family history, blood pressure, body mass index, and smoking. We estimate the reductions needed in modifiable risk factors for individuals with different levels of genomic risk and suggest that, for individuals with high metaGRS, achieving risk factor levels recommended by current guidelines may be insufficient to mitigate risk., Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.

Published
2019

24. 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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25. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

Author

Danish Saleheen, Krishna G. Aragam, Wendy S. Post, Jerome I. Rotter, Pradeep Natarajan, Jennifer A. Mattera, Roberto Elosua, Usman Baber, Matthew J. Bown, Ruth McPherson, John Danesh, Yii-Der Ida Chen, Stephen S. Rich, Derek Klarin, Paul M. Ridker, Sekar Kathiresan, Kent D. Taylor, James G. Wilson, Seyedeh M. Zekavat, Akihiro Nomura, Diego Ardissino, Amit Khera, Connor A. Emdin, John A. Spertus, Bruce M. Psaty, Daniel I. Chasman, Namrata Gupta, Wayne H-H Sheu, Judith H. Lichtman, Joshua C. Denny, Hugh Watkins, Harlan M. Krumholz, Heribert Schunkert, Gail D'Onofrio, Stacey Gabriel, Mark Chaffin, Alexander G. Bick, Jeanette Erdmann, Mary E. Haas, Lisa Bastarache, Nilesh J. Samani, Emdin, Connor A [0000-0002-2385-8259], Chaffin, Mark [0000-0002-1234-5562], Erdmann, Jeanette [0000-0002-4486-6231], Saleheen, Danish [0000-0001-6193-020X], Kathiresan, Sekar [0000-0002-6724-032X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, General Physics and Astronomy, Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, Gene Frequency, Databases, Genetic, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, 2. Zero hunger, Genetics, Multidisciplinary, Diabetis, medicine.diagnostic_test, Metabolisme, 3. Good health, Fenotip, Heart Disease, Phenotype, Type 2, Biotechnology, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Frameshift mutation, Databases, 03 medical and health sciences, Genetic, Genetic variation, Diabetes Mellitus, medicine, Respiratory Hypersensitivity, Humans, Genetic Testing, Obesity, Allele, Allele frequency, Gene, Heart Disease - Coronary Heart Disease, Metabolic and endocrine, Loss function, Genetic testing, Human Genome, Genetic Variation, Proteins, General Chemistry, Atherosclerosis, United Kingdom, Good Health and Well Being, 030104 developmental biology, Diabetes Mellitus, Type 2, lcsh:Q
Abstract

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency, Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

Published
2018

26. Author Correction: Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author

Klaudia Walter, Giorgio E. M. Melloni, Arthur Gilly, George Dedoussis, Martin O. Pollard, Nigel W. Rayner, Karoline Kuchenbaecker, Emil V. R. Appel, Thea Bjørnland, Emmanouil Tsafantakis, Kousik Kundu, Britt Kilian, Aliki-Eleni Farmaki, Lorraine Southam, Ryan K. Waples, Ida Moltke, Ioanna Ntalla, Elisabetta Casalone, Eleftheria Zeggini, Daniel Suveges, Adam S. Butterworth, Inês Barroso, John Danesh, and Konstantinos Hatzikotoulas

Subjects
0301 basic medicine, Whole genome sequencing, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, GeneralLiterature_MISCELLANEOUS, 03 medical and health sciences, 030104 developmental biology, Cohort, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, Allele, Architecture, lcsh:Science
Abstract

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items “rare” and “common” were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

Published
2018

27. Author Correction: Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

Author

Asya Lyass, Heiko Runz, Paul Courchesne, Ci Song, Michael M. Mendelson, Chen Yao, Daniel Levy, Tianxiao Huan, Johannes Graumann, Shih-Jen Hwang, Adam S. Butterworth, George Chen, Annika Laser, Andrew D. Johnson, Martin G. Larson, Joshua Keefe, Jennifer E. Ho, Hongsheng Wu, Chunyu Liu, Karsten Suhre, Benjamin B. Sun, Joseph C. Maranville, Christian Gieger, and John Danesh

Subjects
0301 basic medicine, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Disease, Computational biology, Genome, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 030104 developmental biology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lcsh:Q, Psychology, lcsh:Science, Gene, Sentence
Abstract

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment., Genetic variation can influence levels of disease-related plasma proteins and, thus, contribute to the pathogenesis of complex diseases. Here, the authors perform genome-wide QTL analysis for 71 plasma proteins to identify causal proteins for coronary heart disease and provide a molecular QTL browser.

Published
2018

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