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1. NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke

Author: Juan Lorenzo Rodriguez-Flores, Shareef Khalid, Neelroop Parikshak, Asif Rasheed, Bin Ye, Manav Kapoor, Joshua Backman, Farshid Sepehrband, Silvio Alessandro Di Gioia, Sahar Gelfman, Tanima De, Nilanjana Banerjee, Deepika Sharma, Hector Martinez, Sofia Castaneda, David D’Ambrosio, Xingmin A. Zhang, Pengcheng Xun, Ellen Tsai, I-Chun Tsai, Regeneron Genetics Center, Maleeha Zaman Khan, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Khalid Mahmood, Tanvir Us Salam, Muhammad Hussain, Javed Iqbal, Faizan Aslam, Michael N. Cantor, Gannie Tzoneva, John Overton, Jonathan Marchini, Jeffrey G. Reid, Aris Baras, Niek Verweij, Luca A. Lotta, Giovanni Coppola, Katia Karalis, Aris Economides, Sergio Fazio, Wolfgang Liedtke, John Danesh, Ayeesha Kamal, Philippe Frossard, Thomas Coleman, Alan R. Shuldiner, and Danish Saleheen
Subjects: Science
Abstract: Abstract The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p = 3.87 × 10−9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10−10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p = 3.0 × 10−6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.
Published: 2024
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2. A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology

Author: Parsa Akbari, Dragana Vuckovic, Luca Stefanucci, Tao Jiang, Kousik Kundu, Roman Kreuzhuber, Erik L. Bao, Janine H. Collins, Kate Downes, Luigi Grassi, Jose A. Guerrero, Stephen Kaptoge, Julian C. Knight, Stuart Meacham, Jennifer Sambrook, Denis Seyres, Oliver Stegle, Jeffrey M. Verboon, Klaudia Walter, Nicholas A. Watkins, John Danesh, David J. Roberts, Emanuele Di Angelantonio, Vijay G. Sankaran, Mattia Frontini, Stephen Burgess, Taco Kuijpers, James E. Peters, Adam S. Butterworth, Willem H. Ouwehand, Nicole Soranzo, and William J. Astle
Subjects: Science
Abstract: Abstract Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.
Published: 2023
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3. Evaluation of interventions to prevent vasovagal reactions among whole blood donors: rationale and design of a large cluster randomised trial

Author: Amy McMahon, Stephen Kaptoge, Matthew Walker, Susan Mehenny, Philippe T Gilchrist, Jennifer Sambrook, Naim Akhtar, Michael Sweeting, Angela M Wood, Kathleen Stirrups, Ryan Chung, Sarah Fahle, Elisha Johnson, Donna Cullen, Rosemary Godfrey, Shannon Duthie, Louise Allen, Paul Harvey, Michael Berkson, Elizabeth Allen, Nicholas A Watkins, John R Bradley, Nathalie Kingston, Gail Miflin, Jane Armitage, David J Roberts, John Danesh, and Emanuele Di Angelantonio
Subjects: Vasovagal reactions, Blood donors, Blood donation, Cluster randomised trial, Cross-over, Stepped-wedge, Medicine (General), R5-920
Abstract: Abstract Background Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations and are disruptive and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension [AMT]), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors. Methods STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site (“cluster”) has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions is compared to NHSBT’s current practices: (i) 500-ml isotonic drink before donation (vs current 500-ml plain water); (ii) 3-min rest on donation chair after donation (vs current 2 min); (iii) new modified AMT (vs current practice of AMT); and (iv) psychosocial intervention using preparatory materials (vs current practice of nothing). The primary outcome is the number of in-session VVRs with loss of consciousness (i.e. episodes involving loss of consciousness of any duration, with or without additional complications). Secondary outcomes include all in-session VVRs (i.e. with and without loss of consciousness), all delayed VVRs (i.e. those occurring after leaving the venue) and any in-session non-VVR adverse events or reactions. Discussion The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency. Trial registration ISRCTN: 10412338. Registration date: October 24, 2019.
Published: 2023
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4. 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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5. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved]

Author: Natasha H. J. Ng, Sara M. Willems, Jian'an Luan, Rebecca S. Fine, Juan Fernandez, Jennifer Wessel, Eleanor Wheeler, Gaelle Marenne, Hidetoshi Kitajima, Hanieh Yaghootkar, Xueling Sim, Ian J. Deary, Sai Chen, Shuai Wang, Yii-Der Ida Chen, Caroline Hayward, Yuning Chen, Jennifer L. Asimit, Claudia Langenberg, Tibor V. Varga, Archie Campbell, Rona J. Strawbridge, Shuang Feng, Tarunveer S. Ahluwalia, Erica L. Kleinbrink, Emil V. Appel, Ping An, Lawrence F. Bielak, Dan E. Arking, Jennifer A. Brody, Nathan A. Bihlmeyer, David Porteous, Ayse Demirkan, Audrey Y. Chu, Franco Giulianini, James S. Floyd, Stefan Gustafsson, Xiuqing Guo, Johanna Jakobsdottir, Anne U. Jackson, Stavroula Kanoni, Richard A. Jensen, Igor Rudan, Man Li, Sirkka Keinanen-Kiukaanniemi, Alisa K. Manning, Yingchang Lu, Karina Meidtner, Jonathan Marten, Giorgio Pistis, Taulant Muka, Kenneth M. Rice, Bram Prins, Albert Vernon Smith, Serena Sanna, Lorraine Southam, Jennifer A. Smith, Vinicius Tragante, Heather M. Stringham, Helen R. Warren, Sander W. van der Laan, Andrianos M. Yiorkas, Jie Yao, Wei Zhao, Weihua Zhang, Heather M. Highland, Mariaelisa Graff, Eirini Marouli, Anne E. Justice, Wesam A. Alhejily, Saima Afaq, Folkert W. Asselbergs, Najaf Amin, Michiel L. Bots, Lori L. Bonnycastle, Ji Chen, Ivan Brandslund, Abbas Dehghan, John Danesh, Tapani Ebeling, Jessica D. Faul, Aliki-Eleni Farmaki, Steve Franks, Paul W. Franks, Anette P. Gjesing, Andreas Fritsche, Göran Hallmans, Mark O. Goodarzi, Karl-Heinz Herzig, Tamara B. Harris, Min A Jhun, Marie-France Hivert, Marit E. Jørgensen, Torben Jørgensen, Eero Kajantie, Pekka Jousilahti, Sharon L.R. Kardia, Maria Karaleftheri, Heikki A. Koistinen, Leena Kinnunen, Peter Kovacs, Pirjo Komulainen, Markku Laakso, Johanna Kuusisto, Aaron Leong, Lenore J. Launer, Jocelyn E. Manning Fox, Jaana Lindström, Nisa M. Maruthur, Satu Männistö, Antonella Mulas, Leena Moilanen, Matthew Neville, Mike A. Nalls, Alison Pattie, James S. Pankow, Hannu Puolijoki, Eva R.B. Petersen, Paul Redmond, Asif Rasheed, Michael Roden, Frida Renström, Juha Saltevo, Danish Saleheen, Sylvain Sebert, Kai Savonen, Alena Stančáková, Kerrin S. Small, Konstantin Strauch, Jakob Stokholm, Betina H. Thuesen, Juha Auvinen, E-Shyong Tai, Emmanouil Tsafantakis, Anke Tönjes, Jaakko Tuomilehto, Tiinamaija Tuomi, Marja Vääräsmäki, Matti Uusitupa, Magdalena Zoledziewska, Ilonca Vaartjes, Beverley Balkau, Goncalo Abecasis, Alexandra I. Blakemore, Hans Bisgaard, Heiner Boeing, Ruth J.F. Loos, Matthias Blüher, Klaus Bønnelykke, Eric Boerwinkle, Mark J. Caulfield, Erwin P. Bottinger, Daniel I. Chasman, John C. Chambers, Francis S. Collins, Ching-Yu Cheng, Francesco Cucca, Josef Coresh, George Dedoussis, Gert J. de Borst, Hester M. den Ruijter, Panos Deloukas, Ele Ferrannini, Michele K. Evans, Harald Grallert, Oscar H. Franco, Arfan Ikram, Joel N. Hirschhorn, Fredrik Karpe, Erik Ingelsson, Wieland Kiess, Carolina Medina-Gomez, Kay-Tee Kaw, Antje Körner, Jaspal S. Kooner, Cecilia M. Lindgren, Timo Lakka, Ching-Ti Liu, Leonard Lipovich, Patrick E. MacDonald, Jun Liu, Andrew D. Morris, Karen L. Mohlke, Alison Murray, Patricia B. Munroe, Gerard Pasterkamp, Colin N. A . Palmer, Patricia A. Peyser, Oluf Pedersen, Paul M. Ridker, Rainer Rauramaa, Patrik Rorsman, Olov Rolandsson, Veikko Salomaa, Frits R. Rosendaal, Robert Sladek, Matthias B. Schulze, Michael Stumvoll, Timothy D. Spector, Mark Walker, Cornelia M. van Duijn, David R. Weir, Nick J. Wareham, Tien Yin Wong, James G. Wilson, Alan B. Zonderman, Eleftheria Zeggini, Andrew P. Morris, Jerome I. Rotter, Jose C. Florez, Michael Boehnke, James B. Meigs, Mark I. McCarthy, Robert A. Scott, Anubha Mahajan, Inês Barroso, Anna L. Gloyn, Michael A. Province, Niels Grarup, Ruifang Li-Gao, Jette Bork-Jensen, Yongmei Liu, Allan Linneberg, Leslie A. Lange, Sandosh Padmanabhan, Gail Davies, Lars Lind, Bruce M. Psaty, Tea Skaaby, Torben Hansen, Ozren Polasek, John M. Starr, Dennis O. Mook-Kanamori, Vilmundur Gudnason, Kent D. Taylor, Marjo-Riitta Järvelin, Renée de Mutsert, Paul Elliott, Josée Dupuis, Blair H. Smith, and Andrew T. Hattersley
Subjects: exome chip, glycaemic traits, genetic discovery, effector genes, summary statistics resources, eng, Medicine, Science
Abstract: Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
Published: 2023
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6. Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women

Author: Lena Tschiderer, Sanne A. E. Peters, Yvonne T. van der Schouw, Anniek C. van Westing, Tammy Y. N. Tong, Peter Willeit, Lisa Seekircher, Conchi Moreno‐Iribas, José María Huerta, Marta Crous‐Bou, Martin Söderholm, Matthias B. Schulze, Cecilia Johansson, Sara Själander, Alicia K. Heath, Alessandra Macciotta, Christina C. Dahm, Daniel B. Ibsen, Valeria Pala, Lene Mellemkjær, Stephen Burgess, Angela Wood, Rudolf Kaaks, Verena Katzke, Pilar Amiano, Miguel Rodriguez‐Barranco, Gunnar Engström, Elisabete Weiderpass, Anne Tjønneland, Jytte Halkjær, Salvatore Panico, John Danesh, Adam Butterworth, and N. Charlotte Onland‐Moret
Subjects: age at menopause, Mendelian randomization analysis, observational analysis, stroke, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC‐CVD (European Prospective Investigation Into Cancer and Nutrition‐Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC‐CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow‐up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2‐sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.
Published: 2023
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7. Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants

Author: Scott C. Ritchie, Praveen Surendran, Savita Karthikeyan, Samuel A. Lambert, Thomas Bolton, Lisa Pennells, John Danesh, Emanuele Di Angelantonio, Adam S. Butterworth, and Michael Inouye
Subjects: Science
Abstract: Abstract Metabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy in approximately 121,000 UK Biobank participants has recently been released as a community resource, comprising absolute concentrations and ratios of 249 circulating metabolites, lipids, and lipoprotein sub-fractions. Here we identify and characterise additional sources of unwanted technical variation influencing individual biomarkers in the data available to download from UK Biobank. These included sample preparation time, shipping plate well, spectrometer batch effects, drift over time within spectrometer, and outlier shipping plates. We developed a procedure for removing this unwanted technical variation, and demonstrate that it increases signal for genetic and epidemiological studies of the NMR metabolic biomarker data in UK Biobank. We subsequently developed an R package, ukbnmr, which we make available to the wider research community to enhance the utility of the UK Biobank NMR metabolic biomarker data and to facilitate rapid analysis.
Published: 2023
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8. 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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9. 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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10. A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study.

Author: Jakub G Sobiecki, Fumiaki Imamura, Courtney R Davis, Stephen J Sharp, Albert Koulman, Jonathan M Hodgson, Marcela Guevara, Matthias B Schulze, Ju-Sheng Zheng, Claudia Agnoli, Catalina Bonet, Sandra M Colorado-Yohar, Guy Fagherazzi, Paul W Franks, Thomas E Gundersen, Franziska Jannasch, Rudolf Kaaks, Verena Katzke, Esther Molina-Montes, Peter M Nilsson, Domenico Palli, Salvatore Panico, Keren Papier, Olov Rolandsson, Carlotta Sacerdote, Anne Tjønneland, Tammy Y N Tong, Yvonne T van der Schouw, John Danesh, Adam S Butterworth, Elio Riboli, Karen J Murphy, Nicholas J Wareham, and Nita G Forouhi
Subjects: Medicine
Abstract: BackgroundSelf-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet.Methods and findingsWe derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding.ConclusionsThese findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860.
Published: 2023
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11. 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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12. Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations

Author: Karoline Kuchenbaecker, Arthur Gilly, Daniel Suveges, Lorraine Southam, Olga Giannakopoulou, Britt Kilian, Emmanouil Tsafantakis, Maria Karaleftheri, Aliki-Eleni Farmaki, Deepti Gurdasani, Kousik Kundu, Manjinder S. Sandhu, John Danesh, Adam Butterworth, Inês Barroso, George Dedoussis, and Eleftheria Zeggini
Subjects: Medicine, Science
Abstract: Abstract Haematological traits are linked to cardiovascular, metabolic, infectious and immune disorders, as well as cancer. Here, we examine the role of genetic variation in shaping haematological traits in two isolated Mediterranean populations. Using whole-genome sequencing data at 22× depth for 1457 individuals from Crete (MANOLIS) and 1617 from the Pomak villages in Greece, we carry out a genome-wide association scan for haematological traits using linear mixed models. We discover novel associations (p A) (rs35004220). In the Pomak population, c.364C>A (“HbO-Arab”, rs33946267) is most frequent (4.4% allele frequency). We demonstrate effects on haematological and other traits, including bilirubin, cholesterol, and, in MANOLIS, height and gestation age. We find less severe effects on red blood cell traits for HbS, HbO, and IVS-I-6 (T>C) compared to other b+ mutations. Overall, we uncover allelic diversity of HBB in Greek isolated populations and find an important role for additional rare variants outside of HBB.
Published: 2022
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13. Risk factors and prediction models for incident heart failure with reduced and preserved ejection fraction

Author: Liam Gaziano, Kelly Cho, Luc Djousse, Petra Schubert, Ashley Galloway, Yuk‐Lam Ho, Katherine Kurgansky, David R. Gagnon, John P. Russo, Emanuele Di Angelantonio, Angela M. Wood, John Danesh, John Michael Gaziano, Adam S. Butterworth, Peter W.F. Wilson, and Jacob Joseph
Subjects: Risk prediction, Heart failure, Heart failure with reduced ejection fraction, Heart failure with preserved ejection fraction, Electronic health records, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract Aims This study aims to develop the first race‐specific and sex‐specific risk prediction models for heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods and results We created a cohort of 1.8 million individuals who had an outpatient clinic visit between 2002 and 2007 within the Veterans Affairs (VA) Healthcare System and obtained information on HFpEF, HFrEF, and several risk factors from electronic health records (EHR). Variables were selected for the risk prediction models in a ‘derivation cohort’ that consisted of individuals with baseline date in 2002, 2003, or 2004 using a forward stepwise selection based on a change in C‐index threshold. Discrimination and calibration were assessed in the remaining participants (internal ‘validation cohort’). A total of 66 831 individuals developed HFpEF, and 92 233 developed HFrEF (52 679 and 71 463 in the derivation cohort) over a median of 11.1 years of follow‐up. The HFpEF risk prediction model included age, diabetes, BMI, COPD, previous MI, antihypertensive treatment, SBP, smoking status, atrial fibrillation, and estimated glomerular filtration rate (eGFR), while the HFrEF model additionally included previous CAD. For the HFpEF model, C‐indices were 0.74 (SE = 0.002) for white men, 0.76 (0.005) for black men, 0.79 (0.015) for white women, and 0.77 (0.026) for black women, compared with 0.72 (0.002), 0.72 (0.004), 0.77 (0.017), and 0.75 (0.028), respectively, for the HFrEF model. These risk prediction models were generally well calibrated in each race‐specific and sex‐specific stratum of the validation cohort. Conclusions Our race‐specific and sex‐specific risk prediction models, which used easily obtainable clinical variables, can be a useful tool to implement preventive strategies or subtype‐specific prevention trials in the nine million users of the VA healthcare system and the general population after external validation.
Published: 2021
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14. Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.

Author: Manish D Paranjpe, Mark Chaffin, Sohail Zahid, Scott Ritchie, Jerome I Rotter, Stephen S Rich, Robert Gerszten, Xiuqing Guo, Susan Heckbert, Russ Tracy, John Danesh, Eric S Lander, Michael Inouye, Sekar Kathiresan, Adam S Butterworth, and Amit V Khera
Subjects: Genetics, QH426-470
Abstract: For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.
Published: 2022
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15. Risk Factors of Secondary Cardiovascular Events in a Multi-Ethnic Asian Population with Acute Myocardial Infarction: A Retrospective Cohort Study from Malaysia

Author: Sophia Rasheeqa Ismail, Mohd Shawal Faizal Mohammad, Adam S. Butterworth, Rajiv Chowdhury, John Danesh, Emanuele Di Angelantonio, Simon J. Griffin, Lisa Pennells, Angela M. Wood, Mohd Fairulnizal Md Noh, and Shamsul Azhar Shah
Subjects: myocardial infarction, risk factors, major adverse cardiovascular events, cardiovascular mortality, Asian, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22–2.12] and 1.46 [95%CI 1.09–1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15–6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02–4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59–10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals.
Published: 2023
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16. Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.

Author: Allan Gurtan, John Dominy, Shareef Khalid, Linh Vong, Shari Caplan, Treeve Currie, Sean Richards, Lindsey Lamarche, Daniel Denning, Diana Shpektor, Anastasia Gurinovich, Asif Rasheed, Shahid Hameed, Subhan Saeed, Imran Saleem, Anjum Jalal, Shahid Abbas, Raffat Sultana, Syed Zahed Rasheed, Fazal-Ur-Rehman Memon, Nabi Shah, Mohammad Ishaq, Amit V Khera, John Danesh, Philippe Frossard, and Danish Saleheen
Subjects: Genetics, QH426-470
Abstract: Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.
Published: 2022
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17. Investigating Genetic and Other Determinants of First-Onset Myocardial Infarction in Malaysia: Protocol for the Malaysian Acute Vascular Events Risk Study

Author: Rajiv Chowdhury, Mohd Fairulnizal Md Noh, Sophia Rasheeqa Ismail, Kim Robin van Daalen, Puteri Sofia Nadira Megat Kamaruddin, Siti Hafizah Zulkiply, Nur Hayati Azizul, Norhayati Mustafa Khalid, Azizan Ali, Izyan Mohd Idris, Yong Shih Mei, Shazana Rifham Abdullah, Norfashihah Faridus, Nur Azirah Md Yusof, Nur Najwa Farahin M Yusoff, Rahman Jamal, Aizai Azan Abdul Rahim, Abdul Kahar Abdul Ghapar, Ammu Kutty Radhakrishnan, Alan Yean Yip Fong, Omar Ismail, Saravanan Krishinan, Chuey Yan Lee, Liew Houng Bang, Eashwary Mageswaren, Kauthaman Mahendran, Nor Hanim Mohd Amin, Gunavathy Muthusamy, Aaron Ong Hean Jin, Ahmad Wazi Ramli, Noel Thomas Ross, Anwar Irawan Ruhani, Mansor Yahya, Yusniza Yusoff, Siti Khairani Zainal Abidin, Laryssa Amado, Thomas Bolton, Sophie Weston, Jason Crawte, Niko Ovenden, Ank Michielsen, Md Mostafa Monower, Wan Rozita Wan Mahiyuddin, Angela Wood, Emanuele Di Angelantonio, Nur Suffia Sulaiman, John Danesh, and Adam S Butterworth
Subjects: Medicine, Computer applications to medicine. Medical informatics, R858-859.7
Abstract: BackgroundAlthough the burden of premature myocardial infarction (MI) is high in Malaysia, direct evidence on the determinants of MI in this multi-ethnic population remains sparse. ObjectiveThe Malaysian Acute Vascular Events Risk (MAVERIK) study is a retrospective case-control study established to investigate the genomic, lipid-related, and other determinants of acute MI in Malaysia. In this paper, we report the study protocol and early results. MethodsBy June 2019, we had enrolled approximately 2500 patients with their first MI and 2500 controls without cardiovascular disease, who were frequency-matched by age, sex, and ethnicity, from 17 hospitals in Malaysia. For each participant, serum and whole blood have been collected and stored. Clinical, demographic, and behavioral information has been obtained using a 200-item questionnaire. ResultsTobacco consumption, a history of diabetes, hypertension, markers of visceral adiposity, indicators of lower socioeconomic status, and a family history of coronary disease were more prevalent in cases than in controls. Adjusted (age and sex) logistic regression models for traditional risk factors indicated that current smoking (odds ratio [OR] 4.11, 95% CI 3.56-4.75; P30 kg/m2; OR 1.19, 95% CI 1.05-1.34; P=.009) were associated with MI in age- and sex-adjusted models. ConclusionsThe MAVERIK study can serve as a useful platform to investigate genetic and other risk factors for MI in an understudied Southeast Asian population. It should help to hasten the discovery of disease-causing pathways and inform regionally appropriate strategies that optimize public health action. International Registered Report Identifier (IRRID)RR1-10.2196/31885
Published: 2022
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18. Machine learning optimized polygenic scores for blood cell traits identify sex-specific trajectories and genetic correlations with disease

Author: Yu Xu, Dragana Vuckovic, Scott C. Ritchie, Parsa Akbari, Tao Jiang, Jason Grealey, Adam S. Butterworth, Willem H. Ouwehand, David J. Roberts, Emanuele Di Angelantonio, John Danesh, Nicole Soranzo, and Michael Inouye
Subjects: Polygenic score, Blood cell trait, Method, Machine learning, Population stratification, Disease assocations, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract: Summary: Genetic association studies for blood cell traits, which are key indicators of health and immune function, have identified several hundred associations and defined a complex polygenic architecture. Polygenic scores (PGSs) for blood cell traits have potential clinical utility in disease risk prediction and prevention, but designing PGS remains challenging and the optimal methods are unclear. To address this, we evaluated the relative performance of 6 methods to develop PGS for 26 blood cell traits, including a standard method of pruning and thresholding (P + T) and 5 learning methods: LDpred2, elastic net (EN), Bayesian ridge (BR), multilayer perceptron (MLP) and convolutional neural network (CNN). We evaluated these optimized PGSs on blood cell trait data from UK Biobank and INTERVAL. We find that PGSs designed using common machine learning methods EN and BR show improved prediction of blood cell traits and consistently outperform other methods. Our analyses suggest EN/BR as the top choices for PGS construction, showing improved performance for 25 blood cell traits in the external validation, with correlations with the directly measured traits increasing by 10%–23%. Ten PGSs showed significant statistical interaction with sex, and sex-specific PGS stratification showed that all of them had substantial variation in the trajectories of blood cell traits with age. Genetic correlations between the PGSs for blood cell traits and common human diseases identified well-known as well as new associations. We develop machine learning-optimized PGS for blood cell traits, demonstrate their relationships with sex, age, and disease, and make these publicly available as a resource.
Published: 2022
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19. Reproducible disease phenotyping at scale: Example of coronary artery disease in UK Biobank.

Author: Riyaz S Patel, Spiros Denaxas, Laurence J Howe, Rosalind M Eggo, Anoop D Shah, Naomi E Allen, John Danesh, Aroon Hingorani, Cathie Sudlow, and Harry Hemingway
Subjects: Medicine, Science
Abstract: ImportanceA lack of internationally agreed standards for combining available data sources at scale risks inconsistent disease phenotyping limiting research reproducibility.ObjectiveTo develop and then evaluate if a rules-based algorithm can identify coronary artery disease (CAD) sub-phenotypes using electronic health records (EHR) and questionnaire data from UK Biobank (UKB).DesignCase-control and cohort study.SettingProspective cohort study of 502K individuals aged 40-69 years recruited between 2006-2010 into the UK Biobank with linked hospitalization and mortality data and genotyping.ParticipantsWe included all individuals for phenotyping into 6 predefined CAD phenotypes using hospital admission and procedure codes, mortality records and baseline survey data. Of these, 408,470 unrelated individuals of European descent had a polygenic risk score (PRS) for CAD estimated.ExposureCAD Phenotypes.Main outcomes and measuresAssociation with baseline risk factors, mortality (n = 14,419 over 7.8 years median f/u), and a PRS for CAD.ResultsThe algorithm classified individuals with CAD into prevalent MI (n = 4,900); incident MI (n = 4,621), prevalent CAD without MI (n = 10,910), incident CAD without MI (n = 8,668), prevalent self-reported MI (n = 2,754); prevalent self-reported CAD without MI (n = 5,623), yielding 37,476 individuals with any type of CAD. Risk factors were similar across the six CAD phenotypes, except for fewer men in the self-reported CAD without MI group (46.7% v 70.1% for the overall group). In age- and sex- adjusted survival analyses, mortality was highest following incident MI (HR 6.66, 95% CI 6.07-7.31) and lowest for prevalent self-reported CAD without MI at baseline (HR 1.31, 95% CI 1.15-1.50) compared to disease-free controls. There were similar graded associations across the six phenotypes per SD increase in PRS, with the strongest association for prevalent MI (OR 1.50, 95% CI 1.46-1.55) and the weakest for prevalent self-reported CAD without MI (OR 1.08, 95% CI 1.05-1.12). The algorithm is available in the open phenotype HDR UK phenotype library (https://portal.caliberresearch.org/).ConclusionsAn algorithmic, EHR-based approach distinguished six phenotypes of CAD with distinct survival and PRS associations, supporting adoption of open approaches to help standardize CAD phenotyping and its wider potential value for reproducible research in other conditions.
Published: 2022
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20. Dietary Fatty Acids, Macronutrient Substitutions, Food Sources and Incidence of Coronary Heart Disease: Findings From the EPIC‐CVD Case‐Cohort Study Across Nine European Countries

Author: Marinka Steur, Laura Johnson, Stephen J. Sharp, Fumiaki Imamura, Ivonne Sluijs, Timothy J. Key, Angela Wood, Rajiv Chowdhury, Marcela Guevara, Marianne U. Jakobsen, Ingegerd Johansson, Albert Koulman, Kim Overvad, Maria‐José Sánchez, Yvonne T. van der Schouw, Antonia Trichopoulou, Elisabete Weiderpass, Maria Wennberg, Ju‐Sheng Zheng, Heiner Boeing, Jolanda M. A. Boer, Marie‐Christine Boutron‐Ruault, Ulrika Ericson, Alicia K. Heath, Inge Huybrechts, Liher Imaz, Rudolf Kaaks, Vittorio Krogh, Tilman Kühn, Cecilie Kyrø, Giovanna Masala, Olle Melander, Conchi Moreno‐Iribas, Salvatore Panico, José R. Quirós, Miguel Rodríguez‐Barranco, Carlotta Sacerdote, Carmen Santiuste, Guri Skeie, Anne Tjønneland, Rosario Tumino, W. M. Monique Verschuren, Raul Zamora‐Ros, Christina C. Dahm, Aurora Perez‐Cornago, Matthias B. Schulze, Tammy Y. N. Tong, Elio Riboli, Nicholas J. Wareham, John Danesh, Adam S. Butterworth, and Nita G. Forouhi
Subjects: coronary heart disease, dietary guidelines, nutritional epidemiology, primary prevention, saturated fat, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. Methods and Results We conducted a case‐cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country‐specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice‐weighted Cox regression models and pooled results using random‐effects meta‐analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). Conclusions This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.
Published: 2021
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21. 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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22. 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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23. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

24. Risk Factors of Secondary Cardiovascular Events in a Multi-Ethnic Asian Population with Acute Myocardial Infarction: A Retrospective Cohort Study from Malaysia

Author: Shah, Sophia Rasheeqa Ismail, Mohd Shawal Faizal Mohammad, Adam S. Butterworth, Rajiv Chowdhury, John Danesh, Emanuele Di Angelantonio, Simon J. Griffin, Lisa Pennells, Angela M. Wood, Mohd Fairulnizal Md Noh, and Shamsul Azhar
Subjects: myocardial infarction, risk factors, major adverse cardiovascular events, cardiovascular mortality, Asian
Abstract: This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22–2.12] and 1.46 [95%CI 1.09–1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15–6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02–4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59–10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals.
Published: 2023
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25. Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

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

26. A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study

Author: Jakub G. Sobiecki, Fumiaki Imamura, Courtney R. Davis, Stephen J. Sharp, Albert Koulman, Jonathan M. Hodgson, Marcela Guevara, Matthias B. Schulze, Ju-Sheng Zheng, Claudia Agnoli, Catalina Bonet, Sandra M. Colorado-Yohar, Guy Fagherazzi, Paul W. Franks, Thomas E. Gundersen, Franziska Jannasch, Rudolf Kaaks, Verena Katzke, Esther Molina-Montes, Peter M. Nilsson, Domenico Palli, Salvatore Panico, Keren Papier, Olov Rolandsson, Carlotta Sacerdote, Anne Tjønneland, Tammy Y. N. Tong, Yvonne T. van der Schouw, John Danesh, Adam S. Butterworth, Elio Riboli, Karen J. Murphy, Nicholas J. Wareham, Nita G. Forouhi, Sobiecki, Jakub G [0000-0003-2641-2313], Imamura, Fumiaki [0000-0002-6841-8396], Davis, Courtney R [0000-0002-3866-2603], Sharp, Stephen J [0000-0003-2375-1440], Koulman, Albert [0000-0001-9998-051X], Hodgson, Jonathan M [0000-0001-6184-7764], Guevara, Marcela [0000-0001-9242-6364], Schulze, Matthias B [0000-0002-0830-5277], Zheng, Ju-Sheng [0000-0001-6560-4890], Agnoli, Claudia [0000-0003-4472-1179], Colorado-Yohar, Sandra M [0000-0002-6700-0780], Fagherazzi, Guy [0000-0001-5033-5966], Franks, Paul W [0000-0002-0520-7604], Jannasch, Franziska [0000-0003-3478-4758], Katzke, Verena [0000-0002-6509-6555], Molina-Montes, Esther [0000-0002-0428-2426], Nilsson, Peter M [0000-0002-5652-8459], Papier, Keren [0000-0002-4102-6835], Sacerdote, Carlotta [0000-0002-8008-5096], Tjønneland, Anne [0000-0003-4385-2097], Tong, Tammy YN [0000-0002-0284-8959], van der Schouw, Yvonne T [0000-0002-4605-435X], Butterworth, Adam S [0000-0002-6915-9015], Riboli, Elio [0000-0001-6795-6080], Wareham, Nicholas J [0000-0003-1422-2993], Forouhi, Nita G [0000-0002-5041-248X], Apollo - University of Cambridge Repository, Sobiecki, Jakub G, Imamura, Fumiaki, Davis, Courtney R, Sharp, Stephen J, and Forouhi, Nita G
Subjects: Adult, Clinical Trials and Supportive Activities, 32 Biomedical and Clinical Sciences, Endocrinology and Diabetes, Diet, Mediterranean, Cohort Studies, Diabetes Mellitus, Type 2/diagnosis, Risk Factors, Clinical Research, Mediterranean diet, Neoplasms, Humans, Neoplasms/complications, Obesity, nutritional biomarker score, Metabolic and endocrine, Nutrition, Cancer, Nutrition and Dietetics, Prevention, Diabetes, Australia, 42 Health Sciences, General Medicine, Näringslära, Diabetes Mellitus, Type 2, Endokrinologi och diabetes, 3210 Nutrition and Dietetics, type 2 diabetes, Biomarkers
Abstract: The MedLey trial was funded by a National Health and Medical Research Council Grant (#APP1050949 to KJM). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197 to NJW). Biomarker measurements for carotenoids were funded jointly by the InterAct project, the EPIC-CVD project, and the MRC Cambridge Initiative (RG71466 and SJAH/004 to NJW, NGF, JD, AB). EPIC-CVD has been supported by the UK Medical Research Council (MR/L003120/1 to ASB and JD), the British Heart Foundation (RG/13/13/30194 and RG/18/13/33946 to ASB and JD), the European Commission Framework Programme 7 (HEALTH -F2-2012-279233 to ASB and JD), the European Research Council (268834 to ASB and JD), and the National Institute for Health Research (NIHR; Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust, BRC-1215-20014 to ASB and JD). This work was also supported by Health Data Research UK (to ASB and JD), which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), and Wellcome. The coordination of EPIC is financially supported by the International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Ge'ne'rale de l'Education Nationale, Institut National de la Sante' et de la Recherche Me'dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Iblea Ricerca Epidemiologica (A.I.R.E. - ONLUS) Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di San Paolo, National Research Council and Sicilian Regional Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands~Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluci'a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology -ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to NJW; C8221/A29017), Medical Research Council (1000143 to NJW; MR/M012190/1) (United Kingdom). JGS was supported by the MRC PhD studentship. NJW, NGF, and FI acknowledge funding from the Medical Research Council Epidemiology Unit (MC_UU_00006/1, MC_UU_00006/3); and NJW, NGF and AK from the NIHR Cambridge Biomedical Research Centre (IS-BRC-1215-20014; NIHR203312). NGF and JD are NIHR Senior Investigators. JD holds a British Heart Foundation Professorship. MBS acknowledges funding from the Federal Ministry of Education and Research and the State of Brandenburg (DZD grant 82DZD03D03). JSZ has received funding from Westlake University (No YSYY0209) and European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701708. PWF has received funding from Novo Nordisk, Swedish Diabetes Association, Swedish Heart-Lung Foundation, European Research Council. ER has received funding from Imperial College Biomedical Research Centre. The funders of the studies had no role in the study design, data collection, data analysis, data interpretation, or report preparation. Trial Australian., Background Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. Methods and findings We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. Conclusions These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully., EU FP6 programme LSHM_CT_2006_037197, European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), World Health Organization, Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Catalan Institute of Oncology - ICO (Spain), Spanish Government 701708, Marie Curie Actions 701708, European Union's Horizon 2020, Marie Sklodowska-Curie 701708
Published: 2023

27. An atlas of genetic scores to predict multi-omic traits

Author: Yu Xu, Scott C. Ritchie, Yujian Liang, Paul R. H. J. Timmers, Maik Pietzner, Loïc Lannelongue, Samuel A. Lambert, Usman A. Tahir, Sebastian May-Wilson, Carles Foguet, Åsa Johansson, Praveen Surendran, Artika P. Nath, Elodie Persyn, James E. Peters, Clare Oliver-Williams, Shuliang Deng, Bram Prins, Jian’an Luan, Lorenzo Bomba, Nicole Soranzo, Emanuele Di Angelantonio, Nicola Pirastu, E. Shyong Tai, Rob M. van Dam, Helen Parkinson, Emma E. Davenport, Dirk S. Paul, Christopher Yau, Robert E. Gerszten, Anders Mälarstig, John Danesh, Xueling Sim, Claudia Langenberg, James F. Wilson, Adam S. Butterworth, Michael Inouye, Xu, Yu [0000-0002-7304-5045], Ritchie, Scott C [0000-0002-8454-9548], Timmers, Paul RHJ [0000-0002-5197-1267], Pietzner, Maik [0000-0003-3437-9963], Lannelongue, Loïc [0000-0002-9135-1345], Lambert, Samuel A [0000-0001-8222-008X], May-Wilson, Sebastian [0000-0003-2668-5717], Foguet, Carles [0000-0001-8494-9595], Johansson, Åsa [0000-0002-2915-4498], Persyn, Elodie [0000-0001-9104-1972], Peters, James E [0000-0002-9415-3440], Prins, Bram [0000-0001-5774-034X], Luan, Jian'an [0000-0003-3137-6337], Soranzo, Nicole [0000-0003-1095-3852], Tai, E Shyong [0000-0003-2929-8966], Paul, Dirk S [0000-0002-8230-0116], Yau, Christopher [0000-0001-7615-8523], Gerszten, Robert E [0000-0002-6767-7687], Mälarstig, Anders [0000-0003-2608-1358], Sim, Xueling [0000-0002-1233-7642], Langenberg, Claudia [0000-0002-5017-7344], Wilson, James F [0000-0001-5751-9178], Butterworth, Adam S [0000-0002-6915-9015], Inouye, Michael [0000-0001-9413-6520], and Apollo - University of Cambridge Repository
Subjects: Proteomics, European People, Internet, Multidisciplinary, Asian, Proteome, Databases, Factual, Datasets as Topic, Reproducibility of Results, Coronary Artery Disease, Multiomics, United Kingdom, Machine Learning, Black or African American, Cohort Studies, Plasma, Phenotype, Metabolome, Humans, Metabolomics
Abstract: The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
Published: 2023

28. Genomic discovery and functional validation of MRP1 as a novel fetal hemoglobin modulator and potential therapeutic target in sickle cell disease

Author: Yannis Hara, Emily Kawabata, Viktor T. Lemgart, Paola G. Bronson, Alexandra Hicks, Robert Peters, Sriram Krishnamoorthy, Jean-Antoine Ribeil, Lisa J. Schmunk, Jennifer Eglinton, Nicholas A. Watkins, David J. Roberts, Emanuele Di Angelantonio, John Danesh, William J. Astle, Dirk S. Paul, Samuel Lessard, and Adam S. Butterworth
Abstract: Sickle cell disease (SCD) remains a major health burden with limited treatment options. Despite promising gene-editing clinical trials, there is an unmet need for cost-effective therapies. As induction of fetal hemoglobin (HbF) is an established therapeutic strategy for SCD, we conducted a genome-wide association study of circulating HbF levels in ~11,000 participants to identify further HbF modulators. We identified associations in 11 genomic regions, including eight novel loci such asABCC1(encoding multidrug resistance-associated protein 1, MRP1). Using gene-editing and pharmacological approaches, we showed that inhibition of MRP1 increases HbF, intracellular glutathione levels, and reduces sickling in erythroid cells from SCD patients. Overall, our findings identify several novel genetically-validated potential therapeutic targets for SCD, including promising proof-of-principle results from small molecule inhibition of MRP1.
Published: 2023

29. Age at menopause and the risk of stroke: Observational and Mendelian Randomization analysis in 204,244 postmenopausal women

Author: Lena Tschiderer, Sanne AE Peters, Yvonne T van der Schouw, Anniek C van Westing, Tammy YN Tong, Peter Willeit, Lisa Seekircher, Conchi Moreno-Iribas, José María Huerta, Marta Crous-Bou, Martin Söderholm, Matthias B Schulze, Cecilia Johansson, Sara Själander, Alicia K Heath, Alessandra Macciotta, Christina C Dahm, Daniel B Ibsen, Valeria Pala, Lene Mellemkjær, Stephen Burgess, Angela Wood, Rudolf Kaaks, Verena Katzke, Pilar Amiano, Miguel Rodriguez-Barranco, Gunnar Engström, Elisabete Weiderpass, Anne Tjønneland, Jytte Halkjær, Salvatore Panico, John Danesh, Adam Butterworth, and N Charlotte Onland-Moret
Abstract: BackgroundObservational studies have shown that women with an early menopause are at higher risk of stroke compared to women with a later menopause. However, associations with stroke subtypes are inconsistent and the causality is unclear. Therefore, we conducted a large-scale analysis to investigate the observational association between age at menopause and different types of stroke accompanied by a Mendelian Randomization analysis to evaluate causality.MethodsWe analyzed data of the UK Biobank and EPIC-CVD study. Postmenopausal women without a history of stroke at baseline were eligible for inclusion. The study endpoints were total stroke and stroke subtypes (i.e., ischemic stroke, hemorrhagic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage). We investigated the observational association between age at menopause and risk of stroke using Cox-regression analysis in each study separately before combining effect sizes using random-effects meta-analysis. Cox-regression analyses were progressively adjusted for (1) age, (2) smoking status, body mass index, glycated hemoglobin, total cholesterol, and hypertension, and (3) ever use of hormone replacement therapy and age at menarche. We used two-sample Mendelian Randomization analysis to study whether there is a causal relationship between genetically proxied age at menopause and risk of stroke.ResultsA total of 204,244 women were included (7,883 from EPIC-CVD [5,292 from the sub-cohort]; 196,361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD 5.8) and pooled mean age at menopause was 47.8 years (SD 6.2). Natural menopause occurred in 77.6% of all women. Over a median follow-up of 12.6 years (IQR 11.8, 13.3), 6,770 women experienced a stroke. In multivariable adjusted observational analyses, the pooled hazard ratios per five years younger age at menopause were 1.09 (95% CI: 1.07, 1.12) for stroke, 1.09 (1.06, 1.13) for ischemic stroke, 1.10 (1.04, 1.16) for hemorrhagic stroke, 1.14 (1.08, 1.20) for intracerebral hemorrhage, and 1.00 (0.84, 1.20) for subarachnoid hemorrhage. The Mendelian Randomization analysis found no evidence for a causal relationship between genetically proxied age at menopause and risk of any type of stroke.ConclusionsEarlier age at menopause is associated with, but not causally related to the risk of stroke.Clinical PerspectiveWhat is new?This analysis involves over 200,000 postmenopausal women and more than 6,000 incident stroke cases and investigates the observational association between age at menopause and various subtypes of stroke. Furthermore, a Mendelian Randomization analysis was conducted to study whether associations are causal or not.Earlier age at menopause was statistically significantly associated with a higher risk of stroke and its subtypes ischemic stroke, hemorrhagic stroke, and intracerebral hemorrhage. We found no statistically significant relationship between earlier or later age at menopause and risk of subarachnoid hemorrhage.The Mendelian Randomization analysis suggested no causal effect of genetically proxied age at menopause and risk of any type of stroke.What are the clinical implications?Women with earlier age at menopause are at higher risk of stroke. The underlying reasons need to be further investigated.Our analysis suggested that earlier menopauseper sedoes not cause stroke. For prevention and adequate treatment of stroke in women, a better understanding of the specific role of menopause and the mechanistic background that leads to higher risk of stroke is needed.
Published: 2023

30. Physical activity attenuates but does not eliminate coronary heart disease risk amongst adults with risk factors: EPIC-CVD case-cohort study

Author: Melony C Fortuin-de Smidt, Maquins Odhiambo Sewe, Camille Lassale, Elisabete Weiderpass, Jonas Andersson, José María Huerta, Ulf Ekelund, Krasimira Aleksandrova, Tammy YN Tong, Christina C Dahm, Anne Tjønneland, Cecilie Kyrø, Karen Steindorf, Matthias B Schulze, Verena Katzke, Carlotta Sacerdote, Claudia Agnoli, Giovanna Masala, Rosario Tumino, Salvatore Panico, Jolanda MA Boer, N Charlotte Onland-Moret, GC Wanda Wendel-Vos, Yvonne T van der Schouw, Kristin Benjaminsen Borch, Antonio Agudo, Dafina Petrova, María Dolores Chirlaque, Moreno Iribas Conchi, Pilar Amiano, Olle Melander, Alicia K Heath, Dagfinn Aune, Nita G Forouhi, Claudia Langenberg, Soren Brage, Elio Riboli, Nicholas J Wareham, John Danesh, Adam S Butterworth, Patrik Wennberg, Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Brage, Soren [0000-0002-1265-7355], Wareham, Nicholas [0000-0003-1422-2993], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Adult, Cardiac & Cardiovascular Systems, population preventable fraction, Epidemiology, Hypercholesterolemia, QUESTIONNAIRE, physical activity, BLOOD-PRESSURE, EXERCISE, Coronary Disease, ALL-CAUSE, Cohort Studies, Risk Factors, Humans, risk factors, Obesity, Prospective Studies, coronary heart disease, Exercise, POPULATION, Science & Technology, Physical activity, MORTALITY, Incidence, Public Health, Global Health, Social Medicine and Epidemiology, ASSOCIATION, PREVENTION, case-cohort study, Coronary heart disease, Population preventable fraction, Risk factors, Case-cohort study, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, CARDIOVASCULAR-DISEASE, Hypertension, Cardiovascular System & Cardiology, LIFE-STYLE, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine
Abstract: Aims This study aimed to evaluate the association between physical activity and the incidence of coronary heart disease (CHD) in individuals with and without CHD risk factors. Methods and results EPIC-CVD is a case-cohort study of 29 333 participants that included 13 582 incident CHD cases and a randomly selected sub-cohort nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Self-reported physical activity was summarized using the Cambridge physical activity index (inactive, moderately inactive, moderately active, and active). Participants were categorized into sub-groups based on the presence or the absence of the following risk factors: obesity (body mass index ≥30 kg/m2), hypercholesterolaemia (total cholesterol ≥6.2 mmol/L), history of diabetes, hypertension (self-reported or ≥140/90 mmHg), and current smoking. Prentice-weighted Cox regression was used to assess the association between physical activity and incident CHD events (non-fatal and fatal). Compared to inactive participants without the respective CHD risk factor (referent), excess CHD risk was highest in physically inactive and lowest in moderately active participants with CHD risk factors. Corresponding excess CHD risk estimates amongst those with obesity were 47% [95% confidence interval (CI) 32–64%] and 21% (95%CI 2–44%), with hypercholesterolaemia were 80% (95%CI 55–108%) and 48% (95%CI 22–81%), with hypertension were 80% (95%CI 65–96%) and 49% (95%CI 28–74%), with diabetes were 142% (95%CI 63–260%), and 100% (95%CI 32–204%), and amongst smokers were 152% (95%CI 122–186%) and 109% (95%CI 74–150%). Conclusions In people with CHD risk factors, moderate physical activity, equivalent to 40 mins of walking per day, attenuates but does not completely offset CHD risk.
Published: 2022

31. Evaluation of interventions to prevent vasovagal reactions among whole blood donors: rationale and design of a large cluster randomised trial

Author: Amy McMahon, Stephen Kaptoge, Matthew Walker, Susan Mehenny, Philippe T Gilchrist, Jennifer Sambrook, Naim Akhtar, Michael Sweeting, Angela M Wood, Kathleen Stirrups, Ryan Chung, Sarah Fahle, Elisha Johnson, Donna Cullen, Rosemary Godfrey, Shannon Duthie, Louise Allen, Paul Harvey, Michael Berkson, Elizabeth Allen, Nicholas A Watkins, John R Bradley, Nathalie Kingston, Gail Miflin, Jane Armitage, David J Roberts, John Danesh, Emanuele Di Angelantonio, and Apollo - University of Cambridge Repository
Abstract: Background: Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations, and are disruptive and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension [AMT]), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors. Methods: STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site (“cluster”) has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions are compared to NHSBT’s current practices: (i) 500ml isotonic drink before donation vs current 500ml plain water; (ii) 3-minutes rest on donation chair after donation vs current 2 minutes; (iii) new modified AMT vs current practice of AMT; and (iv) psychosocial intervention using preparatory materials vs current practice of nothing. The primary outcome is the number of in-session VVRs with loss of consciousness (i.e., episodes involving loss of consciousness of any duration, with or without additional complications). Secondary outcomes include all in-session VVRs (i.e., with and without loss of consciousness) and delayed VVRs (i.e., those occurring after leaving the venue). Discussion: The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency. Trial registration: ISRCTN: 10412338
Published: 2022

32. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author: Liam Gaziano, Luanluan Sun, Matthew Arnold, Steven Bell, Kelly Cho, Stephen K. Kaptoge, Rebecca J. Song, Stephen Burgess, Daniel C. Posner, Katja Mosconi, Cassianne Robinson-Cohen, Amy M. Mason, Thomas R. Bolton, Ran Tao, Elias Allara, Petra Schubert, Lingyan Chen, James R. Staley, Natalie Staplin, Servet Altay, Pilar Amiano, Volker Arndt, Johan Ärnlöv, Elizabeth L.M. Barr, Cecilia Björkelund, Jolanda M.A. Boer, Hermann Brenner, Edoardo Casiglia, Paolo Chiodini, Jackie A. Cooper, Josef Coresh, Mary Cushman, Rachel Dankner, Karina W. Davidson, Renate T. de Jongh, Chiara Donfrancesco, Gunnar Engström, Heinz Freisling, Agustín Gómez de la Cámara, Vilmundur Gudnason, Graeme J. Hankey, Per-Olof Hansson, Alicia K. Heath, Ewout J. Hoorn, Hironori Imano, Simerjot K. Jassal, Rudolf Kaaks, Verena Katzke, Jussi Kauhanen, Stefan Kiechl, Wolfgang Koenig, Richard A. Kronmal, Cecilie Kyrø, Deborah A. Lawlor, Börje Ljungberg, Conor MacDonald, Giovanna Masala, Christa Meisinger, Olle Melander, Conchi Moreno Iribas, Toshiharu Ninomiya, Dorothea Nitsch, Børge G. Nordestgaard, Charlotte Onland-Moret, Luigi Palmieri, Dafina Petrova, Jose Ramón Quirós Garcia, Annika Rosengren, Carlotta Sacerdote, Masaru Sakurai, Carmen Santiuste, Matthias B. Schulze, Sabina Sieri, Johan Sundström, Valérie Tikhonoff, Anne Tjønneland, Tammy Tong, Rosario Tumino, Ioanna Tzoulaki, Yvonne T. van der Schouw, W.M. Monique Verschuren, Henry Völzke, Robert B. Wallace, S. Goya Wannamethee, Elisabete Weiderpass, Peter Willeit, Mark Woodward, Kazumasa Yamagishi, Raul Zamora-Ros, Elvis A. Akwo, Saiju Pyarajan, David R. Gagnon, Philip S. Tsao, Sumitra Muralidhar, Todd L. Edwards, Scott M. Damrauer, Jacob Joseph, Lisa Pennells, Peter W.F. Wilson, Seamus Harrison, Thomas A. Gaziano, Michael Inouye, Colin Baigent, Juan P. Casas, Claudia Langenberg, Nick Wareham, Elio Riboli, J.Michael Gaziano, John Danesh, Adriana M. Hung, Adam S. Butterworth, Angela M. Wood, Emanuele Di Angelantonio, Anna Koettgen, Jonathan Shaw, Robert Atkins, Paul Zimmet, Peter Whincup, Johann Willeit, Christoph Leitner, Anne Tybjaerg-Hansen, Peter Schnohr, Shoaib Afzal, David Lora Pablos, Cristina Martin Arriscado, Carmen Romero Ferreiro, Hannah Stocker, Ben Schöttker, Bernd Holleczek, Angela Chetrit, Lennart Welin, Kurt Svärdsudd, Lauren Lissner, Dominique Hange, Kirsten Mehlig, Dorothea Nagel, Paul E. Norman, Osvaldo Almeida, Leon Flicker, Jun Hata, Takanori Honda, Yoshihiko Furuta, Hiroyasu Iso, Akihiko Kitamura, Isao Muraki, Jukka T. Salonen, Tomi-Pekka Tuomainen, E. M. van Zutphen, N. M. van Schoor, Cinzia Lo Noce, Richard Kronmal, Georg Lappas, Peter M. Nilsson, Bo Hedblad, Jonathan Shaffer, Joseph Schwartz, Daichi Shimbo, Shinichi Sato, Mina Hayama-Terada, Simerjot Jassal, Thor Aspelund, Bolli Thorsson, Gunnar Sigurdsson, Layal Chaker, Kamran M. Ikram, Maryam Kavousi, Hugh Tunstall-Pedoe, Günay Can, Hüsniye Yüksel, Uğur Özkan, Hideaki Nakagawa, Yuko Morikawa, Masao Ishizaki, Edith Feskens, Johanna M Geleijnse, Daan Kromhout, Internal Medicine, Neurology, Epidemiology, Bell, Steven [0000-0001-6774-3149], Posner, Daniel C [0000-0002-3056-6924], Mason, Amy M [0000-0002-8019-0777], Allara, Elias [0000-0002-1634-8330], Staplin, Natalie [0000-0003-4482-4418], Arndt, Volker [0000-0001-9320-8684], Ärnlöv, Johan [0000-0002-6933-4637], Barr, Elizabeth LM [0000-0003-4284-1716], Boer, Jolanda MA [0000-0002-9714-4304], Brenner, Hermann [0000-0002-6129-1572], Casiglia, Edoardo [0000-0002-0003-3289], Chiodini, Paolo [0000-0003-0139-2264], Coresh, Josef [0000-0002-4598-0669], Cushman, Mary [0000-0002-7871-6143], Davidson, Karina W [0000-0002-9162-477X], de Jongh, Renate T [0000-0001-8414-3938], Engström, Gunnar [0000-0002-8618-9152], de la Cámara, Agustín Gómez [0000-0001-6827-6319], Gudnason, Vilmundur [0000-0001-5696-0084], Hankey, Graeme J [0000-0002-6044-7328], Hansson, Per-Olof [0000-0001-6323-0506], Heath, Alicia K [0000-0001-6517-1300], Hoorn, Ewout J [0000-0002-8738-3571], Imano, Hironori [0000-0002-6661-4254], Katzke, Verena [0000-0002-6509-6555], Kiechl, Stefan [0000-0002-9836-2514], Koenig, Wolfgang [0000-0002-2064-9603], Kronmal, Richard A [0000-0002-9897-7076], Kyrø, Cecilie [0000-0002-9083-8960], Ljungberg, Börje [0000-0002-4121-3753], MacDonald, Conor [0000-0002-4989-803X], Masala, Giovanna [0000-0002-5758-9069], Ninomiya, Toshiharu [0000-0003-1345-9032], Nordestgaard, Børge G [0000-0002-1954-7220], Onland-Moret, Charlotte [0000-0002-2360-913X], Palmieri, Luigi [0000-0002-4298-2642], Rosengren, Annika [0000-0002-5409-6605], Schulze, Matthias B [0000-0002-0830-5277], Sieri, Sabina [0000-0001-5201-172X], Sundström, Johan [0000-0003-2247-8454], Tikhonoff, Valérie [0000-0001-7846-0101], Tong, Tammy [0000-0002-0284-8959], Tzoulaki, Ioanna [0000-0002-4275-9328], van der Schouw, Yvonne T [0000-0002-4605-435X], Wannamethee, S Goya [0000-0001-9484-9977], Weiderpass, Elisabete [0000-0003-2237-0128], Willeit, Peter [0000-0002-1866-7159], Woodward, Mark [0000-0001-9800-5296], Yamagishi, Kazumasa [0000-0003-3301-5519], Zamora-Ros, Raul [0000-0002-6236-6804], Gagnon, David R [0000-0002-6367-3179], Tsao, Philip S [0000-0001-7274-9318], Edwards, Todd L [0000-0003-4318-6119], Damrauer, Scott M [0000-0001-8009-1632], Joseph, Jacob [0000-0002-7279-4896], Pennells, Lisa [0000-0002-8594-3061], Gaziano, Thomas A [0000-0002-5985-345X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nick [0000-0003-1422-2993], Hung, Adriana M [0000-0002-3203-1608], Butterworth, Adam S [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Gaziano, Liam, Sun, Luanluan, Arnold, Matthew, Bell, Steven, Cho, Kelly, Kaptoge, Stephen K, Song, Rebecca J, Burgess, Stephen, Posner, Daniel C, Mosconi, Katja, Robinson-Cohen, Cassianne, Mason, Amy M, Bolton, Thomas R, Tao, Ran, Allara, Elia, Schubert, Petra, Chen, Lingyan, Staley, James R, Staplin, Natalie, Altay, Servet, Amiano, Pilar, Arndt, Volker, Ärnlöv, Johan, Barr, Elizabeth L M, Björkelund, Cecilia, Boer, Jolanda M A, Brenner, Hermann, Casiglia, Edoardo, Chiodini, Paolo, Cooper, Jackie A, Coresh, Josef, Cushman, Mary, Dankner, Rachel, Davidson, Karina W, de Jongh, Renate T, Donfrancesco, Chiara, Engström, Gunnar, Freisling, Heinz, de la Cámara, Agustín Gómez, Gudnason, Vilmundur, Hankey, Graeme J, Hansson, Per-Olof, Heath, Alicia K, Hoorn, Ewout J, Imano, Hironori, Jassal, Simerjot K, Kaaks, Rudolf, Katzke, Verena, Kauhanen, Jussi, Kiechl, Stefan, Koenig, Wolfgang, Kronmal, Richard A, Kyrø, Cecilie, Lawlor, Deborah A, Ljungberg, Börje, Macdonald, Conor, Masala, Giovanna, Meisinger, Christa, Melander, Olle, Moreno Iribas, Conchi, Ninomiya, Toshiharu, Nitsch, Dorothea, Nordestgaard, Børge G, Onland-Moret, Charlotte, Palmieri, Luigi, Petrova, Dafina, Garcia, Jose Ramón Quiró, Rosengren, Annika, Sacerdote, Carlotta, Sakurai, Masaru, Santiuste, Carmen, Schulze, Matthias B, Sieri, Sabina, Sundström, Johan, Tikhonoff, Valérie, Tjønneland, Anne, Tong, Tammy, Tumino, Rosario, Tzoulaki, Ioanna, van der Schouw, Yvonne T, Monique Verschuren, W M, Völzke, Henry, Wallace, Robert B, Wannamethee, S Goya, Weiderpass, Elisabete, Willeit, Peter, Woodward, Mark, Yamagishi, Kazumasa, Zamora-Ros, Raul, Akwo, Elvis A, Pyarajan, Saiju, Gagnon, David R, Tsao, Philip S, Muralidhar, Sumitra, Edwards, Todd L, Damrauer, Scott M, Joseph, Jacob, Pennells, Lisa, Wilson, Peter W F, Harrison, Seamu, Gaziano, Thomas A, Inouye, Michael, Baigent, Colin, Casas, Juan P, Langenberg, Claudia, Wareham, Nick, Riboli, Elio, Gaziano, J Michael, Danesh, John, Hung, Adriana M, Butterworth, Adam S, Wood, Angela M, Di Angelantonio, Emanuele, Internal medicine, AMS - Ageing & Vitality, AMS - Musculoskeletal Health, Amsterdam Gastroenterology Endocrinology Metabolism, Epidemiology and Data Science, APH - Aging & Later Life, and APH - Personalized Medicine
Subjects: kidney disease, General Practice, Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program, Coronary Disease, coronary disease, Kidney, Malalties coronàries, 1117 Public Health and Health Services, Coronary diseases, SDG 3 - Good Health and Well-being, cardiovascular disease, Risk Factors, Physiology (medical), Diabetes Mellitus, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, 1102 Cardiorespiratory Medicine and Haematology, Kardiologi, Kidney diseases, Malalties cardiovasculars, Cardiovascular Diseases, Kidney Diseases, Stroke, 1103 Clinical Sciences, Mendelian Randomization Analysis, kidney diseases, stroke, Allmänmedicin, Cardiovascular diseases, Cardiovascular System & Hematology, Malalties del ronyó, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract: Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
Published: 2022

33. Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study

Author: Emily Sonestedt, Krassimira Aleksandrova, H. Boeing, Fumiaki Imamura, L E T Vissers, Stephen Burgess, Anne Tjønneland, Cecilie Kyrø, E. Riboli, Y. T. van der Schouw, Liher Imaz, Catalina Bonet, John Danesh, W M M Verschuren, J.M.A. Boer, Nita G. Forouhi, I. Sluijs, Ioanna Tzoulaki, Olle Melander, Elisabete Weiderpass, Adam S. Butterworth, M J Sánches, M-D Chirlaque, M I Conchi, Matthias B. Schulze, Heinz Freisling, Dagfinn Aune, S Jäger, Salvatore Panico, Tammy Y.N. Tong, Vittorio Krogh, C C Dahm, Giovanna Masala, Torbjörn K. Nilsson, Frida Renström, Nicholas J. Wareham, Kim Overvad, Aurora Perez-Cornago, Vissers, LET [0000-0001-9044-0744], Freisling, H [0000-0001-8648-4998], Dahm, CC [0000-0003-0481-2893], Tong, TYN [0000-0002-0284-8959], Kyrø, C [0000-0002-9083-8960], van der Schouw, YT [0000-0002-4605-435X], and Apollo - University of Cambridge Repository
Subjects: European People, 030309 nutrition & dietetics, Multifunction cardiogram, Medicine (miscellaneous), ISCHEMIC-HEART-DISEASE, 0302 clinical medicine, Mendelian Randomization, Risk Factors, Neoplasms, PARTICIPANTS, Prospective Studies, Mendelian randomisation, Stroke, 2. Zero hunger, RISK, 0303 health sciences, Nutrition and Dietetics, Confounding, Mendelian Randomization Analysis, stroke, 3. Good health, PROSTATE-CANCER, Milk, Cardiovascular Diseases, LACTASE PERSISTENCE GENOTYPE, LIFE-STYLE, HEALTH, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Dairy, 03 medical and health sciences, Internal medicine, Mendelian randomization, BLOOD-PRESSURE RESPONSE, 0702 Animal Production, medicine, Humans, Animals, COHORT, cardiovascular diseases, Science & Technology, Nutrition & Dietetics, Proportional hazards model, business.industry, CONSUMPTION, Odds ratio, medicine.disease, Lactase persistence, CHD, dairy, 1111 Nutrition and Dietetics, business, 0908 Food Sciences
Abstract: We thank all EPIC participants and staff for their contribution to the study. We also thank staff from the EPIC-CVD coordinating centres for sample preparation and data handling. This research has been conducted using the UK Biobank Resource (application number 29916). Data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.I Sluijswas supported by a personal Dr. Dekker postdoctoral grant (2015T019) from the Netherlands Heart Foundation. NGF and FI acknowledge core Medical Research Council Epidemiology Unit support (MC_UU_12015/5) and NGF acknowledges NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. These analyses were supported by Cancer Research UK (C8221/A19170). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) PI13/00061 (EPIC-Granada) and PI13/01162 (EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII Health Research Funds RD12/0036/0018 (cofounded by FEDER funds/European Regional Development Fund ERDF) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 for EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). EPIC-CVD has been supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG13/13/30194 and RG/18/13/33946) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. L.E.T.V.analysed the data and drafted the manuscript. L. E. T. V., I. S. and Y. T. vdS. had access to all data for this study. L. E. T. V., I. S., Y. T. vdS., S. B., N. G. F., H. F., F. I., T. K. N., F. R., E. W., K. A., C. D., A. P. C., M. B. S., T. Y. N. T. and A. S. B. contributed to study conception, design and interpretation of data. All authors contributed to critical revision of the manuscript and approval of version to be published., Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (beta = 13 center dot 7 g/d; 95 % CI 8 center dot 4, 19 center dot 1) and EPIC-NL (36 center dot 8 g/d; 95 % CI 20 center dot 0, 53 center dot 5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1 center dot 05; 95 % CI 0 center dot 94, 1 center dot 16) or CHD (1 center dot 02; 95 % CI 0 center dot 96, 1 center dot 08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1 center dot 02; 95 % CI 0 center dot 99, 1 center dot 05) or CHD (OR 0 center dot 99; 95 % CI 0 center dot 95, 1 center dot 03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk., Netherlands Heart Foundation 2015T019, UK Research & Innovation (UKRI) Medical Research Council UK (MRC), European Commission MC_UU_12015/5, NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, European Commission LSHM_CT_2006_037197, Cancer Research UK C8221/A19170, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Deutsche Krebshilfe Deutsches Krebsforschungszentrum (Germany), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), ISCIII Health Research Funds (FEDER funds/European Regional Development Fund ERDF) (Spain) RD12/0036/0018, Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), European Commission Framework Programme 7 HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/L003120/1 British Heart Foundation RG13/13/30194 RG/18/13/33946 National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust) UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1 Cancer Research UK C8221/A19170 14136 C570/A16491
Published: 2022

34. Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease

Author: Amit V. Khera, Minxian Wang, Mark Chaffin, Connor A. Emdin, Nilesh J. Samani, Heribert Schunkert, Hugh Watkins, Ruth McPherson, Jeanette Erdmann, Roberto Elosua, Eric Boerwinkle, Diego Ardissino, Adam S. Butterworth, Emanuele Di Angelantonio, Aliya Naheed, John Danesh, Rajiv Chowdhury, Harlan M. Krumholz, Wayne H.-H. Sheu, Stephen S. Rich, Jerome I. Rotter, Yii-der Ida Chen, Stacey Gabriel, Eric S. Lander, Danish Saleheen, and Sekar Kathiresan
Subjects: General Medicine
Abstract: Background: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene ( LDLR ) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia. Methods: To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls. Results: Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene ( NOS3 ), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80–3.26; P =5.50×10 −9 ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; [95% CI, 1.86–4.65]; P =5.00×10 −6 ) and increased risk of hypertension (adjusted odds ratio 1.31; [95% CI, 1.14–1.51]; P =2.00×10 −4 ) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk. Conclusions: Beyond LDLR , we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.
Published: 2022

35. Telomere length and risk of incident fracture and arthroplasty:findings from UK Biobank

Author: Elizabeth M. Curtis, Veryan Codd, Christopher Nelson, Stefania D'Angelo, Qingning Wang, Elias Allara, Stephen Kaptoge, Paul M. Matthews, Jonathan H. Tobias, John Danesh, Cyrus Cooper, Nilesh J. Samani, and Nicholas C. Harvey
Subjects: Male, Hand Strength, Hip Fractures, Endocrinology, Diabetes and Metabolism, Arthroplasty, Replacement, Hip, Middle Aged, Telomere, United Kingdom, Fractures, Bone, Bone Density, Risk Factors, Humans, Orthopedics and Sports Medicine, Female, Arthroplasty, Replacement, Knee, Osteoporotic Fractures, Biological Specimen Banks
Abstract: We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leukocyte telomere length (LTL) was measured in baseline samples using a validated polymerase chain reaction (PCR) method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio (HR) for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity, and menopause (women). In further analyses we adjusted for either estimated bone mineral density (eBMD) from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance), or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean ± standard deviation (SD) age 56.4 ± 8.0 and 57.0 ± 8.3 years, respectively. During follow-up there were 5619 fractures; 5285 hip and 4261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men (HR/SD 0.93; 95% confidence interval [CI], 0.88-0.97) and women (0.92; 95% CI, 0.88-0.96), and hip arthroplasty in men (0.91; 95% CI, 0.87-0.95), but not women (0.98; 95% CI, 0.94-1.01). Longer LTL was weakly associated with reduced risk of any incident fracture in women (HR/SD 0.96; 95% CI, 0.93-1.00) with less evidence in men (0.98; 95% CI, 0.93-1.02). Associations with incident outcomes were not materially altered by adjustment for heel eBMD, grip strength, gait speed, fat mass, or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeletal systems might influence later life musculoskeletal outcomes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Published: 2022

36. Inhibition of MRP1 Induces Fetal Hemoglobin through NRF2 Activation to Protect Human Erythroid Cells from Sickling

Author: Yannis Hara, Emily Kawabata, Viktor T. Lemgart, Paola G. Bronson, Alexandra Hicks, Sriram Krishnamoorthy, Nicholas Watkins, Robert Peters, David J. Roberts, Emanuele Di Angelantonio, John Danesh, William Astle, Dirk S. Paul, Samuel Lessard, and Adam S. Butterworth
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022

37. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
Subjects: Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022

38. An atlas of genetic scores to predict multi-omic traits

Author: Yu Xu, Scott C. Ritchie, Yujian Liang, Paul R. H. J. Timmers, Maik Pietzner, Loïc Lannelongue, Samuel A. Lambert, Usman A. Tahir, Sebastian May-Wilson, Åsa Johansson, Praveen Surendran, Artika P Nath, Elodie Persyn, James E. Peters, Clare Oliver-Williams, Shuliang Deng, Bram Prins, Carles Foguet, Jian’an Luan, Lorenzo Bomba, Nicole Soranzo, Emanuele Di Angelantonio, Nicola Pirastu, E Shyong Tai, Rob M van Dam, Emma E Davenport, Dirk S. Paul, Christopher Yau, Robert E. Gerszten, Anders Mälarstig, John Danesh, Xueling Sim, Claudia Langenberg, James F. Wilson, Adam S. Butterworth, and Michael Inouye
Abstract: Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL; N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175; Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within diverse individuals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal (OmicsPred.org) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
Published: 2022

39. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author: Tetsushi, Nakao, Alexander G, Bick, Margaret A, Taub, Seyedeh M, Zekavat, Md M, Uddin, Abhishek, Niroula, Cara L, Carty, John, Lane, Michael C, Honigberg, Joshua S, Weinstock, Akhil, Pampana, Christopher J, Gibson, Gabriel K, Griffin, Shoa L, Clarke, Romit, Bhattacharya, Themistocles L, Assimes, Leslie S, Emery, Adrienne M, Stilp, Quenna, Wong, Jai, Broome, Cecelia A, Laurie, Alyna T, Khan, Albert V, Smith, Thomas W, Blackwell, Veryan, Codd, Christopher P, Nelson, Zachary T, Yoneda, Juan M, Peralta, Donald W, Bowden, Marguerite R, Irvin, Meher, Boorgula, Wei, Zhao, Lisa R, Yanek, Kerri L, Wiggins, James E, Hixson, C Charles, Gu, Gina M, Peloso, Dan M, Roden, Muagututi'a S, Reupena, Chii-Min, Hwu, Dawn L, DeMeo, Kari E, North, Shannon, Kelly, Solomon K, Musani, Joshua C, Bis, Donald M, Lloyd-Jones, Jill M, Johnsen, Michael, Preuss, Russell P, Tracy, Patricia A, Peyser, Dandi, Qiao, Pinkal, Desai, Joanne E, Curran, Barry I, Freedman, Hemant K, Tiwari, Sameer, Chavan, Jennifer A, Smith, Nicholas L, Smith, Tanika N, Kelly, Bertha, Hidalgo, L Adrienne, Cupples, Daniel E, Weeks, Nicola L, Hawley, Ryan L, Minster, Ranjan, Deka, Take T, Naseri, Lisa, de Las Fuentes, Laura M, Raffield, Alanna C, Morrison, Paul S, Vries, Christie M, Ballantyne, Eimear E, Kenny, Stephen S, Rich, Eric A, Whitsel, Michael H, Cho, M Benjamin, Shoemaker, Betty S, Pace, John, Blangero, Nicholette D, Palmer, Braxton D, Mitchell, Alan R, Shuldiner, Kathleen C, Barnes, Susan, Redline, Sharon L R, Kardia, Gonçalo R, Abecasis, Lewis C, Becker, Susan R, Heckbert, Jiang, He, Wendy, Post, Donna K, Arnett, Ramachandran S, Vasan, Dawood, Darbar, Scott T, Weiss, Stephen T, McGarvey, Mariza, de Andrade, Yii-Der Ida, Chen, Robert C, Kaplan, Deborah A, Meyers, Brian S, Custer, Adolfo, Correa, Bruce M, Psaty, Myriam, Fornage, JoAnn E, Manson, Eric, Boerwinkle, Barbara A, Konkle, Ruth J F, Loos, Jerome I, Rotter, Edwin K, Silverman, Charles, Kooperberg, John, Danesh, Nilesh J, Samani, Siddhartha, Jaiswal, Peter, Libby, Patrick T, Ellinor, Nathan, Pankratz, Benjamin L, Ebert, Alexander P, Reiner, Rasika A, Mathias, Ron, Do, and Pradeep, Natarajan
Subjects: Multidisciplinary
Abstract: Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
Published: 2022

40. Genome-wide analysis in over 1 million individuals reveals over 2,000 independent genetic signals for blood pressure

Author: Helen Warren, Todd Edwards, Ahmad Vaez, Jacob Keaton, Zoha Kamali, Tian Xie, Alireza Ani, Evangelos Evangelou, Jacklyn Hellwege, Loïc Yengo, William Young, Matthew Traylor, Ayush Giri, Peter Visscher, Daniel Chasman, Andrew Morris, Mark Caulfield, Shih-Jen Hwang, Jaspal Kooner, David Conen, John Attia, Alanna Morrison, Ruth Loos, Kati Kristiansson, Reinhold Schmidt, Andrew Hicks, Peter Pramstaller, Christopher Nelson, Nilesh Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriëtte Riese, James Wilson, Harry Campbell, Bruce Psaty, Yingchang Lu, Jerome Rotter, Xiuqing Guo, Kenneth Rice, Peter Vollenweider, Johan Sundstrom, Claudia Langenberg, Martin Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim van der Harst, Paul Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah Harris, Ian Deary, Peter van der Most, Albertine Oldehinkel, Bernard Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Jarvelin, Annette Peters, Christian Gieger, Edward Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin de Borst, Ozren Polasek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli Raitakari, Andrew Johnson, Christopher Newton-Cheh, Morris Brown, Anna Dominiczak, Peter Sever, Neil Poulter, John Chambers, Roberto Elosua, David Siscovick, Tōnu Esko, Andres Metspalu, Rona Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco de Geus, Colin Palmer, Ilja Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna Howson, Christopher O'Donnell, Tim Spector, Mike Nalls, Eleanor Simonsick, Yongmei Liu, Cornelia van Duijn, Adam Butterworth, John Danesh, Cristina Menni, Nick Wareham, Kay Khaw, Joshua Denny, Daniel Levy, Patricia Munroe, and Harold Snieder
Abstract: Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P − 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
Published: 2022

41. Investigating Genetic and Other Determinants of First-Onset Myocardial Infarction in Malaysia: Protocol for the Malaysian Acute Vascular Events Risk Study

Author: Izyan Mohd Idris, Sophia Rasheeqa Ismail, Eashwary Mageswaren, Niko Ovenden, Rajiv Chowdhury, Thomas A. W. Bolton, Rahman Jamal, Siti Hafizah Zulkiply, Ammu Kutty Radhakrishnan, Jason Crawte, Puteri Sofia Nadira Megat Kamaruddin, Nur Suffia Sulaiman, Siti Khairani Zainal Abidin, Abdul Kahar Abdul Ghapar, Mohd Fairulnizal Md Noh, Kauthaman A Mahendran, Alan Yean Yip Fong, John Danesh, Ahmad Wazi Ramli, Liew Houng Bang, Anwar Irawan Ruhani, Shazana Rifham Abdullah, Noel Thomas Ross, Aizai Azan Abdul Rahim, Angela M. Wood, Wan Rozita Wan Mahiyuddin, Kim Robin van Daalen, Sophie Weston, Nur Hayati Azizul, Lee Chuey Yan, Laryssa Amado, Yong Shih Mei, Azizan Ali, Mansor Yahya, Omar Ismail, Nor Hanim Mohd Amin, Aaron Ong Hean Jin, Gunavathy Muthusamy, Ank Michielsen, Emanuele Di Angelantonio, Saravanan Krishinan, Norfashihah Faridus, Adam S. Butterworth, Yusniza Yusoff, Mostafa Monower, Nur Azirah Md Yusof, Nur Najwa Farahin M Yusoff, and Norhayati Mustafa Khalid
Subjects: Protocol (science), medicine.medical_specialty, myocardial infarction, Genetic, business.industry, Emergency medicine, medicine, Malaysia, General Medicine, Myocardial infarction, medicine.disease, business, MAVERICK
Abstract: Background Although the burden of premature myocardial infarction (MI) is high in Malaysia, direct evidence on the determinants of MI in this multi-ethnic population remains sparse. Objective The Malaysian Acute Vascular Events Risk (MAVERIK) study is a retrospective case-control study established to investigate the genomic, lipid-related, and other determinants of acute MI in Malaysia. In this paper, we report the study protocol and early results. Methods By June 2019, we had enrolled approximately 2500 patients with their first MI and 2500 controls without cardiovascular disease, who were frequency-matched by age, sex, and ethnicity, from 17 hospitals in Malaysia. For each participant, serum and whole blood have been collected and stored. Clinical, demographic, and behavioral information has been obtained using a 200-item questionnaire. Results Tobacco consumption, a history of diabetes, hypertension, markers of visceral adiposity, indicators of lower socioeconomic status, and a family history of coronary disease were more prevalent in cases than in controls. Adjusted (age and sex) logistic regression models for traditional risk factors indicated that current smoking (odds ratio [OR] 4.11, 95% CI 3.56-4.75; P30 kg/m2; OR 1.19, 95% CI 1.05-1.34; P=.009) were associated with MI in age- and sex-adjusted models. Conclusions The MAVERIK study can serve as a useful platform to investigate genetic and other risk factors for MI in an understudied Southeast Asian population. It should help to hasten the discovery of disease-causing pathways and inform regionally appropriate strategies that optimize public health action. International Registered Report Identifier (IRRID) RR1-10.2196/31885
Published: 2022

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

Author: George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K. Arnett, Stella Aslibekyan, Gil Atzmon, Christie M. Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Matthew J. Bown, Jennifer A. Brody, Jai G. Broome, Noël P. Burtt, Brian E. Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I. Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J. Córdova, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, John Danesh, Paul S. de Vries, Ralph A. DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Jose C. Florez, Myriam Fornage, Barry I. Freedman, Valentin Fuster, Ma. Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A. Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E. Graham, Niels Grarup, Leif C. Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L. Hanis, Torben Hansen, Jiang He, Nancy L. Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R. Irvin, Sergio Islas-Andrade, Gail P. Jarvik, Hyun Min Kang, Sharon L.R. Kardia, Tanika Kelly, Eimear E. Kenny, Alyna T. Khan, Bong-Jo Kim, Ryan W. Kim, Young Jin Kim, Heikki A. Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A. Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M. Lehman, Rozenn N. Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J.F. Loos, Steven A. Lubitz, Valeriya Lyssenko, Ronald C.W. Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A. Mathias, Stephen T. McGarvey, Ruth McPherson, James B. Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A. Metcalf, Xuenan Mi, Karen L. Mohlke, May E. Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C. Morrison, Donna M. Muzny, Sarah C. Nelson, Peter M. Nilsson, Jeffrey R. O’Connell, Marju Orho-Melander, Lorena Orozco, Colin N.A. Palmer, Nicholette D. Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M. Peralta, Patricia A. Peyser, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Qibin Qi, D.C. Rao, Susan Redline, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Adrienne M. Stilp, E. Shyong Tai, Claudia H.T. Tam, Kent D. Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y. Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S. Udler, Rob M. van Dam, Ramachandran S. Vasan, Karine A. Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E. Weeks, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Lisa R. Yanek, Sekar Kathiresan, Daniel J. Rader, Jerome I. Rotter, Michael Boehnke, Mark I. McCarthy, Cristen J. Willer, Pradeep Natarajan, Jason A. Flannick, Amit V. Khera, Gina M. Peloso, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, and Department of Public Health
Subjects: APOC3, Blood Glucose, Multifactorial Inheritance, gene-based association, Polymorphism, Single Nucleotide, Article, Open Reading Frames, ANGPTL3, lipid, OF-FUNCTION MUTATIONS, BINDING, Databases, Genetic, SEQUENCE VARIANTS, Genetics, Humans, Exome, Genetic Predisposition to Disease, SINUSOIDAL ENDOTHELIAL-CELLS, Genetics (clinical), Alleles, RISK, IDENTIFICATION, 1184 Genetics, developmental biology, physiology, association, cholesterol, Genetic Variation, Computational Biology, Molecular Sequence Annotation, PERILIPIN, Lipid Metabolism, Lipids, Genetics, Population, Phenotype, Diabetes Mellitus, Type 2, Liver, Case-Control Studies, exome sequencing, TRIGLYCERIDES, Genome-Wide Association Study
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 frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 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; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, 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 (SNPs). 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. This work was supported by a grant from the Swedish Research Council (2016-06830) and grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 and R01HL127564. Please refer to the supplemental information for the full acknowledgements. Sí
Published: 2022

43. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Author: Harry D Wilson, Elaine O'Toole, Andrew Bassett, Moritz U. G. Kraemer, Beth Blane, Scott Goodwin, Giri Shankar, Joseph Hughes, Lucy R. Frost, Alicia Thornton, Scott Elliott, Tammy V Merrill, Sheila Waugh, Alexander Adams, Peter Muir, Graciela Sluga, Rebecca Williams, Hannah Dent, Christophe Fraser, Shavanthi Rajatileka, John C. Hartley, Luke B Snell, Benjamin J Cogger, Lance Turtle, Alex Makunin, John A. Todd, Victoria Wright, Daniela De Angelis, James McKenna, Dinesh Aggarwal, Jonathan K. Ball, Jillian Durham, Garren Scott, Thushan I de Silva, Veena Raviprakash, Hannah M Pymont, Jason Coombes, Anita Lucaci, Luke R. Green, Leigh M Jackson, Hermione J. Webster, Louis du Plessis, David A. Jackson, Minal Patel, Áine O'Toole, Ravi Gupta, Marc Niebel, Garry Scarlett, Rajiv Shah, Guy Mollett, Kathy Li, Rory Gunson, Matthew Bashton, Carl Jones, Sara Kumziene-Summerhayes, Zoltan Molnar, Siona Silveira, Malte L Pinckert, Catherine Ludden, Angeliki Karamani, Leanne Kane, Brendan A I Payne, Alan McNally, Clare M. McCann, Holli Carden, Mohammad Raza, Alison E. Mather, Kate B. Cook, Amy Gaskin, David J. Williams, Shaun R. Seaman, Christopher I. Jones, Gilberto Betancor, Matthew T. G. Holden, Jennifier Liddle, Meera Unnikrishnan, Angie Green, Ben Taylor, Kelly Bicknell, Alexander J. Trotter, Emma Meader, Leanne M Kermack, Nathaniel Storey, Michelle Cronin, Sally Forrest, Sarah Jeremiah, Asad Zaidi, M Morgan, Alasdair MacLean, Thomas R. Connor, Johnathan M Evans, Rachael Stanley, Ryan P George, Nadine Holmes, Richard H. Myers, Christine Sambles, Bernardo Gutierrez, Jeffrey K. J. Cheng, Tim Wyatt, Natasha Jesudason, Lindsay Coupland, Monika Pusok, Manon Ragonnet-Cronin, Jenifer Mason, Joshua Maksimovic, Russell Hope, Alison Holmes, David Simpson, Radoslaw Poplawski, Amelia Joseph, Erwan Acheson, James Bonfield, Mara K. N. Lawniczak, Sascha Ott, Lesley-Anne Williams, Jessica Lynch, Graham P. Taylor, Anita Kenyon, Elizabeth Wastenge, Megan Mayhew, Adhyana I K Mahanama, Stavroula F Louka, Chloe Bishop, Esther Robinson, Darren Smith, Anne M. Presanis, Matthew Carlile, Thomas D Stanton, Dennis Wang, Katerina Galai, Adam P Westhorpe, Flavia Flaviani, Michelle Wantoch, Max Whiteley, Yann Bourgeois, Matthew Gemmell, Mary Ramsay, A Lloyd, Simon Thelwall, Hannah C. Howson-Wells, Joseph G. Chappell, Steve Paterson, Gary Eltringham, Robert Impey, Siddharth Mookerjee, Steven Platt, Emma Swindells, Laura Letchford, Alex Alderton, Lee Graham, Safiah Afifi, David C. Lee, Cassie Breen, Melisa Louise Fenton, Benita Percival, Adrian W Signell, Tanya Golubchik, Ian B Vipond, Eleri Wilson-Davies, Angie Lackenby, Laura Atkinson, Sarojini Pandey, Nazreen F. Hadjirin, Michael A Chapman, Huw Gulliver, Joana Dias, Grant Hall, Antony D Hale, Hassan Hartman, Alp Aydin, Louise Smith, Ashok Dadrah, Johnny Debebe, Sarah Walsh, Stephanie W. Lo, Andrew Bosworth, Bridget Knight, Hannah E Bridgewater, Nadua Bayzid, Gemma L. Kay, Richard Gregory, Sally Kay, Ellena Brooks, Andre Charlett, Georgina M McManus, Riaz Jannoo, Victoria Blakey, Carol Scott, Rachel Nelson, Liz Ratcliffe, Gerry Tonkin-Hill, Verity Hill, Joanne D. Stockton, Danielle Leek, Steven Leonard, Stephanie Hutchings, Jonathan D. Moore, Kathryn Ann Harris, Sophie Jones, Venkat Sivaprakasam, Amy Plimmer, Tanzina Haque, Katherine L. Bellis, Khalil Abudahab, Dianne Irish-Tavares, Gaia Nebbia, Kathryn A Jackson, Stephen W Attwood, Daniel Mair, Sreenu Vattipally, Susanne Stonehouse, Ian Merrick, Lucille Rainbow, Mathew A. Beale, Angela Helen Beckett, Ember Hilvers, Thomas Helmer, Jenna Nichols, Giselda Bucca, Salman Goudarzi, Christopher Ruis, Surendra Parmar, Angela Cowell, Alberto C Cerda, Divya K. Shah, Judith Heaney, E. Thomson, Kyriaki Nomikou, Nicole Pacchiarini, Katherine L Harper, Fatima Downing, M. Estée Török, Michelle L Michelsen, Aaron R. Jeffries, Jennifer Collins, Christopher Williams, Katie F. Loveson, Steven Rudder, Theocharis Tsoleridis, Robert Davies, David Robertson, Katherine Smollett, Kathryn McCluggage, Liam Crawford, Inigo Martincorena, Charlotte Beaver, Oliver Megram, Karla Spellman, Sam Haldenby, Emma Betteridge, William D. Fuller, Will P. M. Rowe, Cherian Koshy, Tim E. A. Peto, Alison Cox, Natasha Johnson, Tanya Curran, Sharif Shaaban, Tamyo Mbisa, Cordelia Langford, Eric Witele, Andrew J. Page, Christoph Puethe, Nicola Reynolds, Paul W Bird, Louise Aigrain, Ronan Lyons, Amy Trebes, Sally Corden, Steven Rushton, Jack Cd Lee, Jane Greenaway, Hibo Asad, Amanda Bradley, Mohammed O Hassan-Ibrahim, Shane McCarthy, Fei Sang, Matthew Loose, Hannah Jones, Keith D. James, Chloe L Fisher, Chrystala Constantinidou, Alex G. Richter, Jane A. H. Masoli, Michael Gallagher, Vicki M. Fleming, Anna Price, Amy Ash, Michaela John, Alex Zarebski, Fenella D. Halstead, John Danesh, Christine Kitchen, Aminu S Jahun, Mark Whitehead, Julianne R Brown, Catherine Bresner, Marius Cotic, Stefanie V Lensing, Nick Levene, Louissa R Macfarlane-Smith, Wendy Hogsden, Cressida Auckland, Eleanor Drury, Richard Eccles, Jennifer Hart, Seema Nickbakhsh, Alisha Davies, David M. Aanensen, Shirelle Burton-Fanning, Ben Farr, Buddhini Samaraweera, Sarah Wyllie, Hannah Lowe, Richard J. Orton, Martin D. Curran, Carol Churcher, Karen Oliver, Elihu Aranday-Cortes, Wen Yew, Thanh Le-Viet, Matthew Parker, Katherine A Twohig, Shahjahan Miah, Samuel M. Nicholls, G MacIntyre-Cockett, Tranprit Saluja, Charlotte Nelson, Vicki Chalker, Roberto Amato, Ellen Higginson, Timothy M. Freeman, Christopher W Holmes, Yasmin Chaudhry, Elias Allara, Alec Birchley, Iraad Bronner, Emma Moles-Garcia, Angus I. Best, Anna L. Casey, Audrey Farbos, Nicholas W Machin, David W Eyre, Tim Boswell, Charlotte A Williams, Elen De Lacy, Matthew J. Bull, Matilde Mori, Carmen F. Manso, Peijun Zhang, Sahar Eldirdiri, Dimitris Grammatopoulos, Corin Yeats, Claudia Wierzbicki, David G Partridge, Kordo Saeed, Nichola Duckworth, David J. Studholme, Harmeet K Gill, Juan Ledesma, Thomas R. A. Davis, Sushmita Sridhar, Clive Graham, Husam Osman, Julian A. Hiscox, Helen Adams, Christopher Fearn, Fabrícia F. Nascimento, Ulf Schaefer, James W. Harrison, Andrew J. Nelson, Joshua Quick, Mohammad Tauqeer Alam, Liam Prestwood, Nikos Manesis, Julian Tang, Justin O'Grady, Sophia T Girgis, Louise Berry, Gemma Clark, Marina Escalera Zamudio, Karlie Fallon, Tim J Sloan, Joanne Watkins, Clare Pearson, Andrew D Beggs, Rachel Williams, Luke Bedford, Trevor Robinson, Nicholas M Redshaw, Richard Hopes, Mirko Menegazzo, Katherine Twohig, Gabrielle Vernet, Steven Liggett, Mariateresa de Cesare, Derrick W. Crook, Dominic P. Kwiatkowski, Mark Kristiansen, Miren Iturriza-Gomara, Christopher I. Moore, Claire Cormie, Olivia Boyd, Nikki Smith, Noel Craine, Kathleen A. Williamson, John Boyes, Sian Ellard, Cristina V. Ariani, Wendy Chatterton, David Bonsall, Kevin Lewis, David Jorgensen, Ian Harrison, Christopher Jackson, Martin P McHugh, Danni Weldon, Michael A. Quail, Amita Patel, Lily Geidelberg, Myra Hosmillo, Judith Breuer, Cariad Evans, Edward Barton, Trudy Workman, Derek Fairley, Vineet Patel, Daniel Bradshaw, Robin Manley, Scott Aj Thurston, John Sillitoe, Monique Andersson, Sharon J. Peacock, Jamie Lopez-Bernal, Thomas Thompson, Nabil-Fareed Alikhan, Ben Temperton, Paul Baker, Robin J Moll, Laura Gifford, Nicholas J. Loman, Jayna Raghwani, Jacqui Prieto, Andrew Hesketh, Oliver G. Pybus, Adela Alcolea-Medina, David Buck, Gregory R Young, Alistair C. Darby, Sónia Gonçalves, Aileen G. Rowan, Tabitha Mahungu, Nicholas Ellaby, Jon-Paul Keatley, Lily Tong, Robert Beer, Martyn Guest, Lisa J Levett, Ali R Awan, Iliana Georgana, Paul E Brown, Li Xu-McCrae, Stephen P. Kidd, Sara Rey, Shazaad Ahmad, Danielle C. Groves, Tetyana I. Vasylyeva, David F. Bibby, Nathan Moore, Fiona Ashcroft, Igor Starinskij, Hannah Paul, Claire McMurray, Michael Spencer Chapman, Carlos Balcazar, Joanna Warwick-Dugdale, Pinglawathee Madona, Edith Vamos, Lesley Shirley, Kate Templeton, Luke Foulser, Igor Siveroni, Ewan M. Harrison, Sian Morgan, Diana Rajan, S Taylor, Laia Fina, Naomi Park, Sarah J. O'Brien, Alessandro M Carabelli, Angela Marchbank, Sunando Roy, Leonardo de Oliveira Martins, Steve Palmer, Jonathan Hubb, Alexander J Keeley, Francesc Coll, Malorie Perry, Paul J. Parsons, Anthony Underwood, Patawee Asamaphan, William L Hamilton, Tommy Nyberg, Sophie Palmer, Amanda Symmonds, Anoop Chauhan, Robert Johnson, Christopher J. R. Illingworth, James Shepherd, Wendy Smith, Rich Livett, Rachel Blacow, Margaret Hughes, Jeremy Mirza, Joanne Watts, Jonathan D. Edgeworth, Sarah François, Sue Edwards, Adrienn Angyal, Thomas N. Williams, Marta Gallis, Lauren Gilbert, Paul Randell, Kate Johnson, Eileen Gallagher, Nick Cortes, Yusri Taha, Leah Ensell, Emanuela Pelosi, Stefan Rooke, Michelle Lister, Ana da Silva Filipe, Cassandra S Malone, Themoula Charalampous, Benjamin B Lindsey, Natalie Groves, Colin Smith, Ross J Harris, Rebekah E Wilson, Stephen Bonner, Richard Stark, Sharon Campbell, Nicola Sheriff, Helen L Lowe, Rachel Jones, Ben Warne, Rose K Davidson, Declan Bradley, Ian Johnston, Jeffrey C. Barrett, Joshua B Singer, Shirin Aliabadi, Andrew Whitwham, Patrick McClure, Samuel Robson, Sharon Glaysher, Robert J. Munn, Emma L. Wise, Laura Baxter, Kim S Smith, Catherine Moore, Bree Gatica-Wilcox, Alice Broos, Sarah Essex, David Baker, Manjinder Khakh, Dorota Jamrozy, Rachel Tucker, Ian Goodfellow, S.E. Moses, Nicola Cumley, Robin Howe, Meera Chand, James I. Price, Marina Gourtovaia, Debra Padgett, Jaime Tovar-Corona, Stephen L. Michell, Matthew J. Dorman, Lizzie Meadows, David Heyburn, Iona Willingham, Rocio Martinez Nunez, Grace Taylor-Joyce, Claire M Bewshea, Anita Justice, Simon Cottrell, Rebecca C H Brown, Jamie Young, Gavin Dabrera, Matthew Wyles, Stephen Carmichael, Lisa Berry, Frances Bolt, Andrew Rambaut, Samir Dervisevic, Erik M. Volz, Rahul Batra, Caoimhe McKerr, Samantha McGuigan, Katie Jones, Mailis Maes, Rebecca Dewar, Mary Sinnathamby, Joel Southgate, and Lynn Monaghan
Subjects: medicine.medical_specialty, business.industry, Proportional hazards model, Public health, Hazard ratio, Attendance, C500, Vaccination, Infectious Diseases, Relative risk, Internal medicine, Cohort, medicine, business, Cohort study
Abstract: Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.
Published: 2022

44. 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

45. Dietary fatty acids, macronutrient substitutions, food sources and incidence of coronary heart disease: Findings from the EPIC-CVD case-cohort study across nine european countries

Author: Matthias B. Schulze, Vittorio Krogh, Rosario Tumino, Nita G. Forouhi, Christina C. Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Angela M. Wood, Yvonne T. van der Schouw, Guri Skeie, Laura Johnson, Fumiaki Imamura, Ivonne Sluijs, José R Quirós, Elisabete Weiderpass, Nicholas J. Wareham, Timothy J. Key, Adam S. Butterworth, Giovanna Masala, Alicia K Heath, Albert Koulman, Conchi Moreno-Iribas, Inge Huybrechts, John Danesh, Stephen J. Sharp, Salvatore Panico, Carlotta Sacerdote, Aurora Perez-Cornago, Olle Melander, Rudolf Kaaks, Elio Riboli, Tammy Y.N. Tong, María José Sánchez, Rajiv Chowdhury, Ju-Sheng Zheng, Miguel Rodríguez-Barranco, W M Monique Verschuren, Marinka Steur, Ingegerd Johansson, Heiner Boeing, Anne Tjønneland, Carmen Santiuste, Antonia Trichopoulou, Maria Wennberg, Jolanda M. A. Boer, Marcela Guevara, Cecilie Kyrø, Raul Zamora-Ros, Liher Imaz, Tilman Kühn, Marianne Uhre Jakobsen, Ulrika Ericson, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, G0800270, MR/L003120/1, Pfizer, AstraZeneca, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, Merck Sharp and Dohme, MSD, Seventh Framework Programme, FP7: HEALTH-F2-2012-279233, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MC_UU_00006/1, National Institute for Health Research, NIHR, British Heart Foundation, BHF: RG/18/13/33946, RG13/13/30194, SP/09/002, Cancer Research UK, CRUK: C8221/A29017, MR/M012190/1, World Cancer Research Fund, WCRF, Imperial College London, European Research Council, ERC: 268834, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, European Social Fund, ESF, Sixth Framework Programme, FP6: LSHM_CT_2006_037197, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Akademi Sains Malaysia, ASM: MR/P013880/1, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, UCLH Biomedical Research Centre, NIHR BRC: BRC-1215-20014, NIHR Imperial Biomedical Research Centre, BRC, Hellenic Health Foundation, HHF: CP15/00100, IS-BRC-1215-20014, MC_UU_00006/3, Dr Danesh reports grants, personal fees and non-financial support from Merck Sharp & Dohme, grants, personal fees, and nonfinancial support from Novartis, grants from Pfizer, and grants from AstraZeneca outside the submitted work. He is member of the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis, and the Astra Zeneca Genomics Advisory Board (2018). Dr Butterworth reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer, and Sanofi and personal fees from Novartis. The remaining authors have no disclosures to report., EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270, MR/L003120/1), British Heart Foundation (BHF) (SP/09/002, RG13/13/30194, RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands), Health Research Fund– Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R.Z.-R. thanks the 'Miguel Servet' program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund–European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart). R.C. was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award., Steur, Marinka [0000-0002-9028-0290], Imamura, Fumiaki [0000-0002-6841-8396], Key, Timothy J [0000-0003-2294-307X], Chowdhury, Rajiv [0000-0003-4881-5690], Guevara, Marcela [0000-0001-9242-6364], Jakobsen, Marianne U [0000-0001-6518-4136], Johansson, Ingegerd [0000-0002-9227-8434], Weiderpass, Elisabete [0000-0003-2237-0128], Boer, Jolanda MA [0000-0002-9714-4304], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Heath, Alicia K [0000-0001-6517-1300], Huybrechts, Inge [0000-0003-3838-855X], Imaz, Liher [0000-0002-3777-4953], Masala, Giovanna [0000-0002-5758-9069], Zamora-Ros, Raul [0000-0002-6236-6804], Perez-Cornago, Aurora [0000-0002-5652-356X], Tong, Tammy YN [0000-0002-0284-8959], Wareham, Nicholas J [0000-0003-1422-2993], Forouhi, Nita G [0000-0002-5041-248X], and Apollo - University of Cambridge Repository
Subjects: Saturated fat, Physiology, Coronary Disease, 030204 cardiovascular system & hematology, EPIC, Cohort Studies, 0302 clinical medicine, Medicine, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, 2. Zero hunger, chemistry.chemical_classification, Nutrition and Dietetics, Kardiologi, Primary prevention, Incidence, Incidence (epidemiology), Fatty Acids, Fatty acids in human nutrition, 3. Good health, Europe, Näringslära, Coronary heart disease, Dietary guidelines, Cardiology and Cardiovascular Medicine, Polyunsaturated fatty acid, Cohort study, Malalties coronàries, 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Àcids grassos en la nutrició, Diseases of the circulatory (Cardiovascular) system, Humans, Nutritional epidemiology, business.industry, Nutrients, Dietary Fats, chemistry, Food, RC666-701, SPS Exercise, Nutrition and Health Sciences, business
Abstract: EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award
Published: 2021

46. Genetically predicted levels of the human plasma proteome and risk of stroke: a Mendelian Randomization study

Author: Adam S. Butterworth, Cathryn M. Lewis, John Danesh, Nicholas A. Watkins, James E. Peters, Lingyan Chen, David J. Roberts, Matthew Traylor, Praveen Surendran, Stephen Burgess, Joanna M. M. Howson, Emanuele Di Angelantonio, Willem H. Ouwehand, Elodie Persyn, Hugh S. Markus, Paola G. Bronson, Ekaterina Yonova-Doing, Bram Prins, and Savita Karthikeyan
Subjects: Blood pressure, business.industry, Mendelian randomization, medicine, Genome-wide association study, Atrial fibrillation, Type 2 diabetes, medicine.disease, Bioinformatics, business, Stroke, Body mass index, Hyperintensity
Abstract: Proteins are the effector molecules of biology and are the target of most drugs. To identify proteins and related pathways that may play a causal role in stroke pathogenesis, we used Mendelian randomisation (MR). We tested potential causal effects of 308 plasma proteins (measured in 4,994 blood donors from the INTERVAL study) on stroke outcomes (derived from the MEGASTROKE GWAS) in a two-sample MR framework and assessed whether these associations could be mediated by cardiovascular risk factors. We extended the analysis to identify whether pharmacological targeting of these proteins might have potential adverse side-effects or beneficial effects for other conditions through Phenome-wide MR (Phe-MR) in UK Biobank. MR showed an association between stroke and genetically predicted plasma levels of TFPI, IL6RA, MMP12, CD40, TMPRSS5 and CD6 (P≤1.62⋅10−4). We identified six risk factors (atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes) that were associated with stroke (P≤0.0071) using MR. The association of TFPI, IL6RA and TMPRSS5 with stroke could be mediated by these risk factors, such as body mass index, white matter hyperintensity and atrial fibrillation. Thirty-six additional proteins were potentially causal for one or more of these risk factors. The Phe-MR suggested that targeting TFPI could have potential beneficial effects on other disorders of arteries and hyperlipidaemia in addition to stroke. Our results highlight novel causal pathways and potential therapeutic targets for stroke.
Published: 2021

47. COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

Author: Johan H Thygesen, Christopher Tomlinson, Sam Hollings, Mehrdad A Mizani, Alex Handy, Ashley Akbari, Amitava Banerjee, Jennifer Cooper, Alvina G Lai, Kezhi Li, Bilal A Mateen, Naveed Sattar, Reecha Sofat, Ana Torralbo, Honghan Wu, Angela Wood, Jonathan A C Sterne, Christina Pagel, William N Whiteley, Cathie Sudlow, Harry Hemingway, Spiros Denaxas, Hoda Abbasizanjani, Nida Ahmed, Badar Ahmed, Abdul Qadr Akinoso-Imran, Elias Allara, Freya Allery, Emanuele Di Angelantonio, Mark Ashworth, Vandana Ayyar-Gupta, Sonya Babu-Narayan, Seb Bacon, Steve Ball, Ami Banerjee, Mark Barber, Jessica Barrett, Marion Bennie, Colin Berry, Jennifer Beveridge, Ewan Birney, Lana Bojanić, Thomas Bolton, Anna Bone, Jon Boyle, Tasanee Braithwaite, Ben Bray, Norman Briffa, David Brind, Katherine Brown, Maya Buch, Dexter Canoy, Massimo Caputo, Raymond Carragher, Alan Carson, Genevieve Cezard, Jen-Yu Amy Chang, Kate Cheema, Richard Chin, Yogini Chudasama, Emma Copland, Rebecca Crallan, Rachel Cripps, David Cromwell, Vasa Curcin, Gwenetta Curry, Caroline Dale, John Danesh, Jayati Das-Munshi, Ashkan Dashtban, Alun Davies, Joanna Davies, Gareth Davies, Neil Davies, Joshua Day, Antonella Delmestri, Rachel Denholm, John Dennis, Alastair Denniston, Salil Deo, Baljean Dhillon, Annemarie Docherty, Tim Dong, Abdel Douiri, Johnny Downs, Alexandru Dregan, Elizabeth A Ellins, Martha Elwenspoek, Fabian Falck, Florian Falter, Yat Yi Fan, Joseph Firth, Lorna Fraser, Rocco Friebel, Amir Gavrieli, Moritz Gerstung, Ruth Gilbert, Clare Gillies, Myer Glickman, Ben Goldacre, Raph Goldacre, Felix Greaves, Mark Green, Luca Grieco, Rowena Griffiths, Deepti Gurdasani, Julian Halcox, Nick Hall, Tuankasfee Hama, Anna Hansell, Pia Hardelid, Flavien Hardy, Daniel Harris, Camille Harrison, Katie Harron, Abdelaali Hassaine, Lamiece Hassan, Russell Healey, Angela Henderson, Naomi Herz, Johannes Heyl, Mira Hidajat, Irene Higginson, Rosie Hinchliffe, Julia Hippisley-Cox, Frederick Ho, Mevhibe Hocaoglu, Elsie Horne, David Hughes, Ben Humberstone, Mike Inouye, Samantha Ip, Nazrul Islam, Caroline Jackson, David Jenkins, Xiyun Jiang, Shane Johnson, Umesh Kadam, Costas Kallis, Zainab Karim, Jake Kasan, Michalis Katsoulis, Kim Kavanagh, Frank Kee, Spencer Keene, Seamus Kent, Sara Khalid, Anthony Khawaja, Kamlesh Khunti, Richard Killick, Deborah Kinnear, Rochelle Knight, Ruwanthi Kolamunnage-Dona, Evan Kontopantelis, Amanj Kurdi, Ben Lacey, Alvina Lai, Andrew Lambarth, Milad Nazarzadeh Larzjan, Deborah Lawler, Thomas Lawrence, Claire Lawson, Qiuju Li, Ken Li, Miguel Bernabeu Llinares, Paula Lorgelly, Deborah Lowe, Jane Lyons, Ronan Lyons, Pedro Machado, Mary Joan Macleod, John Macleod, Evaleen Malgapo, Mamas Mamas, Mohammad Mamouei, Sinduja Manohar, Rutendo Mapeta, Javiera Leniz Martelli, David Moreno Martos, Bilal Mateen, Aoife McCarthy, Craig Melville, Rebecca Milton, Mehrdad Mizani, Marta Pineda Moncusi, Daniel Morales, Ify Mordi, Lynn Morrice, Carole Morris, Eva Morris, Yi Mu, Tanja Mueller, Lars Murdock, Vahé Nafilyan, George Nicholson, Elena Nikiphorou, John Nolan, Tom Norris, Ruth Norris, Laura North, Teri-Louise North, Dan O'Connell, Dominic Oliver, Adejoke Oluyase, Abraham Olvera-Barrios, Efosa Omigie, Sarah Onida, Sandosh Padmanabhan, Tom Palmer, Laura Pasea, Riyaz Patel, Rupert Payne, Jill Pell, Carmen Petitjean, Arun Pherwani, Owen Pickrell, Livia Pierotti, Munir Pirmohamed, Rouven Priedon, Dani Prieto-Alhambra, Alastair Proudfoot, Terry Quinn, Jennifer Quint, Elena Raffetti, Kazem Rahimi, Shishir Rao, Cameron Razieh, Brian Roberts, Caroline Rogers, Jennifer Rossdale, Safa Salim, Nilesh Samani, Christian Schnier, Roy Schwartz, David Selby, Olena Seminog, Sharmin Shabnam, Ajay Shah, Jon Shelton, James Sheppard, Shubhra Sinha, Mirek Skrypak, Martina Slapkova, Katherine Sleeman, Craig Smith, Filip Sosenko, Matthew Sperrin, Sarah Steeg, Jonathan Sterne, Serban Stoica, Maria Sudell, Luanluan Sun, Arun Karthikeyan Suseeladevi, Michael Sweeting, Matt Sydes, Rohan Takhar, Howard Tang, Johan Thygesen, George Tilston, Claire Tochel, Clea du Toit, Renin Toms, Fatemeh Torabi, Julia Townson, Adnan Tufail, Tapiwa Tungamirai, Susheel Varma, Sebastian Vollmer, Venexia Walker, Tianxiao Wang, Huan Wang, Alasdair Warwick, Ruth Watkinson, Harry Watson, William Whiteley, Hannah Whittaker, Harry Wilde, Tim Wilkinson, Gareth Williams, Michelle Williams, Richard Williams, Eloise Withnell, Charles Wolfe, Lucy Wright, Jinge Wu, Jianhua Wu, Tom Yates, Francesco Zaccardi, Haoting Zhang, Huayu Zhang, Luisa Zuccolo, Apollo - University of Cambridge Repository, Consortium, Longitudinal Health and Wellbeing COVID-19 National Core Study and the CVD-COVID-UK/COVID-IMPACT, and Khalid, S
Subjects: SARS-CoV-2, Medicine (miscellaneous), COVID-19, Health Informatics, State Medicine, Cohort Studies, COVID-19 Testing, Health Information Management, England, Longitudinal Health and Wellbeing COVID-19 National Core Study and the CVD-COVID-UK/COVID-IMPACT Consortium, Electronic Health Records, Humans, Decision Sciences (miscellaneous), England/epidemiology, COVID-19/epidemiology
Abstract: Background Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. Methods In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. Findings Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. Interpretation Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. Funding British Heart Foundation Data Science Centre, led by Health Data Research UK.
Published: 2021

48. 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

49. Genetic Contributions to Early and Late Onset Ischemic Stroke

Author: Cristina Sanchez-Mora, Jie Hu, Philippe Amouyel, Annette Peters, Charles C Hong, Mary Cushman, Kathleen A. Ryan, Jiang Li, Liming Li, Thomas Jaworek, Sylvia Wassertheil-Smoller, Tiina Metso, Martin Soderholm, Kathryn M. Rexrode, Nicholas L. Smith, Jane Maguire, Martina Müller-Nurasyid, Agnieszka Slowik, Marguerite R. Irvin, Adam S. Butterworth, Martin O’Donnell, Leema Reddy Peddareddygari, Rainer Malik, Ralph L. Sacco, Brady Gaynor, Christian Geiger, Debashree Ray, Anne-Katrin Giese, John W. Cole, Jon Peter Durda, Vincent Thijs, Jukka Putaala, Michiaki Kubo, O. Colin Stine, Rebecca D. Jackson, Israel Fernandez-Cadenas, Reinhold Schmidt, Aki S. Havulinna, Kuang Lin, Christopher Levi, Steven Bell, Timothy O’Connor, Daniel Woo, Jara Cárcel-Márquez, Braxton D. Mitchell, Christina Jern, Jonathan Rosand, Sharon L.R. Kardia, Pankaj Sharma, Mina A. Jacob, Masaru Koido, Vida Abedi, Yoichiro Kamatani, Kristiina Rannikmäe, Michael Chong, Nuria P. Torres-Aguila, Cathie L. M. Sudlow, Ramin Zand, Elizabeth Holliday, Tatjana Rundek, Jessica D. Faul, Leslie Lange, Gunnar Engstrom, Marc C. Hochberg, Bradford B. Worrall, Hugh S. Markus, Joanna Pera, Jordi Jimenez-Conde, Caitrin W. McDonough, Raji P. Grewal, Owen Ross, Robin G. Walters, David J. Duggan, Guillaume Paré, Turgut Tatlisumak, Laura Heitsch, Jin-Moo Lee, Natalie Fecteau, Robin Lemmens, Jennifer A. Smith, Daniel Strbian, Patrick F. McArdle, Martin Dichgans, Jan H. Veldink, Liisa Tomppo, Arne G. Lindgren, Zhengming Chen, Chikashi Terao, Ulrike Grittner, Marta Ribasés, David R. Weir, James F. Meschia, Sothear Luke, Raquel Rabionet Janssen, Tara M. Stanne, Stephanie Debette, Nicole D. Armstrong, James A. Perry, Julie A. Johnson, Huichun Xu, Christopher D. Anderson, Giorgio B. Boncoraglio, Christian Enzinger, Haley Lopez, Anil Man Tuladhar, Oscar R. Benavente, Veikko Salomaa, David-Alexandre Trégouët, John Danesh, F-E de Leeuw, John Attia, Peter M. Rothwell, Steven J. Kittner, Andreea Ilinca, and Carlos Cruchaga
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Late onset, Locus (genetics), 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, Venous thrombosis, 0302 clinical medicine, ABO blood group system, Internal medicine, Ischemic stroke, medicine, Cardiology, SNP, business, Stroke, 030304 developmental biology, Genetic association
Abstract: ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.
Published: 2021

50. 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

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