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

Author

Zheng, Jie, Haberland, Valeriia, Baird, Denis, Walker, Venexia, Haycock, Philip C., Hurle, Mark R., Gutteridge, Alex, Erola, Pau, Liu, Yi, Luo, Shan, Robinson, Jamie, Richardson, Tom G., Staley, James R., Elsworth, Benjamin, Burgess, Stephen, Sun, Benjamin B., Danesh, John, Runz, Heiko, Maranville, Joseph C., Martin, Hannah M., Yarmolinsky, James, Laurin, Charles, Holmes, Michael V., Liu, Jimmy Z., Estrada, Karol, Santos, Rita, McCarthy, Linda, Waterworth, Dawn, Nelson, Matthew R., Smith, George Davey, Butterworth, Adam S., Hemani, Gibran, Scott, Robert A., and Gaunt, Tom R.

Published
2020
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7. Genomic atlas of the human plasma proteome

Author

Sun, Benjamin B., Maranville, Joseph C., Peters, James E., Stacey, David, Staley, James R., Blackshaw, James, and Burgess, Stephen

Subjects
Blood plasma -- Physiological aspects, Proteomics -- Methods, Respiratory system agents, Gene expression, Genes, Disease susceptibility, Biological markers, Blood donation, Blood proteins, Quantitative genetics, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets., Author(s): Benjamin B. Sun [sup.1] , Joseph C. Maranville [sup.2] [sup.20] , James E. Peters [sup.1] [sup.3] , David Stacey [sup.1] , James R. Staley [sup.1] , James Blackshaw [sup.1] [...]

Published
2018
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8. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Gaziano, Liam, primary, Sun, Luanluan, additional, Arnold, Matthew, additional, Bell, Steven, additional, Cho, Kelly, additional, Kaptoge, Stephen K., additional, Song, Rebecca J., additional, Burgess, Stephen, additional, Posner, Daniel C., additional, Mosconi, Katja, additional, Robinson-Cohen, Cassianne, additional, Mason, Amy M., additional, Bolton, Thomas R., additional, Tao, Ran, additional, Allara, Elias, additional, Schubert, Petra, additional, Chen, Lingyan, additional, Staley, James R., additional, Staplin, Natalie, additional, Altay, Servet, additional, Amiano, Pilar, additional, Arndt, Volker, additional, Ärnlöv, Johan, additional, Barr, Elizabeth L.M., additional, Björkelund, Cecilia, additional, Boer, Jolanda M.A., additional, Brenner, Hermann, additional, Casiglia, Edoardo, additional, Chiodini, Paolo, additional, Cooper, Jackie A., additional, Coresh, Josef, additional, Cushman, Mary, additional, Dankner, Rachel, additional, Davidson, Karina W., additional, de Jongh, Renate T., additional, Donfrancesco, Chiara, additional, Engström, Gunnar, additional, Freisling, Heinz, additional, de la Cámara, Agustín Gómez, additional, Gudnason, Vilmundur, additional, Hankey, Graeme J., additional, Hansson, Per-Olof, additional, Heath, Alicia K., additional, Hoorn, Ewout J., additional, Imano, Hironori, additional, Jassal, Simerjot K., additional, Kaaks, Rudolf, additional, Katzke, Verena, additional, Kauhanen, Jussi, additional, Kiechl, Stefan, additional, Koenig, Wolfgang, additional, Kronmal, Richard A., additional, Kyrø, Cecilie, additional, Lawlor, Deborah A., additional, Ljungberg, Börje, additional, MacDonald, Conor, additional, Masala, Giovanna, additional, Meisinger, Christa, additional, Melander, Olle, additional, Moreno Iribas, Conchi, additional, Ninomiya, Toshiharu, additional, Nitsch, Dorothea, additional, Nordestgaard, Børge G., additional, Onland-Moret, Charlotte, additional, Palmieri, Luigi, additional, Petrova, Dafina, additional, Garcia, Jose Ramón Quirós, additional, Rosengren, Annika, additional, Sacerdote, Carlotta, additional, Sakurai, Masaru, additional, Santiuste, Carmen, additional, Schulze, Matthias B., additional, Sieri, Sabina, additional, Sundström, Johan, additional, Tikhonoff, Valérie, additional, Tjønneland, Anne, additional, Tong, Tammy, additional, Tumino, Rosario, additional, Tzoulaki, Ioanna, additional, van der Schouw, Yvonne T., additional, Monique Verschuren, W.M., additional, Völzke, Henry, additional, Wallace, Robert B., additional, Wannamethee, S. Goya, additional, Weiderpass, Elisabete, additional, Willeit, Peter, additional, Woodward, Mark, additional, Yamagishi, Kazumasa, additional, Zamora-Ros, Raul, additional, Akwo, Elvis A., additional, Pyarajan, Saiju, additional, Gagnon, David R., additional, Tsao, Philip S., additional, Muralidhar, Sumitra, additional, Edwards, Todd L., additional, Damrauer, Scott M., additional, Joseph, Jacob, additional, Pennells, Lisa, additional, Wilson, Peter W.F., additional, Harrison, Seamus, additional, Gaziano, Thomas A., additional, Inouye, Michael, additional, Baigent, Colin, additional, Casas, Juan P., additional, Langenberg, Claudia, additional, Wareham, Nick, additional, Riboli, Elio, additional, Gaziano, J.Michael, additional, Danesh, John, additional, Hung, Adriana M., additional, Butterworth, Adam S., additional, Wood, Angela M., additional, Di Angelantonio, Emanuele, additional, Koettgen, Anna, additional, Shaw, Jonathan, additional, Atkins, Robert, additional, Zimmet, Paul, additional, Whincup, Peter, additional, Willeit, Johann, additional, Leitner, Christoph, additional, Tybjaerg-Hansen, Anne, additional, Schnohr, Peter, additional, Afzal, Shoaib, additional, Pablos, David Lora, additional, Arriscado, Cristina Martin, additional, Ferreiro, Carmen Romero, additional, Stocker, Hannah, additional, Schöttker, Ben, additional, Holleczek, Bernd, additional, Chetrit, Angela, additional, Welin, Lennart, additional, Svärdsudd, Kurt, additional, Lissner, Lauren, additional, Hange, Dominique, additional, Mehlig, Kirsten, additional, Nagel, Dorothea, additional, Norman, Paul E., additional, Almeida, Osvaldo, additional, Flicker, Leon, additional, Hata, Jun, additional, Honda, Takanori, additional, Furuta, Yoshihiko, additional, Iso, Hiroyasu, additional, Kitamura, Akihiko, additional, Muraki, Isao, additional, Salonen, Jukka T., additional, Tuomainen, Tomi-Pekka, additional, van Zutphen, E. M., additional, van Schoor, N. M., additional, Lo Noce, Cinzia, additional, Kronmal, Richard, additional, Lappas, Georg, additional, Nilsson, Peter M., additional, Hedblad, Bo, additional, Shaffer, Jonathan, additional, Schwartz, Joseph, additional, Shimbo, Daichi, additional, Sato, Shinichi, additional, Hayama-Terada, Mina, additional, Jassal, Simerjot, additional, Aspelund, Thor, additional, Thorsson, Bolli, additional, Sigurdsson, Gunnar, additional, Chaker, Layal, additional, Ikram, Kamran M., additional, Kavousi, Maryam, additional, Tunstall-Pedoe, Hugh, additional, Can, Günay, additional, Yüksel, Hüsniye, additional, Özkan, Uğur, additional, Nakagawa, Hideaki, additional, Morikawa, Yuko, additional, Ishizaki, Masao, additional, Feskens, Edith, additional, Geleijnse, Johanna M, additional, and Kromhout, Daan, additional

Published
2022
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9. The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study

Author

Borges, Maria-Carolina, primary, Haycock, Phillip, additional, Zheng, Jie, additional, Hemani, Gibran, additional, Howe, Laurence J, additional, Schmidt, A Floriaan, additional, Staley, James R, additional, Lumbers, R Thomas, additional, Henry, Albert, additional, Lemaitre, Rozenn N, additional, Gaunt, Tom R, additional, Holmes, Michael V, additional, Davey Smith, George, additional, Hingorani, Aroon D, additional, and Lawlor, Deborah A, additional

Published
2022
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10. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease : Observational and Mendelian Randomization Analyses

Author

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, Elias, 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 Quirós, 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, Seamus, 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, 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, Elias, 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 Quirós, 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, Seamus, 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, and Di Angelantonio, Emanuele

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 <60 or >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 <60 mL·min-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 a

Published
2022
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11. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease:Observational and Mendelian Randomization Analyses

Author

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, Elias, 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, Wood, AM, Angelantonio, Emanuele Di, 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, Elias, 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, Wood, AM, and Angelantonio, Emanuele Di

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 <60 or >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 <60 mL·min-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 preventiv

Published
2022

12. The EWAS Catalog: a database of epigenome-wide association studies

Author

Battram, Thomas, primary, Yousefi, Paul, additional, Crawford, Gemma, additional, Prince, Claire, additional, Sheikhali Babaei, Mahsa, additional, Sharp, Gemma, additional, Hatcher, Charlie, additional, Vega-Salas, María Jesús, additional, Khodabakhsh, Sahar, additional, Whitehurst, Oliver, additional, Langdon, Ryan, additional, Mahoney, Luke, additional, Elliott, Hannah R., additional, Mancano, Giulia, additional, Lee, Matthew A., additional, Watkins, Sarah H., additional, Lay, Abigail C., additional, Hemani, Gibran, additional, Gaunt, Tom R., additional, Relton, Caroline L., additional, Staley, James R., additional, and Suderman, Matthew, additional

Published
2022
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13. The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

Author

Borges, Maria Carolina, primary, Haycock, Phillip, additional, Zheng, Jie, additional, Hemani, Gibran, additional, Howe, Laurence J, additional, Schmidt, A Floriaan, additional, Staley, James R, additional, Thomas Lumbers, R, additional, Henry, Albert, additional, Lemaitre, Rozenn N, additional, Gaunt, Tom R, additional, Holmes, Michael V, additional, Smith, George Davey, additional, Hingorani, Aroon D, additional, and Lawlor, Deborah A, additional

Published
2022
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15. The effect of ADHD on physical health outcomes - a two-sample Mendelian randomization study

Author

Leppert, Beate, Riglin, Lucy, Wootton, Robyn E, Dardani, Christina, Thapar, Ajay, Staley, James R, Tilling, Kate, Smith, George Davey, Thapar, Anita, and Stergiakouli, Evie

Subjects
Mendelian Randomization, mental disorders, ADHD, childhood obesity, coronary artery disease
Abstract

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is of great importance because comorbid health problems further increase the serious social and economic impacts of ADHD. We used two-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings were taken forward for bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (OR (Odds Ratio):1.29 (95% CI (Confidence Intervals):1.02,1.63)) and coronary artery disease (OR:1.11(95% CI:1.03,1.19)) with consistent results across MR approaches. There was further MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD. It also suggests that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease.

Published
2021
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17. Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Author

Experimentele Afd. Cardiologie 1, Centraal Diagnostisch Laboratorium, Circulatory Health, Holdsworth, Gill, Staley, James R., Hall, Peter, van Koeverden, Ian, Vangjeli, Ciara, Okoye, Remi, Boyce, Rogely W., Turk, James R., Armstrong, Martin, Wolfreys, Alison, Pasterkamp, Gerard, Experimentele Afd. Cardiologie 1, Centraal Diagnostisch Laboratorium, Circulatory Health, Holdsworth, Gill, Staley, James R., Hall, Peter, van Koeverden, Ian, Vangjeli, Ciara, Okoye, Remi, Boyce, Rogely W., Turk, James R., Armstrong, Martin, Wolfreys, Alison, and Pasterkamp, Gerard

Published
2021

18. The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes:A two-sample Mendelian randomization study

Author

Leppert, Beate, Riglin, Lucy, Wootton, Robyn E, Dardani, Christina, Thapar, Ajay, Staley, James R, Tilling, Kate M, Davey Smith, George, Thapar, Anita, and Stergiakouli , Evie

Subjects
Mendelian Randomization, mental disorders, ADHD, childhood obesity, coronary artery disease
Abstract

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is important because comorbid health problems increase the serious social and economic impacts of ADHD. We used 2-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings underwent bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (odds ratio = 1.29, 95% confidence interval: 1.02, 1.63) and coronary artery disease (odds ratio = 1.11, 95% confidence interval: 1.03, 1.19) with consistent results across MR approaches. There was additional MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic, and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD, and suggest that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease.

Published
2020
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19. Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants, or Locally in Atherosclerotic Plaques, Does Not Associate With Cardiovascular Events in Humans

Author

Holdsworth, Gill, primary, Staley, James R, additional, Hall, Peter, additional, Koeverden, Ian, additional, Vangjeli, Ciara, additional, Okoye, Remi, additional, Boyce, Rogely W, additional, Turk, James R, additional, Armstrong, Martin, additional, Wolfreys, Alison, additional, and Pasterkamp, Gerard, additional

Published
2021
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20. Human serum proteome profoundly overlaps with genetic signatures of disease

Author

Emilsson, Valur, Gudmundsdottir, Valborg, Ilkov, Marjan, Staley, James R., Gudjonsson, Alexander, Gudmundsson, Elias F., Launer, Lenore J., Lindeman, Jan H., Morton, Nicholas M., Aspelund, Thor, Lamb, John R., Jennings, Lori L., and Gudnason, Vilmundur

Abstract

Circulating proteins are prognostic for human outcomes including cancer, heart failure, brain trauma and brain amyloid plaque burden. A deep serum proteome survey recently revealed close associations of serum protein networks and common diseases. The present study reveals unprecedented number of individual serum proteins that overlap genetic signatures of diseases emanating from different tissues of the body. Here, 55,932 low-frequency and common exome-array variants were compared with 4782 protein measurements in the serum of 5457 individuals of the deeply annotated AGES Reykjavik cohort. At a Bonferroni adjusted P-value threshold < 2.16×10 −10 , 5553 variants affecting levels of 1931 serum proteins were detected. These associated variants overlapped genetic loci for hundreds of complex disease traits, emphasizing the emerging role for serum proteins as biomarkers of and potential causative agents of multiple diseases.

Published
2020
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21. A robust mean and variance test with application to epigenome-wide association studies

Author

Staley, James R, Windmeijer, Frank, Suderman, Matthew, Davey Smith, George, and Tilling, Kate

Abstract

Background Most studies of high-dimensional phenotypes focus on assessing differences in mean levels (location) of the phenotype by exposure, e.g. epigenome-wide association studies of the effect of exposure on mean DNA methylation at CpG sites. However, identifying effects on the variability (scale) of these outcomes could provide additional insights into biological mechanisms. Methods We introduce a scale test, based on the Brown-Forsythe test, for analysing phenotype variability for both categorical and continuous exposures. We also present a novel joint location-and-scale score test (JLSsc). These tests were compared to the equivalent likelihood-ratio tests and alternative approaches in simulations and used to test associations of mean and variability of DNA methylation with gender and gestational age using data from the Accessible Resource for Integrated Epigenomics Studies (ARIES). Results The extended Brown-Forsythe test and JLSsc had good statistical properties for both categorical and continuous exposures, without requiring transformation of the methylation levels. All of the other methods assessed had inflated type I error using the raw methylation levels. In ARIES, JLSsc identified 7228 and 340 CpG sites (240 CpGs were associated with methylation variability differences between males and females using the extended Brown-Forsythe test) that were associated with either mean or variability in gender and gestational age in cord blood, respectively. Conclusions The extended Brown-Forsythe test and JLSsc are robust tests of variability and combined mean and variability effects, respectively. These tests can be used to detect associations not solely driven by a mean effect of the exposure on the outcome.

Published
2020
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22. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Author

Surendran, Praveen, Feofanova, Elena V, Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T, Cartwright, James H, Hellwege, Jacklyn N, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J, Prins, Bram P, Stewart, Isobel D, Cabrera, Claudia P, Eales, James M, Akbarov, Artur, Auer, Paul L, Bielak, Lawrence F, Bis, Joshua C, Braithwaite, Vickie S, Brody, Jennifer A, Daw, E Warwick, Warren, Helen R, Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D, Fauman, Eric B, Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N, Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F, Guo, Xiuqing, Harris, Sarah E, Havulinna, Aki S, Helgadottir, Anna, Huffman, Jennifer E, Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G, Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A, Lu, Yingchang, Luan, Jian'an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas G D, Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O, Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S, Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G, Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V, Smith, Jennifer A, Staley, James R, Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V, Velez Edwards, Digna R, Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M, Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L, Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S, Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, Mutsert, Renée de, Dominiczak, Anna F, Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J Michael, Grarup, Niels, Grove, Megan L, Hallmans, Göran, Hansen, Torben, Have, Christian T, Heiss, Gerardo, Jørgensen, Marit E, Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A, Kovesdy, Csaba P, Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, Linneberg, Allan, Martin, Lisa W, Moitry, Marie, Nadkarni, Girish, Neville, Matt J, Palmer, Colin N A, Papanicolaou, George J, Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L, Rayner, N William, Mägi, Reedik, Renström, Frida, Rettig, Rainer, Rossouw, Jacques, Schreiner, Pamela J, Sever, Peter S, Sigurdsson, Emil L, Skaaby, Tea, Sun, Yan V, Sundström, Johan, Thorgeirsson, Gudmundur, Esko, Tõnu, Trabetti, Elisabetta, Tsao, Philip S, Tuomi, Tiinamaija, Turner, Stephen T, Tzoulaki, Ioanna, Vaartjes, Ilonca, Vergnaud, Anne-Claire, Willer, Cristen J, Wilson, Peter W F, Witte, Daniel R, Yonova-Doing, Ekaterina, Zhang, He, Aliya, Naheed, Almgren, Peter, Amouyel, Philippe, Asselbergs, Folkert W, Barnes, Michael R, Blakemore, Alexandra I, Boehnke, Michael, Bots, Michiel L, Bottinger, Erwin P, Buring, Julie E, Chambers, John C, Chen, Yii-Der Ida, Chowdhury, Rajiv, Conen, David, Correa, Adolfo, Davey Smith, George, Boer, Rudolf A de, Deary, Ian J, Dedoussis, George, Deloukas, Panos, Di Angelantonio, Emanuele, Elliott, Paul, Felix, Stephan B, Ferrières, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Franks, Stephen, Frossard, Philippe, Gambaro, Giovanni, Gaunt, Tom R, Groop, Leif, Gudnason, Vilmundur, Harris, Tamara B, Hayward, Caroline, Hennig, Branwen J, Herzig, Karl-Heinz, Ingelsson, Erik, Tuomilehto, Jaakko, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kardia, Sharon L R, Kee, Frank, Kooner, Jaspal S, Kooperberg, Charles, Launer, Lenore J, Lind, Lars, Loos, Ruth J F, Majumder, Abdulla Al Shafi, Laakso, Markku, McCarthy, Mark I, Melander, Olle, Mohlke, Karen L, Murray, Alison D, Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J, Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J, Prentice, Andrew M, Province, Michael A, Relton, Caroline L, Rice, Kenneth, Ridker, Paul M, Rolandsson, Olov, Rosendaal, Frits R, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sattar, Naveed, Sheu, Wayne H-H, Smith, Blair H, Soranzo, Nicole, Spector, Timothy D, Starr, John M, Sebert, Sylvain, Taylor, Kent D, Lakka, Timo A, Timpson, Nicholas J, Tobin, Martin D, van der Harst, Pim, van der Meer, Peter, Ramachandran, Vasan S, Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R, Zeggini, Eleftheria, Charchar, Fadi J, Wareham, Nicholas J, Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S, Caulfield, Mark J, Danesh, John, Edwards, Todd L, Holm, Hilma, Hung, Adriana M, Lindgren, Cecilia M, Liu, Chunyu, Manning, Alisa K, Morris, Andrew P, Morrison, Alanna C, O'Donnell, Christopher J, Psaty, Bruce M, Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I, Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B, Howson, Joanna M M, Surendran, Praveen, Feofanova, Elena V, Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T, Cartwright, James H, Hellwege, Jacklyn N, Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J, Prins, Bram P, Stewart, Isobel D, Cabrera, Claudia P, Eales, James M, Akbarov, Artur, Auer, Paul L, Bielak, Lawrence F, Bis, Joshua C, Braithwaite, Vickie S, Brody, Jennifer A, Daw, E Warwick, Warren, Helen R, Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D, Fauman, Eric B, Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N, Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F, Guo, Xiuqing, Harris, Sarah E, Havulinna, Aki S, Helgadottir, Anna, Huffman, Jennifer E, Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G, Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A, Lu, Yingchang, Luan, Jian'an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas G D, Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O, Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S, Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G, Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V, Smith, Jennifer A, Staley, James R, Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V, Velez Edwards, Digna R, Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M, Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L, Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S, Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, Mutsert, Renée de, Dominiczak, Anna F, Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J Michael, Grarup, Niels, Grove, Megan L, Hallmans, Göran, Hansen, Torben, Have, Christian T, Heiss, Gerardo, Jørgensen, Marit E, Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A, Kovesdy, Csaba P, Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, Linneberg, Allan, Martin, Lisa W, Moitry, Marie, Nadkarni, Girish, Neville, Matt J, Palmer, Colin N A, Papanicolaou, George J, Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L, Rayner, N William, Mägi, Reedik, Renström, Frida, Rettig, Rainer, Rossouw, Jacques, Schreiner, Pamela J, Sever, Peter S, Sigurdsson, Emil L, Skaaby, Tea, Sun, Yan V, Sundström, Johan, Thorgeirsson, Gudmundur, Esko, Tõnu, Trabetti, Elisabetta, Tsao, Philip S, Tuomi, Tiinamaija, Turner, Stephen T, Tzoulaki, Ioanna, Vaartjes, Ilonca, Vergnaud, Anne-Claire, Willer, Cristen J, Wilson, Peter W F, Witte, Daniel R, Yonova-Doing, Ekaterina, Zhang, He, Aliya, Naheed, Almgren, Peter, Amouyel, Philippe, Asselbergs, Folkert W, Barnes, Michael R, Blakemore, Alexandra I, Boehnke, Michael, Bots, Michiel L, Bottinger, Erwin P, Buring, Julie E, Chambers, John C, Chen, Yii-Der Ida, Chowdhury, Rajiv, Conen, David, Correa, Adolfo, Davey Smith, George, Boer, Rudolf A de, Deary, Ian J, Dedoussis, George, Deloukas, Panos, Di Angelantonio, Emanuele, Elliott, Paul, Felix, Stephan B, Ferrières, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Franks, Stephen, Frossard, Philippe, Gambaro, Giovanni, Gaunt, Tom R, Groop, Leif, Gudnason, Vilmundur, Harris, Tamara B, Hayward, Caroline, Hennig, Branwen J, Herzig, Karl-Heinz, Ingelsson, Erik, Tuomilehto, Jaakko, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kardia, Sharon L R, Kee, Frank, Kooner, Jaspal S, Kooperberg, Charles, Launer, Lenore J, Lind, Lars, Loos, Ruth J F, Majumder, Abdulla Al Shafi, Laakso, Markku, McCarthy, Mark I, Melander, Olle, Mohlke, Karen L, Murray, Alison D, Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J, Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J, Prentice, Andrew M, Province, Michael A, Relton, Caroline L, Rice, Kenneth, Ridker, Paul M, Rolandsson, Olov, Rosendaal, Frits R, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sattar, Naveed, Sheu, Wayne H-H, Smith, Blair H, Soranzo, Nicole, Spector, Timothy D, Starr, John M, Sebert, Sylvain, Taylor, Kent D, Lakka, Timo A, Timpson, Nicholas J, Tobin, Martin D, van der Harst, Pim, van der Meer, Peter, Ramachandran, Vasan S, Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R, Zeggini, Eleftheria, Charchar, Fadi J, Wareham, Nicholas J, Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S, Caulfield, Mark J, Danesh, John, Edwards, Todd L, Holm, Hilma, Hung, Adriana M, Lindgren, Cecilia M, Liu, Chunyu, Manning, Alisa K, Morris, Andrew P, Morrison, Alanna C, O'Donnell, Christopher J, Psaty, Bruce M, Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I, Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B, and Howson, Joanna M M

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Published
2020
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23. The EWAS Catalog: a database of epigenome-wide association studies

Author

Battram, Thomas, primary, Yousefi, Paul, additional, Crawford, Gemma, additional, Prince, Claire, additional, Babei, Mahsa Sheikhali, additional, Sharp, Gemma, additional, Hatcher, Charlie, additional, Vega-Salas, Maria Jesus, additional, Khodabakhsh, Sahar, additional, Whitehurst, Oliver, additional, Langdon, Ryan, additional, Mahoney, Luke, additional, Elliott, Hannah R, additional, Mancano, Giulia, additional, Lee, Matthew, additional, Watkins, Sarah H, additional, Lay, Abigail C, additional, Hemani, Gibran, additional, Gaunt, Tom R, additional, Relton, Caroline, additional, Staley, James R, additional, and Suderman, Matthew, additional

Published
2021
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24. DNA methylation signatures of adolescent victimization: analysis of a longitudinal monozygotic twin sample

Author

Kandaswamy, Radhika, primary, Hannon, Eilis, additional, Arseneault, Louise, additional, Mansell, Georgina, additional, Sugden, Karen, additional, Williams, Benjamin, additional, Burrage, Joe, additional, Staley, James R, additional, Pishva, Ehsan, additional, Dahir, Aisha, additional, Roberts, Susanna, additional, Danese, Andrea, additional, Mill, Jonathan, additional, Fisher, Helen L, additional, and Wong, Chloe C. Y., additional

Published
2020
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27. Genetic and atherosclerotic plaque immunohistochemical analyses do not associate reduced sclerostin expression with cardiovascular events

Author

Holdsworth, Gill, primary, Staley, James R, additional, Hall, Peter, additional, van Koeverden, Ian, additional, Vangjeli, Ciara, additional, Okoye, Remi, additional, Boyce, Rogely, additional, Turk, James R, additional, Armstrong, Martin, additional, Wolfreys, Alison, additional, and Pasterkamp, Gerard, additional

Published
2020
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28. Coding and regulatory variants affect serum protein levels and common disease

Author

Emilsson, Valur, primary, Gudmundsdottir, Valborg, additional, Gudjonsson, Alexander, additional, Karim, Mohd A, additional, Ilkov, Marjan, additional, Staley, James R., additional, Gudmundsson, Elias F., additional, Jonsson, Brynjolfur G., additional, Launer, Lenore J., additional, Lindeman, Jan H., additional, Morton, Nicholas M., additional, Aspelund, Thor, additional, Lamb, John R., additional, Jennings, Lori L., additional, and Gudnason, Vilmundur, additional

Published
2020
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30. Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Author

Sun, Yi-Qian, Burgess, Stephen, Staley, James R, Wood, Angela M, Bell, Steven, Kaptoge, Stephen K, Guo, Qi, Bolton, Thomas R, Mason, Amy M, Butterworth, Adam S, Di Angelantonio, Emanuele, Vie, Gunnhild Å, Bjørngaard, Johan H, Kinge, Jonas Minet, Chen, Yue, and Mai, Xiao-Mei

Subjects
Adult, Male, Norway, Research, nutritional and metabolic diseases, Mendelian Randomization Analysis, Middle Aged, United Kingdom, Body Mass Index, Thinness, Cardiovascular Diseases, Risk Factors, Cause of Death, Neoplasms, Humans, Female, Obesity, Sex Distribution, Aged
Abstract

Objective To investigate the shape of the causal relation between body mass index (BMI) and mortality. Design Linear and non-linear mendelian randomisation analyses. Setting Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). Participants Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. Main outcome measures All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. Results 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI

Published
2019
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31. DNA methylation signatures of adolescent victimization: analysis of a longitudinal monozygotic twin sample.

Author

Kandaswamy, Radhika, Hannon, Eilis, Arseneault, Louise, Mansell, Georgina, Sugden, Karen, Williams, Benjamin, Burrage, Joe, Staley, James R, Pishva, Ehsan, Dahir, Aisha, Roberts, Susanna, Danese, Andrea, Mill, Jonathan, Fisher, Helen L, and Wong, Chloe C. Y.

Subjects
TEENAGERS, DNA methylation, TWINS, GENETIC variation, CRIME victims
Abstract

Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (P < 5e-05), with altered DNAm trajectories between ages 10–18 associated with severe adolescent victimization (∆Beta range = −5.5%−5.3%). Age-18 cross-sectional analyses revealed 72 blood (∆Beta range = −2.2%−3.4%) and 42 buccal (∆Beta range = −3.6%−4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) in LGR6 and ANK3 (Šidák P = 5e-09 and 4.07e-06), and one upstream of CCL27 (Šidák P = 2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization. [ABSTRACT FROM AUTHOR]

Published
2021
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32. The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study.

Author

Leppert, Beate, Riglin, Lucy, Wootton, Robyn E, Dardani, Christina, Thapar, Ajay, Staley, James R, Tilling, Kate, Smith, George Davey, Thapar, Anita, and Stergiakouli, Evie

Subjects
ATTENTION-deficit hyperactivity disorder
Abstract

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of physical health problems. Using different research designs to test whether ADHD has a causal role in these associations is important because comorbid health problems increase the serious social and economic impacts of ADHD. We used 2-sample Mendelian randomization (MR) to infer causal relationships between ADHD and previously implicated physical health conditions. Different MR methods were used to test the robustness and plausibility of our findings. Consistent findings underwent bidirectional and multivariable MR. We found evidence of ADHD having a causal effect on childhood obesity (odds ratio = 1.29, 95% confidence interval: 1.02, 1.63) and coronary artery disease (odds ratio = 1.11, 95% confidence interval: 1.03, 1.19) with consistent results across MR approaches. There was additional MR evidence for a bidirectional relationship between ADHD and childhood obesity. The relationship with coronary artery disease attenuated when controlling for childhood obesity. There was little evidence for inferring a causal effect on other cardiometabolic, autoimmune, allergic, and neurological diseases. Our findings strengthen the argument for effective treatment of children with ADHD, and suggest that clinicians who manage ADHD need to be aware of the risk of childhood obesity to reduce future risks of coronary artery disease. [ABSTRACT FROM AUTHOR]

Published
2021
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33. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies

Author

Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia R., Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M. M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom, MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom, Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands, and Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia

Published
2018

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

Author

Zheng, Jie, primary, Haberland, Valeriia, additional, Baird, Denis, additional, Walker, Venexia, additional, Haycock, Philip, additional, Hurle, Mark, additional, Gutteridge, Alex, additional, Erola, Pau, additional, Liu, Yi, additional, Luo, Shan, additional, Robinson, Jamie, additional, Richardson, Tom G., additional, Staley, James R., additional, Elsworth, Benjamin, additional, Burgess, Stephen, additional, Sun, Benjamin B., additional, Danesh, John, additional, Runz, Heiko, additional, Maranville, Joseph C., additional, Martin, Hannah M., additional, Yarmolinsky, James, additional, Laurin, Charles, additional, Holmes, Michael V., additional, Liu, Jimmy, additional, Estrada, Karol, additional, Santos, Rita, additional, McCarthy, Linda, additional, Waterworth, Dawn, additional, Nelson, Matthew R., additional, Hemani, Gibran, additional, Smith, George Davey, additional, Butterworth, Adam S., additional, Scott, Robert A., additional, and Gaunt, Tom R., additional

Published
2019
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38. Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Author

Sun, Yi-Qian, primary, Burgess, Stephen, additional, Staley, James R, additional, Wood, Angela M, additional, Bell, Steven, additional, Kaptoge, Stephen K, additional, Guo, Qi, additional, Bolton, Thomas R, additional, Mason, Amy M, additional, Butterworth, Adam S, additional, Di Angelantonio, Emanuele, additional, Vie, Gunnhild Å, additional, Bjørngaard, Johan H, additional, Kinge, Jonas Minet, additional, Chen, Yue, additional, and Mai, Xiao-Mei, additional

Published
2019
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41. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies : A mendelian randomization analysis

Author

Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., Riboli, Elio, Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., and Riboli, Elio

Published
2018

42. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: A mendelian randomization analysis

Author

Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., Riboli, Elio, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., and Riboli, Elio

Published
2018

43. A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design

Author

Staley, James R, Jones, Edmund, Kaptoge, Stephen, Butterworth, Adam S, Sweeting, Michael J, Wood, Angela M, Howson, Joanna MM, Kaptoge, Stephen [0000-0002-1155-4872], Butterworth, Adam [0000-0002-6915-9015], Sweeting, Michael [0000-0003-0980-8965], Wood, Angela [0000-0002-7937-304X], Howson, Joanna [0000-0001-7618-0050], and Apollo - University of Cambridge Repository

Subjects
Cardiovascular diseases, Logistic Models, Outcomes research, Data Interpretation, Statistical, Genetics research, Humans, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Logistic regression is often used instead of Cox regression to analyse genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP–disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease.

Published
2017
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44. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna MM, Di Angelantonio, Emanuele, Butterworth, Adam S, and Danesh, John

Published
2017

46. Genetic invalidation of Lp-PLA2 as a therapeutic target:Large-scale study of five functional Lp-PLA2-lowering alleles

Author

Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla Al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna Mm, Di Angelantonio, Emanuele, Butterworth, Adam S, Danesh, John, Gregson, John M, Freitag, Daniel F, Surendran, Praveen, Stitziel, Nathan O, Chowdhury, Rajiv, Burgess, Stephen, Kaptoge, Stephen, Gao, Pei, Staley, James R, Willeit, Peter, Nielsen, Sune F, Caslake, Muriel, Trompet, Stella, Polfus, Linda M, Kuulasmaa, Kari, Kontto, Jukka, Perola, Markus, Blankenberg, Stefan, Veronesi, Giovanni, Gianfagna, Francesco, Männistö, Satu, Kimura, Akinori, Lin, Honghuang, Reilly, Dermot F, Gorski, Mathias, Mijatovic, Vladan, Munroe, Patricia B, Ehret, Georg B, Thompson, Alex, Uria-Nickelsen, Maria, Malarstig, Anders, Dehghan, Abbas, Vogt, Thomas F, Sasaoka, Taishi, Takeuchi, Fumihiko, Kato, Norihiro, Yamada, Yoshiji, Kee, Frank, Müller-Nurasyid, Martina, Ferrières, Jean, Arveiler, Dominique, Amouyel, Philippe, Salomaa, Veikko, Boerwinkle, Eric, Thompson, Simon G, Ford, Ian, Wouter Jukema, J, Sattar, Naveed, Packard, Chris J, Shafi Majumder, Abdulla Al, Alam, Dewan S, Deloukas, Panos, Schunkert, Heribert, Samani, Nilesh J, Kathiresan, Sekar, Nordestgaard, Børge G, Saleheen, Danish, Howson, Joanna Mm, Di Angelantonio, Emanuele, Butterworth, Adam S, and Danesh, John

Published
2017

47. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Author

Surendran, Praveen, Drenos, Fotios, Young, Robin, Warren, Helen, Cook, James P, Manning, Alisa K, Grarup, Niels, Sim, Xueling, Barnes, Daniel R, Witkowska, Kate, Staley, James R, Tragante, Vinicius, Tukiainen, Taru, Yaghootkar, Hanieh, Masca, Nicholas, Freitag, Daniel F, Ferreira, Teresa, Giannakopoulou, Olga, Tinker, Andrew, Harakalova, Magdalena, Mihailov, Evelin, Liu, Chunyu, Kraja, Aldi T, Nielsen, Sune Fallgaard, Rasheed, Asif, Samuel, Maria, Zhao, Wei, Bonnycastle, Lori L, Jackson, Anne U, Narisu, Narisu, Swift, Amy J, Southam, Lorraine, Marten, Jonathan, Huyghe, Jeroen R, Stančáková, Alena, Fava, Cristiano, Ohlsson, Therese, Matchan, Angela, Stirrups, Kathleen E, Bork-Jensen, Jette, Gjesing, Anette P, Kontto, Jukka, Perola, Markus, Shaw-Hawkins, Susan, Havulinna, Aki S, Zhang, He, Donnelly, Louise A, de Bakker, Paul I W, Numans, Mattijs E, Asselbergs, Folkert W, and CHARGE-Heart Failure Consortium

Subjects
Journal Article
Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Published
2016

48. Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies

Author

Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., Riboli, Elio, Burgess, Stephen [0000-0001-5365-8760], Mason, Amy [0000-0002-8019-0777], Surendran, Praveen [0000-0002-4911-6077], Karthikeyan, Savita [0000-0002-4798-5746], Di Angelantonio, Emanuele [0000-0001-8776-6719], Howson, Joanna [0000-0001-7618-0050], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Male, medicine.medical_specialty, Population, Coronary Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, Ezetimibe, Risk Factors, law, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Precision Medicine, Prospective cohort study, education, Hypolipidemic Agents, education.field_of_study, biology, Cholesterol, business.industry, Genetic Variation, Mendelian Randomization Analysis, Cholesterol, LDL, Lipoprotein(a), Odds ratio, Middle Aged, Prognosis, Phenotype, chemistry, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, Follow-Up Studies, medicine.drug
Abstract

Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Exposures: Genetic LPA score and plasma Lp(a) mass concentration.Main Outcomes and Measures: Coronary heart disease.Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

Published
2018
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49. Consequences of natural perturbations in the human plasma proteome

Author

Sun, Benjamin B., primary, Maranville, Joseph C., additional, Peters, James E., additional, Stacey, David, additional, Staley, James R., additional, Blackshaw, James, additional, Burgess, Stephen, additional, Jiang, Tao, additional, Paige, Ellie, additional, Surendran, Praveen, additional, Oliver-Williams, Clare, additional, Kamat, Mihir A., additional, Prins, Bram P., additional, Wilcox, Sheri K., additional, Zimmerman, Erik S., additional, Chi, An, additional, Bansal, Narinder, additional, Spain, Sarah L., additional, Wood, Angela M., additional, Morrell, Nicholas W., additional, Bradley, John R., additional, Janjic, Nebojsa, additional, Roberts, David J., additional, Ouwehand, Willem H., additional, Todd, John A., additional, Soranzo, Nicole, additional, Suhre, Karsten, additional, Paul, Dirk S., additional, Fox, Caroline S., additional, Plenge, Robert M., additional, Danesh, John, additional, Runz, Heiko, additional, and Butterworth, Adam S., additional

Published
2017
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