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1. Potential asthma risk factors do not account for global asthma symptom prevalence patterns and time trends in children and adolescents

Author

Charlotte E. Rutter, PhD, Richard J. Silverwood, PhD, Neil Pearce, PhD, and David P. Strachan, MD

Subjects
Asthma, Wheeze, Prevalence, Time trends, Risk factors, Immunologic diseases. Allergy, RC581-607
Abstract

Background: The International Study of Asthma and Allergies in Childhood (ISAAC) and the Global Asthma Network (GAN) conducted a series of global asthma prevalence surveys, between 1990 and 2020, in adolescents aged 13–14 and children aged 6–7 years. We used them to assess whether potential asthma risk factors explain global asthma symptom prevalence trends over this period. Method: We fitted mixed-effects linear regression models to estimate associations between centre-level risk factor prevalence and both the mid-point asthma symptom prevalence and the change per decade. We also estimated the 2019 asthma symptom prevalence across all included centres. Results: For adolescents, across 50 centres in 26 countries there was weak evidence that decreasing asthma prevalence over time was associated with regular fast-food consumption and frequent television viewing. However, frequent television viewing, along with heavy truck traffic, were associated with higher prevalence of asthma symptoms at the study mid-point. For children, across 41 centres in 21 countries, no risk factors were associated with time trends in asthma symptom prevalence, but truck traffic and paracetamol in the first year of life were associated with higher mid-point prevalence.We estimated the 2019 asthma symptom prevalence, across a total of 124 centres, to be 12.8% (11.4%, 14.2%) with little evidence of a difference by age. Low-income countries had lower prevalence (children 5.2% [2.5%, 7.8%], adolescents 5.3% [2.8%, 7.8%]), than lower-middle-, upper-middle- and high-income countries (all approximately 14–15%). Including risk factors in the models did not change the estimates. Conclusion: Potential asthma risk factors do not seem to explain the global prevalence patterns or time trends. Country income accounts for some of the differences, but the unexplained variation is very high.

Published
2024
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2. Author Correction: Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Jonathan P. Bradfeld, Rachel L. Kember, Anna Ulrich, Zhanna Balkhiyarova, Akram Alyass, Izzuddin M. Aris, Joshua A. Bell, K. Alaine Broadaway, Zhanghua Chen, Jin-Fang Chai, Neil M. Davies, Dietmar Fernandez-Orth, Mariona Bustamante, Ruby Fore, Amitavo Ganguli, Anni Heiskala, Jouke-Jan Hottenga, Carmen Íñiguez, Sayuko Kobes, Jaakko Leinonen, Estelle Lowry, Leo-Pekka Lyytikainen, Anubha Mahajan, Niina Pitkänen, Theresia M. Schnurr, Christian Theil Have, David P. Strachan, Elisabeth Thiering, Suzanne Vogelezang, Kaitlin H. Wade, Carol A. Wang, Andrew Wong, Louise Aas Holm, Alessandra Chesi, Catherine Choong, Miguel Cruz, Paul Elliott, Steve Franks, Christine Frithiof-Bøjsøe, W. James Gauderman, Joseph T. Glessner, Vicente Gilsanz, Kendra Griesman, Robert L. Hanson, Marika Kaakinen, Heidi Kalkwarf, Andrea Kelly, Joseph Kindler, Mika Kähönen, Carla Lanca, Joan Lappe, Nanette R. Lee, Shana McCormack, Frank D. Mentch, Jonathan A. Mitchell, Nina Mononen, Harri Niinikoski, Emily Oken, Katja Pahkala, Xueling Sim, Yik-Ying Teo, Leslie J. Baier, Toos van Beijsterveldt, Linda S. Adair, Dorret I. Boomsma, Eco de Geus, Mònica Guxens, Johan G. Eriksson, Janine F. Felix, Frank D. Gilliland, Penn Medicine Biobank, Torben Hansen, Rebecca Hardy, Marie-France Hivert, Jens-Christian Holm, Vincent W. V. Jaddoe, Marjo-Riitta Järvelin, Terho Lehtimäki, David A. Mackey, David Meyre, Karen L. Mohlke, Juha Mykkänen, Sharon Oberfeld, Craig E. Pennell, John R. B. Perry, Olli Raitakari, Fernando Rivadeneira, Seang-Mei Saw, Sylvain Sebert, John A. Shepherd, Marie Standl, Thorkild I. A. Sørensen, Nicholas J. Timpson, Maties Torrent, Gonneke Willemsen, Elina Hypponen, Chris Power, The Early Growth Genetics Consortium, Mark I. McCarthy, Rachel M. Freathy, Elisabeth Widén, Hakon Hakonarson, Inga Prokopenko, Benjamin F. Voight, Babette S. Zemel, Struan F. A. Grant, and Diana L. Cousminer

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Published
2024
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3. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Jonathan P. Bradfield, Rachel L. Kember, Anna Ulrich, Zhanna Balkhiyarova, Akram Alyass, Izzuddin M. Aris, Joshua A. Bell, K. Alaine Broadaway, Zhanghua Chen, Jin-Fang Chai, Neil M. Davies, Dietmar Fernandez-Orth, Mariona Bustamante, Ruby Fore, Amitavo Ganguli, Anni Heiskala, Jouke-Jan Hottenga, Carmen Íñiguez, Sayuko Kobes, Jaakko Leinonen, Estelle Lowry, Leo-Pekka Lyytikainen, Anubha Mahajan, Niina Pitkänen, Theresia M. Schnurr, Christian Theil Have, David P. Strachan, Elisabeth Thiering, Suzanne Vogelezang, Kaitlin H. Wade, Carol A. Wang, Andrew Wong, Louise Aas Holm, Alessandra Chesi, Catherine Choong, Miguel Cruz, Paul Elliott, Steve Franks, Christine Frithioff-Bøjsøe, W. James Gauderman, Joseph T. Glessner, Vicente Gilsanz, Kendra Griesman, Robert L. Hanson, Marika Kaakinen, Heidi Kalkwarf, Andrea Kelly, Joseph Kindler, Mika Kähönen, Carla Lanca, Joan Lappe, Nanette R. Lee, Shana McCormack, Frank D. Mentch, Jonathan A. Mitchell, Nina Mononen, Harri Niinikoski, Emily Oken, Katja Pahkala, Xueling Sim, Yik-Ying Teo, Leslie J. Baier, Toos van Beijsterveldt, Linda S. Adair, Dorret I. Boomsma, Eco de Geus, Mònica Guxens, Johan G. Eriksson, Janine F. Felix, Frank D. Gilliland, Penn Medicine Biobank, Torben Hansen, Rebecca Hardy, Marie-France Hivert, Jens-Christian Holm, Vincent W. V. Jaddoe, Marjo-Riitta Järvelin, Terho Lehtimäki, David A. Mackey, David Meyre, Karen L. Mohlke, Juha Mykkänen, Sharon Oberfield, Craig E. Pennell, John R. B. Perry, Olli Raitakari, Fernando Rivadeneira, Seang-Mei Saw, Sylvain Sebert, John A. Shepherd, Marie Standl, Thorkild I. A. Sørensen, Nicholas J. Timpson, Maties Torrent, Gonneke Willemsen, Elina Hypponen, Chris Power, The Early Growth Genetics Consortium, Mark I. McCarthy, Rachel M. Freathy, Elisabeth Widén, Hakon Hakonarson, Inga Prokopenko, Benjamin F. Voight, Babette S. Zemel, Struan F. A. Grant, and Diana L. Cousminer

Subjects
Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Published
2024
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4. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Ashley Budu-Aggrey, Anna Kilanowski, Maria K. Sobczyk, andMe Research Team, Suyash S. Shringarpure, Ruth Mitchell, Kadri Reis, Anu Reigo, Estonian Biobank Research Team, Reedik Mägi, Mari Nelis, Nao Tanaka, Ben M. Brumpton, Laurent F. Thomas, Pol Sole-Navais, Christopher Flatley, Antonio Espuela-Ortiz, Esther Herrera-Luis, Jesus V. T. Lominchar, Jette Bork-Jensen, Ingo Marenholz, Aleix Arnau-Soler, Ayoung Jeong, Katherine A. Fawcett, Hansjorg Baurecht, Elke Rodriguez, Alexessander Couto Alves, Ashish Kumar, Patrick M. Sleiman, Xiao Chang, Carolina Medina-Gomez, Chen Hu, Cheng-jian Xu, Cancan Qi, Sarah El-Heis, Philip Titcombe, Elie Antoun, João Fadista, Carol A. Wang, Elisabeth Thiering, Baojun Wu, Sara Kress, Dilini M. Kothalawala, Latha Kadalayil, Jiasong Duan, Hongmei Zhang, Sabelo Hadebe, Thomas Hoffmann, Eric Jorgenson, Hélène Choquet, Neil Risch, Pål Njølstad, Ole A. Andreassen, Stefan Johansson, Catarina Almqvist, Tong Gong, Vilhelmina Ullemar, Robert Karlsson, Patrik K. E. Magnusson, Agnieszka Szwajda, Esteban G. Burchard, Jacob P. Thyssen, Torben Hansen, Line L. Kårhus, Thomas M. Dantoft, Alexander C.S.N. Jeanrenaud, Ahla Ghauri, Andreas Arnold, Georg Homuth, Susanne Lau, Markus M. Nöthen, Norbert Hübner, Medea Imboden, Alessia Visconti, Mario Falchi, Veronique Bataille, Pirro Hysi, Natalia Ballardini, Dorret I. Boomsma, Jouke J. Hottenga, Martina Müller-Nurasyid, Tarunveer S. Ahluwalia, Jakob Stokholm, Bo Chawes, Ann-Marie M. Schoos, Ana Esplugues, Mariona Bustamante, Benjamin Raby, Syed Arshad, Chris German, Tõnu Esko, Lili A. Milani, Andres Metspalu, Chikashi Terao, Katrina Abuabara, Mari Løset, Kristian Hveem, Bo Jacobsson, Maria Pino-Yanes, David P. Strachan, Niels Grarup, Allan Linneberg, Young-Ae Lee, Nicole Probst-Hensch, Stephan Weidinger, Marjo-Riitta Jarvelin, Erik Melén, Hakon Hakonarson, Alan D. Irvine, Deborah Jarvis, Tamar Nijsten, Liesbeth Duijts, Judith M. Vonk, Gerard H. Koppelmann, Keith M. Godfrey, Sheila J. Barton, Bjarke Feenstra, Craig E. Pennell, Peter D. Sly, Patrick G. Holt, L. Keoki Williams, Hans Bisgaard, Klaus Bønnelykke, John Curtin, Angela Simpson, Clare Murray, Tamara Schikowski, Supinda Bunyavanich, Scott T. Weiss, John W. Holloway, Josine L. Min, Sara J. Brown, Marie Standl, and Lavinia Paternoster

Subjects
Science
Abstract

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023
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5. Genetic insights into resting heart rate and its role in cardiovascular disease

Author

Yordi J. van de Vegte, Ruben N. Eppinga, M. Yldau van der Ende, Yanick P. Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V. Smith, Vanessa Y. Tan, Dan E. Arking, Ioanna Ntalla, Emil V. Appel, Claudia Schurmann, Jennifer A. Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian’an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U. Jackson, Lawrence F. Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E. Kleber, Xiuqing Guo, Henry J. Lin, Francesca Pavani, Tessel E. Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E. Schraut, Marcel den Hoed, Frauke Degenhardt, Stella Trompet, Marten E. van den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S. Sim, Hengtong L. Li, Peter J. van der Most, Ilja M. Nolte, Leo-Pekka Lyytikäinen, M. Abdullah Said, Daniel R. Witte, Carlos Iribarren, Lenore Launer, Susan M. Ring, Paul S. de Vries, Peter Sever, Allan Linneberg, Erwin P. Bottinger, Sandosh Padmanabhan, Bruce M. Psaty, Nona Sotoodehnia, Ivana Kolcic, The DCCT/EDIC Research Group, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T. Silva, Christopher H. Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L. Mohlke, Patricia A. Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C. Rao, Marilyn C. Cornelis, Jessica D. Faul, Jennifer A. Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F. Sinner, Konstantin Strauch, Graciela E. Delgado, Kent D. Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline de Graaf, Renée de Mutsert, Eco J. C. de Geus, Åsa Johansson, Peter K. Joshi, Lars Lind, Andre Franke, Peter W. Macfarlane, Kirill V. Tarasov, Nicholas Tan, Stephan B. Felix, E-Shyong Tai, Debra Q. Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P. Morris, Olli T. Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J. Timpson, Alanna C. Morrison, Patricia B. Munroe, David P. Strachan, Niels Grarup, Ruth J. F. Loos, Susan R. Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J. Wareham, Cornelia M. van Duijn, Mary F. Feitosa, Christopher J. O’Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes Ohlsson, David J. Porteous, Johan G. Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R. Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C. Chambers, Jaspal S. Kooner, Winfried März, Jerome I. Rotter, Andrew A. Hicks, J. Gustav Smith, Lambertus A. L. M. Kiemeney, Dennis O. Mook-Kanamori, Brenda W. J. H. Penninx, Ulf Gyllensten, James F. Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J. Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, and Pim van der Harst

Subjects
Science
Abstract

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Published
2023
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6. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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7. GWAS on retinal vasculometry phenotypes

Author

Xiaofan Jiang, Pirro G. Hysi, Anthony P. Khawaja, Omar A. Mahroo, Zihe Xu, Christopher J. Hammond, Paul J. Foster, Roshan A. Welikala, Sarah A. Barman, Peter H. Whincup, Alicja R. Rudnicka, Christopher G. Owen, and David P. Strachan

Subjects
Genetics, QH426-470
Abstract

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10−108), 2 loci with arteriolar width (rs12969347, p = 3.30×10−09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa. Author summary Vessels at the back of the eye (the “retina”) can be imaged easily. This paper reports on the largest genetic study of retinal vessel shape and size characteristics so far undertaken, to the best of our knowledge. Our study is novel in using an automated artificial intelligence imaging approach to distinguish between arteries and veins, and in demonstrating more genetic associations with vessel characteristics than any previous study (119 genetic loci in all). We also show that the tortuosity of retinal arteries is the most strongly genetically determined vessel characteristic (replicated remarkable well in a separate second large dataset). In addition, using a particular type of genetic analysis (so called “Mendelian Randomization”) we show for the first time that the tortuosity of arteries in the retina is causally related to elevated diastolic blood pressure and not the other way around. This is important as it provides unique insights into the mechanism of elevated blood pressure and hypertension, providing pointers to novel therapeutic targets for future treatment.

Published
2023

8. Patterns of Allergic Sensitization and Factors Associated With Emergence of Sensitization in the Rural Tropics Early in the Life Course: Findings of an Ecuadorian Birth Cohort

Author

Philip J. Cooper, Irina Chis Ster, Martha E. Chico, Maritza Vaca, Mauricio L. Barreto, and David P. Strachan

Subjects
allergic sensitization, atopy, cohort, childhood, tropics, risk factors, Immunologic diseases. Allergy, RC581-607
Abstract

Introduction: There are limited data on emergence of allergic sensitization (or atopy) during childhood in tropical regions.Methods: We followed a birth cohort of 2,404 newborns to 8 years in tropical Ecuador and collected: risk factor data by maternal questionnaires periodically from birth; atopy was measured by skin prick test reactivity (SPT) to aeroallergens in parents, and aeroallergens and food allergens in children at 2, 3, 5, and 8 years; and stool samples for soil-transmitted helminths (STH) from children periodically to 8 years and from parents and household members at the time of recruitment of cohort children. Data on risk factors were measured either at birth or repeatedly (time-varying) from birth to 8 years. Longitudinal repeated-measures analyses were done using generalized estimating equations to estimate the age-dependent risk of positive SPT (SPT+) to any allergen or mite during early childhood.Results: SPT+ to any allergen was present in 29.0% of fathers and 24.8% of mothers, and in cohort children increased with age, initially to mite but later to cockroach, reaching 14.8% to any allergen (10.7% mite and 5.3% cockroach) at 8 years. Maternal SPT+, particularly presence of polysensitization (OR 2.04, 95% CI 1.49–2.77) significantly increased the risk of SPT+ during childhood, while household overcrowding at birth decreased the risk (OR 0.84, 95% CI 0.72–0.98). For mite sensitization, maternal polysensitization increased (OR 2.14, 95% CI 1.40–3.27) but rural residence (OR 0.69, 95% CI 0.50–0.94) and birth order (3rd−4th vs. 1st−2nd: OR 0.71, 95% CI 0.52–0.98) decreased the risk. Time-varying exposures to agricultural activities (OR 0.77, 95% CI 0.60–0.98) and STH parasites (OR 0.70, 95% CI 0.64–0.91) during childhood decreased while anthelmintics increased the childhood risk (OR 1.47, 95% CI 1.05–2.05) of mite sensitization.Conclusion: Our data show the emergence of allergic sensitization, primarily to mite and cockroach allergens, during childhood in tropical Ecuador. A role for both antenatal and post-natal factors acting as potential determinants of SPT+ emergence was observed.

Published
2021
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9. Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]

Author

Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain

Subjects
Medicine, Science
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2021
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10. Risk factors for excess all-cause mortality during the first wave of the COVID-19 pandemic in England: A retrospective cohort study of primary care data

Author

Iain M. Carey, Derek G. Cook, Tess Harris, Stephen DeWilde, Umar A. R. Chaudhry, and David P. Strachan

Subjects
Medicine, Science
Abstract

Background The COVID-19 pandemic’s first wave in England during spring 2020 resulted in an approximate 50% increase in all-cause mortality. Previously, risk factors such as age and ethnicity, were identified by studying COVID-related deaths only, but these were under-recorded during this period. Objective To use a large electronic primary care database to estimate the impact of risk factors (RFs) on excess mortality in England during the first wave, compared with the impact on total mortality during 2015–19. Methods Medical history, ethnicity, area-based deprivation and vital status data were extracted for an average of 4.8 million patients aged 30–104 years, for each year between 18-March and 19-May over a 6-year period (2015–2020). We used Poisson regression to model total mortality adjusting for age and sex, with interactions between each RF and period (pandemic vs. 2015–19). Total mortality during the pandemic was partitioned into "usual" and "excess" components, assuming 2015–19 rates represented "usual" mortality. The association of each RF with the 2020 "excess" component was derived as the excess mortality ratio (EMR), and compared with the usual mortality ratio (UMR). Results RFs where excess mortality was greatest and notably higher than usual were age >80, non-white ethnicity (e.g., black vs. white EMR = 2.50, 95%CI 1.97–3.18; compared to UMR = 0.92, 95%CI 0.85–1.00), BMI>40, dementia, learning disability, severe mental illness, place of residence (London, care-home, most deprived). By contrast, EMRs were comparable to UMRs for sex. Although some co-morbidities such as cancer produced EMRs significantly below their UMRs, the EMRs were still >1. In contrast current smoking has an EMR below 1 (EMR = 0.80, 95%CI 0.65–0.98) compared to its UMR = 1.64. Conclusions Studying risk factors for excess mortality during the pandemic highlighted differences from studying cause-specific mortality. Our approach illustrates a novel methodology for evaluating a pandemic’s impact by individual risk factor without requiring cause-specific mortality data.

Published
2021

11. Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved]

Author

Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain

Subjects
Medicine, Science
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2020
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12. Comparison of individual-level and population-level risk factors for rhinoconjunctivitis, asthma, and eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three

Author

Charlotte E. Rutter, Richard J. Silverwood, M.Innes Asher, Philippa Ellwood, Neil Pearce, Luis Garcia-Marcos, and David P. Strachan

Subjects
Rhinoconjunctivitis, Asthma, Eczema, Multimorbidity, Global, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in children cluster at both the individual and population levels. Objectives: To assess individual-level and school-level risk factors for symptoms of rhinoconjunctivitis and compare them to corresponding associations with symptoms of asthma and eczema in Phase Three of the International Study of Asthma and Allergies in Childhood. Methods: We studied 116,863 children aged 6–7 years from 2163 schools in 59 centres and 22 countries and 224,436 adolescents aged 13–14 years from 2037 schools in 97 centres in 41 countries. Multilevel logistic regression models were fitted with random intercepts for school, centre, and country, adjusting for sex and maternal education at the child level. Associations between symptoms and a range of lifestyle and environmental risk factors were assessed for both the child's exposure and mean exposure at the school. Models were fitted for rhinoconjunctivitis, asthma, and eczema singly (unimorbidity) and for combinations of these conditions (multimorbidity). Results: Generally, associations between symptoms and exposures at the school level were similar in direction and magnitude to those at the child level. Associations with multimorbidity were stronger than for unimorbidity, particularly in individuals with symptoms of all three diseases, but risk factor associations found in conventional single disease analyses persisted among children with only one condition, after excluding multimorbid groups.Comparisons of individuals with only one disease showed that many risk factor associations were consistent across the three conditions. More strongly associated with asthma were low birthweight, cat exposure in infancy, and current maternal smoking. Current paracetamol use was more strongly associated with asthma and rhinoconjunctivitis than eczema. Breastfeeding was more strongly associated with eczema than asthma or rhinoconjunctivitis.The direction and magnitude of most risk factor associations were similar in affluent and non-affluent countries, although notable exceptions include farm animal contact in infancy and larger sibships, which were associated with increased risk of rhinoconjunctivitis in non-affluent countries but reduced risk in affluent countries. In both age groups, current paracetamol use increased risk of each disease to a greater extent in affluent countries than in non-affluent countries. Effects of paracetamol and antibiotics in infancy were more consistent between richer and poorer settings. Conclusions: Most of the environmental and lifestyle correlates of rhinoconjunctivitis, asthma and eczema in childhood display similarity across the three conditions, even in less affluent settings where allergic sensitisation is less likely to explain the concordant epidemiological patterns. Trial registration: Not applicable.

Published
2020
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13. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Author

Aurélien Macé, Marcus A. Tuke, Patrick Deelen, Kati Kristiansson, Hannele Mattsson, Margit Nõukas, Yadav Sapkota, Ursula Schick, Eleonora Porcu, Sina Rüeger, Aaron F. McDaid, David Porteous, Thomas W. Winkler, Erika Salvi, Nick Shrine, Xueping Liu, Wei Q. Ang, Weihua Zhang, Mary F. Feitosa, Cristina Venturini, Peter J. van der Most, Anders Rosengren, Andrew R. Wood, Robin N. Beaumont, Samuel E. Jones, Katherine S. Ruth, Hanieh Yaghootkar, Jessica Tyrrell, Aki S. Havulinna, Harmen Boers, Reedik Mägi, Jennifer Kriebel, Martina Müller-Nurasyid, Markus Perola, Markku Nieminen, Marja-Liisa Lokki, Mika Kähönen, Jorma S. Viikari, Frank Geller, Jari Lahti, Aarno Palotie, Päivikki Koponen, Annamari Lundqvist, Harri Rissanen, Erwin P. Bottinger, Saima Afaq, Mary K. Wojczynski, Petra Lenzini, Ilja M. Nolte, Thomas Sparsø, Nicole Schupf, Kaare Christensen, Thomas T. Perls, Anne B. Newman, Thomas Werge, Harold Snieder, Timothy D. Spector, John C. Chambers, Seppo Koskinen, Mads Melbye, Olli T. Raitakari, Terho Lehtimäki, Martin D. Tobin, Louise V. Wain, Juha Sinisalo, Annette Peters, Thomas Meitinger, Nicholas G. Martin, Naomi R. Wray, Grant W. Montgomery, Sarah E. Medland, Morris A. Swertz, Erkki Vartiainen, Katja Borodulin, Satu Männistö, Anna Murray, Murielle Bochud, Sébastien Jacquemont, Fernando Rivadeneira, Thomas F. Hansen, Albertine J. Oldehinkel, Massimo Mangino, Michael A. Province, Panos Deloukas, Jaspal S. Kooner, Rachel M. Freathy, Craig Pennell, Bjarke Feenstra, David P. Strachan, Guillaume Lettre, Joel Hirschhorn, Daniele Cusi, Iris M. Heid, Caroline Hayward, Katrin Männik, Jacques S. Beckmann, Ruth J. F. Loos, Dale R. Nyholt, Andres Metspalu, Johan G. Eriksson, Michael N. Weedon, Veikko Salomaa, Lude Franke, Alexandre Reymond, Timothy M. Frayling, and Zoltán Kutalik

Subjects
Science
Abstract

Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

Published
2017
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14. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Anne E. Justice, Thomas W. Winkler, Mary F. Feitosa, Misa Graff, Virginia A. Fisher, Kristin Young, Llilda Barata, Xuan Deng, Jacek Czajkowski, David Hadley, Julius S. Ngwa, Tarunveer S. Ahluwalia, Audrey Y. Chu, Nancy L. Heard-Costa, Elise Lim, Jeremiah Perez, John D. Eicher, Zoltán Kutalik, Luting Xue, Anubha Mahajan, Frida Renström, Joseph Wu, Qibin Qi, Shafqat Ahmad, Tamuno Alfred, Najaf Amin, Lawrence F. Bielak, Amelie Bonnefond, Jennifer Bragg, Gemma Cadby, Martina Chittani, Scott Coggeshall, Tanguy Corre, Nese Direk, Joel Eriksson, Krista Fischer, Mathias Gorski, Marie Neergaard Harder, Momoko Horikoshi, Tao Huang, Jennifer E. Huffman, Anne U. Jackson, Johanne Marie Justesen, Stavroula Kanoni, Leena Kinnunen, Marcus E. Kleber, Pirjo Komulainen, Meena Kumari, Unhee Lim, Jian'an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Jonathan Marten, Rita P. S. Middelberg, Martina Müller-Nurasyid, Pau Navarro, Louis Pérusse, Natalia Pervjakova, Cinzia Sarti, Albert Vernon Smith, Jennifer A. Smith, Alena Stančáková, Rona J. Strawbridge, Heather M. Stringham, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W. van der Laan, Peter J. van der Most, Jana V. Van Vliet-Ostaptchouk, Sailaja L. Vedantam, Niek Verweij, Jacqueline M. Vink, Veronique Vitart, Ying Wu, Loic Yengo, Weihua Zhang, Jing Hua Zhao, Martina E. Zimmermann, Niha Zubair, Gonçalo R. Abecasis, Linda S. Adair, Saima Afaq, Uzma Afzal, Stephan J. L. Bakker, Traci M. Bartz, John Beilby, Richard N. Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Daniele Braga, Brendan M. Buckley, Steve Buyske, Harry Campbell, John C. Chambers, Francis S. Collins, Joanne E. Curran, Gert J. de Borst, Anton J. M. de Craen, Eco J. C. de Geus, George Dedoussis, Graciela E. Delgado, Hester M. den Ruijter, Gudny Eiriksdottir, Anna L. Eriksson, Tõnu Esko, Jessica D. Faul, Ian Ford, Terrence Forrester, Karl Gertow, Bruna Gigante, Nicola Glorioso, Jian Gong, Harald Grallert, Tanja B. Grammer, Niels Grarup, Saskia Haitjema, Göran Hallmans, Anders Hamsten, Torben Hansen, Tamara B. Harris, Catharina A. Hartman, Maija Hassinen, Nicholas D. Hastie, Andrew C. Heath, Dena Hernandez, Lucia Hindorff, Lynne J. Hocking, Mette Hollensted, Oddgeir L. Holmen, Georg Homuth, Jouke Jan Hottenga, Jie Huang, Joseph Hung, Nina Hutri-Kähönen, Erik Ingelsson, Alan L. James, John-Olov Jansson, Marjo-Riitta Jarvelin, Min A. Jhun, Marit E. Jørgensen, Markus Juonala, Mika Kähönen, Magnus Karlsson, Heikki A. Koistinen, Ivana Kolcic, Genovefa Kolovou, Charles Kooperberg, Bernhard K. Krämer, Johanna Kuusisto, Kirsti Kvaløy, Timo A. Lakka, Claudia Langenberg, Lenore J. Launer, Karin Leander, Nanette R. Lee, Lars Lind, Cecilia M. Lindgren, Allan Linneberg, Stephane Lobbens, Marie Loh, Mattias Lorentzon, Robert Luben, Gitta Lubke, Anja Ludolph-Donislawski, Sara Lupoli, Pamela A. F. Madden, Reija Männikkö, Pedro Marques-Vidal, Nicholas G. Martin, Colin A. McKenzie, Barbara McKnight, Dan Mellström, Cristina Menni, Grant W. Montgomery, AW (Bill) Musk, Narisu Narisu, Matthias Nauck, Ilja M. Nolte, Albertine J. Oldehinkel, Matthias Olden, Ken K. Ong, Sandosh Padmanabhan, Patricia A. Peyser, Charlotta Pisinger, David J. Porteous, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Laura J. Rasmussen-Torvik, Rajesh Rawal, Treva Rice, Paul M. Ridker, Lynda M. Rose, Stephanie A. Bien, Igor Rudan, Serena Sanna, Mark A. Sarzynski, Naveed Sattar, Kai Savonen, David Schlessinger, Salome Scholtens, Claudia Schurmann, Robert A. Scott, Bengt Sennblad, Marten A. Siemelink, Günther Silbernagel, P Eline Slagboom, Harold Snieder, Jan A. Staessen, David J. Stott, Morris A. Swertz, Amy J. Swift, Kent D. Taylor, Bamidele O. Tayo, Barbara Thorand, Dorothee Thuillier, Jaakko Tuomilehto, Andre G. Uitterlinden, Liesbeth Vandenput, Marie-Claude Vohl, Henry Völzke, Judith M. Vonk, Gérard Waeber, Melanie Waldenberger, R. G. J. Westendorp, Sarah Wild, Gonneke Willemsen, Bruce H. R. Wolffenbuttel, Andrew Wong, Alan F. Wright, Wei Zhao, M Carola Zillikens, Damiano Baldassarre, Beverley Balkau, Stefania Bandinelli, Carsten A. Böger, Dorret I. Boomsma, Claude Bouchard, Marcel Bruinenberg, Daniel I. Chasman, Yii-DerIda Chen, Peter S. Chines, Richard S. Cooper, Francesco Cucca, Daniele Cusi, Ulf de Faire, Luigi Ferrucci, Paul W. Franks, Philippe Froguel, Penny Gordon-Larsen, Hans- Jörgen Grabe, Vilmundur Gudnason, Christopher A. Haiman, Caroline Hayward, Kristian Hveem, Andrew D. Johnson, J Wouter Jukema, Sharon L. R. Kardia, Mika Kivimaki, Jaspal S. Kooner, Diana Kuh, Markku Laakso, Terho Lehtimäki, Loic Le Marchand, Winfried März, Mark I. McCarthy, Andres Metspalu, Andrew P. Morris, Claes Ohlsson, Lyle J. Palmer, Gerard Pasterkamp, Oluf Pedersen, Annette Peters, Ulrike Peters, Ozren Polasek, Bruce M. Psaty, Lu Qi, Rainer Rauramaa, Blair H. Smith, Thorkild I. A. Sørensen, Konstantin Strauch, Henning Tiemeier, Elena Tremoli, Pim van der Harst, Henrik Vestergaard, Peter Vollenweider, Nicholas J. Wareham, David R. Weir, John B. Whitfield, James F. Wilson, Jessica Tyrrell, Timothy M. Frayling, Inês Barroso, Michael Boehnke, Panagiotis Deloukas, Caroline S. Fox, Joel N. Hirschhorn, David J. Hunter, Tim D. Spector, David P. Strachan, Cornelia M. van Duijn, Iris M. Heid, Karen L. Mohlke, Jonathan Marchini, Ruth J. F. Loos, Tuomas O. Kilpeläinen, Ching-Ti Liu, Ingrid B. Borecki, Kari E. North, and L Adrienne Cupples

Subjects
Science
Abstract

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Published
2017
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15. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Janina S. Ried, Janina Jeff M., Audrey Y. Chu, Jennifer L. Bragg-Gresham, Jenny van Dongen, Jennifer E. Huffman, Tarunveer S. Ahluwalia, Gemma Cadby, Niina Eklund, Joel Eriksson, Tõnu Esko, Mary F. Feitosa, Anuj Goel, Mathias Gorski, Caroline Hayward, Nancy L. Heard-Costa, Anne U. Jackson, Eero Jokinen, Stavroula Kanoni, Kati Kristiansson, Zoltán Kutalik, Jari Lahti, Jian'an Luan, Reedik Mägi, Anubha Mahajan, Massimo Mangino, Carolina Medina-Gomez, Keri L. Monda, Ilja M. Nolte, Louis Pérusse, Inga Prokopenko, Lu Qi, Lynda M. Rose, Erika Salvi, Megan T. Smith, Harold Snieder, Alena Stančáková, Yun Ju Sung, Ioanna Tachmazidou, Alexander Teumer, Gudmar Thorleifsson, Pim van der Harst, Ryan W. Walker, Sophie R. Wang, Sarah H. Wild, Sara M. Willems, Andrew Wong, Weihua Zhang, Eva Albrecht, Alexessander Couto Alves, Stephan J. L. Bakker, Cristina Barlassina, Traci M. Bartz, John Beilby, Claire Bellis, Richard N. Bergman, Sven Bergmann, John Blangero, Matthias Blüher, Eric Boerwinkle, Lori L. Bonnycastle, Stefan R. Bornstein, Marcel Bruinenberg, Harry Campbell, Yii-Der Ida Chen, Charleston W. K. Chiang, Peter S. Chines, Francis S Collins, Fracensco Cucca, L Adrienne Cupples, Francesca D’Avila, Eco J .C. de Geus, George Dedoussis, Maria Dimitriou, Angela Döring, Johan G. Eriksson, Aliki-Eleni Farmaki, Martin Farrall, Teresa Ferreira, Krista Fischer, Nita G. Forouhi, Nele Friedrich, Anette Prior Gjesing, Nicola Glorioso, Mariaelisa Graff, Harald Grallert, Niels Grarup, Jürgen Gräßler, Jagvir Grewal, Anders Hamsten, Marie Neergaard Harder, Catharina A. Hartman, Maija Hassinen, Nicholas Hastie, Andrew Tym Hattersley, Aki S. Havulinna, Markku Heliövaara, Hans Hillege, Albert Hofman, Oddgeir Holmen, Georg Homuth, Jouke-Jan Hottenga, Jennie Hui, Lise Lotte Husemoen, Pirro G. Hysi, Aaron Isaacs, Till Ittermann, Shapour Jalilzadeh, Alan L. James, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Johanne Marie Justesen, Anne E. Justice, Mika Kähönen, Maria Karaleftheri, Kay Tee Khaw, Sirkka M. Keinanen-Kiukaanniemi, Leena Kinnunen, Paul B. Knekt, Heikki A. Koistinen, Ivana Kolcic, Ishminder K. Kooner, Seppo Koskinen, Peter Kovacs, Theodosios Kyriakou, Tomi Laitinen, Claudia Langenberg, Alexandra M. Lewin, Peter Lichtner, Cecilia M. Lindgren, Jaana Lindström, Allan Linneberg, Roberto Lorbeer, Mattias Lorentzon, Robert Luben, Valeriya Lyssenko, Satu Männistö, Paolo Manunta, Irene Mateo Leach, Wendy L. McArdle, Barbara Mcknight, Karen L. Mohlke, Evelin Mihailov, Lili Milani, Rebecca Mills, May E. Montasser, Andrew P. Morris, Gabriele Müller, Arthur W. Musk, Narisu Narisu, Ken K. Ong, Ben A. Oostra, Clive Osmond, Aarno Palotie, James S. Pankow, Lavinia Paternoster, Brenda W. Penninx, Irene Pichler, Maria G. Pilia, Ozren Polašek, Peter P. Pramstaller, Olli T Raitakari, Tuomo Rankinen, D. C. Rao, Nigel W. Rayner, Rasmus Ribel-Madsen, Treva K. Rice, Marcus Richards, Paul M. Ridker, Fernando Rivadeneira, Kathy A. Ryan, Serena Sanna, Mark A. Sarzynski, Salome Scholtens, Robert A. Scott, Sylvain Sebert, Lorraine Southam, Thomas Hempel Sparsø, Valgerdur Steinthorsdottir, Kathleen Stirrups, Ronald P. Stolk, Konstantin Strauch, Heather M. Stringham, Morris A. Swertz, Amy J. Swift, Anke Tönjes, Emmanouil Tsafantakis, Peter J. van der Most, Jana V. Van Vliet-Ostaptchouk, Liesbeth Vandenput, Erkki Vartiainen, Cristina Venturini, Niek Verweij, Jorma S. Viikari, Veronique Vitart, Marie-Claude Vohl, Judith M. Vonk, Gérard Waeber, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Thomas W. Winkler, Alan F. Wright, Laura M. Yerges-Armstrong, Jing Hua Zhao, M. Carola Zillikens, Dorret I. Boomsma, Claude Bouchard, John C. Chambers, Daniel I. Chasman, Daniele Cusi, Ron T. Gansevoort, Christian Gieger, Torben Hansen, Andrew A. Hicks, Frank Hu, Kristian Hveem, Marjo-Riitta Jarvelin, Eero Kajantie, Jaspal S. Kooner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Andres Metspalu, Inger Njølstad, Claes Ohlsson, Albertine J. Oldehinkel, Lyle J. Palmer, Oluf Pedersen, Markus Perola, Annette Peters, Bruce M. Psaty, Hannu Puolijoki, Rainer Rauramaa, Igor Rudan, Veikko Salomaa, Peter E. H. Schwarz, Alan R. Shudiner, Jan H. Smit, Thorkild I. A. Sørensen, Timothy D. Spector, Kari Stefansson, Michael Stumvoll, Angelo Tremblay, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Uwe Völker, Peter Vollenweider, Nicholas J. Wareham, Hugh Watkins, James F. Wilson, Eleftheria Zeggini, Goncalo R. Abecasis, Michael Boehnke, Ingrid B. Borecki, Panos Deloukas, Cornelia M. van Duijn, Caroline Fox, Leif C. Groop, Iris M. Heid, David J. Hunter, Robert C. Kaplan, Mark I. McCarthy, Kari E. North, Jeffrey R. O'Connell, David Schlessinger, Unnur Thorsteinsdottir, David P. Strachan, Timothy Frayling, Joel N. Hirschhorn, Martina Müller-Nurasyid, and Ruth J. F. Loos

Subjects
Science
Abstract

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Published
2016
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16. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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17. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 2; referees: 2 approved]

Author

Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London

Subjects
Genomics, Medicine, Science
Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018
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18. Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution.

Author

Cecilia M. Lindgren, Iris M. Heid, Joshua C. Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K. Speliotes, Gudmar Thorleifsson, Cristen J. Willer, Blanca M. Herrera, Anne U. Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S. Aulchenko, John C. Chambers, Alexander Drong, Jian'an Luan, Helen N. Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J. Timpson, M. Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J. Bennett, Richard N. Bergman, Lori L. Bonnycastle, Suzannah J. Bumpstead, Stephen J. Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S. F. Doney, Shah Ebrahim, Paul Elliott, Michael R. Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G. Forouhi, Christian Gieger, Harald Grallert, Christopher J. Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S. Havulinna, Albert Hofman, Rolf Holle, John W. Holloway, Thomas Illig, Bo Isomaa, Leonie C. Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G. Mark Lathrop, Debbie A. Lawlor, Massimo Mangino, Wendy L. McArdle, Thomas Meitinger, Mario A. Morken, Andrew P. Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A. Oostra, Colin N. A. Palmer, Felicity Payne, John F. Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S. Sandhu, Laura J. Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M. Stringham, Amy J. Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G. Bragi Walters, Michael N. Weedon, Jacqueline C. M. Witteman, Cuilin Zhang, Weihua Zhang, Mark J. Caulfield, Francis S. Collins, George Davey Smith, Ian N. M. Day, Paul W. Franks, Andrew T. Hattersley, Frank B. Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S. Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D. Morris, Leena Peltonen, Nilesh J. Samani, Timothy D. Spector, David P. Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G. Uitterlinden, Cornelia M. van Duijn, Nicholas J. Wareham, Hugh Watkins for the PROCARDIS consortia, Dawn M. Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J. Hunter, Unnur Thorsteinsdottir, David Schlessinger, H.-Erich Wichmann, Timothy M. Frayling, Gonçalo R. Abecasis, Joel N. Hirschhorn, Ruth J. F. Loos, Kari Stefansson, Karen L. Mohlke, Inês Barroso, and Mark I. McCarthy for the GIANT consortium

Subjects
Genetics, QH426-470
Published
2009
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19. 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

21. Asthma management and control in children, adolescents, and adults in 25 countries: a Global Asthma Network Phase I cross-sectional study

Author

Luis García-Marcos, Chen-Yuan Chiang, M Innes Asher, Guy B Marks, Asma El Sony, Refiloe Masekela, Karen Bissell, Eamon Ellwood, Philippa Ellwood, Neil Pearce, David P Strachan, Kevin Mortimer, Eva Morales, Luljeta N. Ahmetaj, Gideon A. Ajeagah, Ghroob Alkhayer, Shaker A. Alomary, Maria J. Ambriz-Moreno, Alfredo Arias-Cruz, Shally Awasthi, Hector Badellino, Nasrin Behniafard, Alberto Bercedo-Sanz, Grzegorz Brożek, Ibadete Bucaliu-Ismajli, Angela Cabrera-Aguilar, Sasawan Chinratanapisit, Blanca E. Del-Río-Navarro, Kostas Douros, Hana El Sadig, Alberto J. Escalante-Dominguez, Adegoke G. Falade, Besa Gacaferri-Lumezi, Roberto García-Almaráz, Rosa Garcia-Muñoz, Valbona Ghashi, Aloke G. Ghoshal, Carlos González-Díaz, Leonora Hana-Lleshi, Luis O. Hernández-Mondragón, Jing-Long Huang, Carlos A. Jiménez-González, M. Ángeles Juan-Pineda, Sanjay K. Kochar, Kseniiay Kuzmicheva, Francisco J. Linares-Zapien, Violeta Lokaj-Berisha, Angel López-Silvarrey, José S. Lozano-Sáenz, Padukudru A. Mahesh, Javier Mallol, Antonia E. Martinez-Torres, J. Valente Mérida-Palacio, Yousser Mohammad, Héctor L. Moreno-Gardea, Elsy M. Navarrete-Rodriguez, Achiri E. Ndikum, Magde Noor, Georgina Ochoa-Lopez, Laura Pajaziti, Javier Pellegrini-Belinchon, Virginia Perez-Fernández, Kostas Priftis, Beatriz C. Ramos-García, Jagath C. Ranasinghe, Steve Robertson, Noel Rodriguez-Perez, Charlotte E. Rutter, José A. Sacre-Hazouri, Sundeep Salvi, Javier F. Sanchez, José F. Sánchez, Maria G. Sanchez-Coronel, Omar J. Saucedo-Ramirez, Meenu Singh, Nishtha Singh, Virendra Singh, Sanjeev Sinha, Niranjan Sit, Suyapa M. Sosa-Ferrari, Manuel E. Soto-Martínez, Marylin Urrutia-Pereira, Kuo-Wei Yeh, Heather J. Zar, and Valbona Zhjeqi

Subjects
General Medicine
Published
2023

23. Retinal microvascular associations with cardiometabolic risk factors differ by diabetes status: results from the UK Biobank

Author

Robyn J, Tapp, Christopher G, Owen, Sarah A, Barman, David P, Strachan, Roshan A, Welikala, Paul J, Foster, Peter H, Whincup, and Alicja R, Rudnicka

Subjects
Arterioles, C-Reactive Protein, Cholesterol, Risk Factors, Endocrinology, Diabetes and Metabolism, Diabetes Mellitus, Internal Medicine, Cardiometabolic Risk Factors, Humans, Retinal Vessels, Blood Pressure, United Kingdom, Biological Specimen Banks
Abstract

Aims/hypothesis The aim of the study was to examine the association of retinal vessel morphometry with BP, body composition and biochemistry, and to determine whether these associations differ by diabetes status. Methods The UK Biobank ocular assessment included 68,550 participants aged 40-70 years who underwent non-mydriatic retinal photography, BP and body composition measurements, and haematological analysis. A fully automated image analysis program provided measurements of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiometabolic risk factors by diabetes status were examined using multilevel linear regression, to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing for within-person clustering). Results A total of 50,233 participants (a reduction from 68,550) were included in these analyses. Overall, those with diabetes had significantly more tortuous venules and wider arteriolar diameters compared with those without. Associations between venular tortuosity and cardiometabolic risk factors differed according to diabetes status (p interaction 1c, C-reactive protein, white cell count and granulocyte count. For example, a unit rise in white cell count was associated with a 0.18% increase (95% CI 0.05, 0.32%) in venular tortuosity for those without diabetes and a 1.48% increase (95% CI 0.90, 2.07%) among those with diabetes. For arteriolar diameter, significant interactions were evident for systolic BP, diastolic BP, mean arterial pressure (MAP) and LDL-cholesterol. For example, a 10 mmHg rise in systolic BP was associated with a −0.92 μm difference (95% CI −0.96 to −0.88 μm) in arteriolar diameter for those without diabetes, and a −0.58 μm difference (95% CI −0.76 to −0.41 μm) among those with diabetes. No interactions were observed for arteriolar tortuosity or venular diameters. Conclusions/interpretation We provide clear evidence of the modifying effect of diabetes on cardiometabolic risk factor associations with retinal microvascular architecture. These observations suggest the occurrence of preclinical disease processes, and may be a sign of impaired autoregulation due to hyperglycaemia, which has been suggested to play a pivotal role in the development of diabetes-related microvascular complications. Data Availability The data supporting the results reported here are available through the UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access). Graphical abstract

Published
2022

25. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author

Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen

Subjects
Genetics, QH426-470
Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017
Full Text
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26. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.

Author

Paul S de Vries, Maria Sabater-Lleal, Daniel I Chasman, Stella Trompet, Tarunveer S Ahluwalia, Alexander Teumer, Marcus E Kleber, Ming-Huei Chen, Jie Jin Wang, John R Attia, Riccardo E Marioni, Maristella Steri, Lu-Chen Weng, Rene Pool, Vera Grossmann, Jennifer A Brody, Cristina Venturini, Toshiko Tanaka, Lynda M Rose, Christopher Oldmeadow, Johanna Mazur, Saonli Basu, Mattias Frånberg, Qiong Yang, Symen Ligthart, Jouke J Hottenga, Ann Rumley, Antonella Mulas, Anton J M de Craen, Anne Grotevendt, Kent D Taylor, Graciela E Delgado, Annette Kifley, Lorna M Lopez, Tina L Berentzen, Massimo Mangino, Stefania Bandinelli, Alanna C Morrison, Anders Hamsten, Geoffrey Tofler, Moniek P M de Maat, Harmen H M Draisma, Gordon D Lowe, Magdalena Zoledziewska, Naveed Sattar, Karl J Lackner, Uwe Völker, Barbara McKnight, Jie Huang, Elizabeth G Holliday, Mark A McEvoy, John M Starr, Pirro G Hysi, Dena G Hernandez, Weihua Guan, Fernando Rivadeneira, Wendy L McArdle, P Eline Slagboom, Tanja Zeller, Bruce M Psaty, André G Uitterlinden, Eco J C de Geus, David J Stott, Harald Binder, Albert Hofman, Oscar H Franco, Jerome I Rotter, Luigi Ferrucci, Tim D Spector, Ian J Deary, Winfried März, Andreas Greinacher, Philipp S Wild, Francesco Cucca, Dorret I Boomsma, Hugh Watkins, Weihong Tang, Paul M Ridker, Jan W Jukema, Rodney J Scott, Paul Mitchell, Torben Hansen, Christopher J O'Donnell, Nicholas L Smith, David P Strachan, and Abbas Dehghan

Subjects
Medicine, Science
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017
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27. 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

28. Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years

Author

Philip J. Cooper, David P. Strachan, Mauricio Lima Barreto, Thomas A.E. Platts-Mills, Maritza Vaca, Augusto Maldonado, Yisela Oviedo, Irina Chis Ster, and Martha E. Chico

Subjects
Hypersensitivity, Immediate, 0301 basic medicine, Pediatrics, medicine.medical_specialty, medicine.drug_class, Immunology, atopy, geohelminths, Asthma and Lower Airway Disease, Atopy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Wheeze, Bronchodilator, parasitic diseases, medicine, Humans, Immunology and Allergy, Eosinophilia, Trichiura, Child, Respiratory Sounds, Skin Tests, Asthma, biology, business.industry, Infant, Newborn, asthma, respiratory system, medicine.disease, biology.organism_classification, Early life, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, wheeze, Exhaled nitric oxide, Original Article, Female, Ecuador, ORIGINAL ARTICLES, medicine.symptom, Ascaris lumbricoides, business
Abstract

Background Early‐life exposures to geohelminths may protect against development of wheeze/asthma and atopy. Objective To study the effect of maternal geohelminths and infections in children during the first 5 years on atopy, wheeze/asthma and airways reactivity/inflammation at 8 years. Methods Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. Results 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite‐specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non‐atopic children. Conclusions Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086)., Maternal geohelminths protect 8‐year‐old children from the development of allergen skin prick test reactivity with strongest effects observed in infected children of infected mothers. Early childhood infections with Trichuris trichiura protect against wheeze at 8 years. Effects of geohelminths on wheeze/asthma and airways reactivity and inflammation at 8 years vary by parasite species and atopy.

Published
2021

29. PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Author

Imran Ahmad, Laura C. A. Galbraith, Gillian M. Mackay, Ernest Mui, Colin Nixon, Owen J. Sansom, Hing Y. Leung, David Sumpton, Ann Hedley, and David P. Strachan

Subjects
0301 basic medicine, Male, Cancer Research, Peroxisome proliferator-activated receptor gamma, Epithelial-Mesenchymal Transition, Peroxisome proliferator-activated receptor, Receptors, Cytoplasmic and Nuclear, Biology, Karyopherins, AKT3, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Cell Line, Tumor, Genetics, Animals, Humans, Epithelial–mesenchymal transition, Cancer models, Molecular Biology, Transcription factor, Protein kinase B, chemistry.chemical_classification, Prostate cancer, Organelle Biogenesis, Prostatic Neoplasms, Lipid Metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cell biology, Mitochondria, Gene Expression Regulation, Neoplastic, PPAR gamma, 030104 developmental biology, chemistry, Mitochondrial biogenesis, 030220 oncology & carcinogenesis, Organelle biogenesis, Proto-Oncogene Proteins c-akt
Abstract

Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

Published
2021

30. Artificial intelligence enabled retinal vasculometry for prediction of circulatory mortality, myocardial infarction and stroke

Author

Alicja R Rudnicka, Roshan A Welikala, Sarah A Barman, Paul J Foster, Robert Luben, Shabina A Hayat, Kay-Tee Khaw, Peter H Whincup, David P Strachan, and Christopher G Owen

Abstract

AimsWe examine whether inclusion of Artificial Intelligence (AI)-enabled retinal vasculometry (RV) improves existing risk algorithms for incident stroke, myocardial infarction (MI) and circulatory mortality.MethodsAI-enabled retinal vessel image analysis processed images from 88,052 UK Biobank (UKB) participants (aged 40-69 years at image capture) and 7,411 EPIC-Norfolk participants (aged 48-92). Retinal arteriolar and venular width, tortuosity and area were extracted. Prediction models were developed in UKB using multivariable Cox proportional hazards regression for circulatory mortality, incident stroke and MI, and externally validated in EPIC-Norfolk. Model performance was assessed using optimism adjusted calibration, C- and R2 statistics. Performance of Framingham risk scores (FRS) for incident stroke and incident MI, with addition of RV to FRS, were compared with a simpler model based on RV, age, smoking status and medical history (antihypertensive/cholesterol lowering medication, diabetes, prevalent stroke/MI).ResultsUKB prognostic models were developed on 65,144 participants (mean age 56.8; median follow-up 7.7 years) and validated in 5,862 EPIC-Norfolk participants (67.6, 9.1 years respectively). Prediction models for circulatory mortality in men and women had optimism adjusted C- and R2 statistics between 0.75-0.77 and 0.33-0.44 respectively. For incident stroke and MI, addition of RV to FRS did not improve model performance in either cohort. However, the simpler RV model performed equally or better than FRS.ConclusionRV offers an alternative predictive biomarker to traditional risk-scores for vascular health, without the need for blood sampling or blood pressure measurement. Further work is needed to examine RV in population screening to triage individuals at high-risk. (250 words)HIGHLIGHTSWhat is already known on this topicPopulation screening for MI and stroke using risk prediction tools exist but have limited uptake; risk scores for circulator mortality do not exist.What this study addsRisk models developed in UK Biobank (validated in EPIC-Norfolk) using Artificial Intelligence (AI)-enabled retinal vasculometry (RV), age, history of cardiovascular disease, use of hypertensive medication and smoking yielded high predictive test performance for circulatory mortality.Risk scores for MI and stroke performed similarly to established risk scores.How this study might affect research, practice or policyAI-enabled RV extraction offers a non-invasive prognostic biomarker of vascular health that does not require blood sampling or blood pressure measurement, and potentially has greater community reach to identify individuals at medium-high risk requiring further clinical assessment.SYNOPSIS/PRECISRisk models developed in UK Biobank (validated in EPIC-Norfolk) using Artificial Intelligence enabled retinal vasculometry indices, age, history of cardiovascular disease, use of hypertensive medication and smoking yielded high predictive test performance for circulatory mortality. Risk scores for MI and stroke performed similarly to established risk scores.

Published
2022

31. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Author

Nick Shrine, Abril G Izquierdo, Jing Chen, Richard Packer, Robert J Hall, Anna L Guyatt, Chiara Batini, Rebecca J Thompson, Chandan Pavuluri, Vidhi Malik, Brian D Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y Millwood, Zhengming Chen, Liming Li, Sara RA Wielscher, Lies Lahousse, Guy Brusselle, Andre G Uitterlinden, Ani Manichaikul, Elizabeth C Oelsner, Stephen S Rich, R. Graham Barr, Shona M Kerr, Veronique Vitart, Michael R Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M Bartz, Sina A Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E Ortega, Deborah A Meyers, Eugene R Bleecker, Stacey B Gabriel, Namrata Gupta, Albert Vernon Smith, Jian’an Luan, Jing-Hua Zhao, Ailin F Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T O’Connor, Gaurav Thareja, Omar M E., Hamdi Mbarek, Karsten Suhre, Raquel Granell, Tariq O Faquih, Pieter S Hiemstra, Annelies M Slats, Benjamin H Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T Koskela, Annah B Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A Kentistou, Peter K Joshi, Paul RHJ Timmers, Alexander T Williams, Robert C Free, Xueyang Wang, John L Morrison, Frank D Gilliland, Zhanghua Chen, Carol A Wang, Rachel E Foong, Sarah E Harris, Adele Taylor, Paul Redmond, James P Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H Pietiläinen, Simon R Cox, Craig E Pennell, Graham L Hall, W. James Gauderman, Chris Brightling, James F Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O Mook-Kanamori, Nicholas J Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo-Riitta Jarvelin, Alanna C Morrison, Ozren Polasek, Igor Rudan, Joo-Hyeon Lee, Ian Sayers, Emma L Rawlins, Frank Dudbridge, Edwin K Silverman, David P Strachan, Robin G Walters, Andrew P Morris, Stephanie J London, Michael H Cho, Louise V Wain, Ian P Hall, and Martin D Tobin

Abstract

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2022

32. Retinal Vascular Tortuosity and Diameter Associations with Adiposity and Components of Body Composition

Author

R.A. Welikala, Alicja R. Rudnicka, Paul J. Foster, Christopher G. Owen, David P. Strachan, Peter H. Whincup, Sarah Barman, and Robyn J. Tapp

Subjects
Adult, Male, medicine.medical_specialty, Waist, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), 030209 endocrinology & metabolism, alliedhealth, Tortuosity, Article, Retina, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Humans, Mass index, 030212 general & internal medicine, Adiposity, Aged, Aged, 80 and over, Nutrition and Dietetics, business.industry, Retinal Vessels, Retinal, Retinal vascular tortuosity, Middle Aged, Circumference, medicine.disease, Obesity, Multilevel regression, chemistry, Microvessels, Cardiology, Body Composition, Female, business, biological
Abstract

The aim of this study was to assess whether adiposity or body composition relates to microvascular characteristics of the retina, indicative of cardiometabolic function. A fully automated QUARTZ software processed retinal images from 68,550 UK Biobank participants (aged 40-69 years). Differences in retinal vessel diameter and tortuosity with body composition measures from the Tanita analyzer were obtained by using multilevel regression analyses adjusted for age, sex, ethnicity, clinic, smoking, and Townsend deprivation index. Venular tortuosity and diameter increased by approximately 2% (P

Published
2020

33. Retinal Vasculometry Associations With Glaucoma: Findings From the European Prospective Investigation of Cancer–Norfolk Eye Study

Author

Kay-Tee Khaw, Paul J. Foster, Anthony P Khawaja, Alicja R. Rudnicka, Christopher G. Owen, Robert Luben, Shabina Hayat, David P. Strachan, Sarah Barman, Peter H. Whincup, R.A. Welikala, David C Broadway, Michelle P.Y. Chan, Luben, Robert [0000-0002-5088-6343], Hayat, Shabina [0000-0001-9068-8723], and Apollo - University of Cambridge Repository

Subjects
Male, medicine.medical_specialty, Biometry, genetic structures, Glaucoma, Ocular hypertension, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ophthalmology, medicine, Humans, Prospective Studies, Intraocular Pressure, 030304 developmental biology, Aged, 0303 health sciences, business.industry, Cancer, Retinal Vessels, Retinal, Glaucoma suspect, medicine.disease, Confidence interval, eye diseases, Europe, Cross-Sectional Studies, chemistry, 030221 ophthalmology & optometry, Retinal imaging, Original Article, Female, sense organs, High intraocular pressure, business, biological, Glaucoma, Open-Angle, Tomography, Optical Coherence
Abstract

Purpose To examine retinal vasculometry associations with different glaucomas in older British people. Design Cross-sectional study. Methods A total of 8,623 European Prospective Investigation into Cancer-Norfolk Eye study participants were examined, who underwent retinal imaging, ocular biometry assessment, and clinical ascertainment of ocular hypertensive or glaucoma status (including glaucoma suspect [GS], high-tension open-angle glaucoma [HTG], and normal-tension glaucoma [NTG]). Automated measures of arteriolar and venular tortuosity, area, and width from retinal images were obtained. MainOutcomeMeasures: Associations between glaucoma and retinal vasculometry outcomes were analyzed using multilevel linear regression, adjusted for age, sex, height, axial length, intraocular and systemic blood pressure, and within-person clustering, to provide absolute differences in width and area, and percentage differences in vessel tortuosity. Presence or absence of within-person-between-eye differences in retinal vasculometry by diagnoses were examined. Results A total of 565,593 vessel segments from 5,947 participants (mean age 67.6 years, SD 7.6 years, 57% women) were included; numbers with HTG, NTG, and GS in at least 1 eye were 87, 82, and 439, respectively. Thinner arterioles (−3.2 μm; 95% confidence interval [CI] −4.4 μm, −1.9 μm) and venules (−2.7 μm; 95% CI −4.9 μm, −0.5 μm) were associated with HTG. Reduced venular area was associated with HTG (−0.2 mm2; 95% CI −0.3 mm2, −0.1 mm2) and NTG (−0.2 mm2; 95% CI −0.3 mm2, −0.0 mm2). Less tortuous retinal arterioles and venules were associated with all glaucomas, but only significantly for GS (−3.9%; 95% CI −7.7%, −0.1% and −4.8%; 95% CI −7.4%, −2.1%, respectively). There was no evidence of within-person-between-eye differences in retinal vasculometry associations by diagnoses. Conclusions Retinal vessel width associations with glaucoma and novel associations with vessel area and tortuosity, together with no evidence of within-person-between-eye differences in retinal vasculometry, suggest a vascular cause of glaucoma., Highlights • Retinal vessel measurements, including (as a first report) vessel tortuosity and area, were associated with high-tension glaucoma and other glaucoma-related outcomes. • Novel analyses showing that within-person-between-eye glaucoma diagnoses, intraocular pressure, and retinal vasculometry were uncorrelated provides further evidence that systemic microvascular changes may cause glaucoma.

Published
2020

34. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Author

Alison D. Murray, Anna L. Guyatt, Jing Hua Zhao, Eugene R. Bleecker, Matthias Wielscher, Frank Dudbridge, Martin D. Tobin, Veronique Vitart, Ida Surakka, Nadia N. Hansel, Ozren Polasek, Caroline Hayward, David P. Strachan, Per Bakke, Stefan Karrasch, Anubha Mahajan, James F. Wilson, Shona M. Kerr, Ruth Tal-Singer, James D. Crapo, Victoria E. Jackson, Jonathan Marten, Olli T. Raitakari, María Soler Artigas, Medea Imboden, Sungho Won, Beate Stubbe, Ulf Gyllensten, George R. Washko, Eleftheria Zeggini, David A. Lynch, Brian D. Hobbs, Matthew Moll, Mika Kähönen, Rajesh Rawal, Guy Brusselle, Ma'en Obeidat, Nicholas J. Wareham, Claudia Langenberg, Nicole Probst-Hensch, Peter K. Joshi, Blair H. Smith, Stefan Weiss, Woo Jin Kim, Kathleen C. Barnes, Sarah E. Harris, David J. Porteous, Stefan Enroth, Ian P. Hall, Alan L. James, Sina A. Gharib, Paul R. H. J. Timmers, Xingnan Li, Louise V. Wain, John E. Hokanson, Holger Schulz, Ralf Ewert, Ani Manichaikul, Lies Lahousse, Georg Homuth, R. Graham Barr, Scott T. Weiss, Phuwanat Sakornsakolpat, Sara R.A. Wijnant, Edwin K. Silverman, Christian Gieger, Jennie Hui, Andrew P. Morris, James P. Cook, Michael J. McGeachie, Dawn L. DeMeo, Nick Shrine, Traci M. Bartz, Amund Gulsvik, Deborah A. Meyers, Katherine A. Kentistou, Igor Rudan, Jian'an Luan, Ian J. Deary, Catherine John, Michael H. Cho, Lars Lind, Marjo-Riitta Järvelin, Ah Ra Do, Terho Lehtimäki, Stephen S. Rich, Bruce M. Psaty, Tampere University, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Epidemiology, and Pulmonary Medicine

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, AMERICAN THORACIC SOCIETY, Vital Capacity, LOCI, Genome-wide association study, EMPHYSEMA, Cohort Studies, 03 medical and health sciences, FEV1/FVC ratio, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Risk Factors, Internal medicine, Forced Expiratory Volume, adult, case-control studies, cohort studies, female, forced expiratory volume, genome-wide association study, humans, male, middle aged, phenotype, pulmonary disease, chronic obstructive, risk factors, vital capacity, Medicine and Health Sciences, medicine, COPD, Humans, SMOKING-BEHAVIOR, 030212 general & internal medicine, GENOME-WIDE ASSOCIATION, FAMILIAL AGGREGATION, GENETIC EPIDEMIOLOGY, Framingham Risk Score, HERITABILITY, business.industry, Case-control study, Family aggregation, Odds ratio, Articles, Middle Aged, medicine.disease, respiratory tract diseases, LUNG-FUNCTION, Phenotype, 030228 respiratory system, Genetic epidemiology, Case-Control Studies, Female, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Published
2020

36. OP03 Comparative analysis of risk factors for excess and usual mortality during the first 2020 COVID-19 pandemic phase in England*

Author

Umar Chaudhry, Tess Harris, Stephen DeWilde, Iain M Carey, David P. Strachan, and Derek G Cook

Subjects
COPD, Coronavirus disease 2019 (COVID-19), business.industry, medicine.disease, Obesity, symbols.namesake, Standardized mortality ratio, Pandemic, symbols, Area deprivation, Medicine, Medical history, Poisson regression, business, Demography
Abstract

Background The first wave of the COVID-19 pandemic in England resulted in an approximate 50% increase in all-cause mortality during mid-March to mid-May 2020. Previous analyses have studied COVID-related deaths, but these were under-recorded early in the pandemic due to paucity of virological testing. We propose a novel method to identify excess mortality during the pandemic by accounting for usual all-cause mortality in pre-pandemic years using a large electronic primary care database. We estimated the impact of risk factors (RFs) on excess mortality during the first wave and compared these with the impact of the same RFs on total mortality in non-pandemic times. Methods An average of 4.8 million patients aged 30–104 years active in 770 CPRD Aurum practices between 18th March and 19th May over a 6-year period (2015–2020) were included. Concurrent medical history, ethnicity, area-based deprivation and fatalities were extracted for each year. Poisson regression models fitted total mortality adjusting for age and sex, with interactions between each RF and the pandemic and reference periods. Total mortality during the pandemic was partitioned into ‘usual’ and ‘excess’ components, assuming 2015–19 rates represented ‘usual’ mortality. The association of each RF with the 2020 ‘excess’ component was derived as the excess mortality ratio (EMR), to compare with the usual mortality ratio (UMR). Results RFs where excess mortality was greatest and notably higher than usual were age >80, black ethnicity, BMI>40, dementia, learning disability, London practices and people in care-homes. For example, people of black ethnicity vs. white had an EMR=2.50 (95%CI 1.97–3.18) compared to a UMR=0.92 (95%CI 0.85–1.00). Excess mortality was more comparable to usual mortality for sex and area deprivation. The EMR for men (1.46, 95%CI 1.32–1.60) was not significantly different than the UMR=1.34 (95%CI 1.32–1.37). The EMR=2.05 (95%CI 1.76–2.38) in the most deprived quintile (vs. least) was only slightly higher than the UMR=1.70 (95%CI 1.65–1.75). Although some RFs produced EMRs significantly lower than their UMRs (Cancer, COPD), the EMRs were still >1. However, current smoking was inversely associated with excess mortality: while current smokers were 64% more likely to die than non-smokers in 2020, when the UMR=2.12 (95%CI 2.07–2.18) was accounted for, the EMR=0.80 (95%CI 0.65–0.98). Conclusion Utilising large electronic patient databases to study trends in excess mortality during the pandemic confirmed some reported findings (e.g. ethnicity, obesity and care-homes), but also highlighted important differences not apparent from studying cause specific mortality during the pandemic (e.g. smoking, sex and area deprivation).

Published
2021

37. Inter-Relationship between Rhinitis and Conjunctivitis in Allergic Rhinoconjunctivitis and Associated Risk Factors in Rural UK Children.

Author

Michael R Perkin, Tara Bader, Alicja R Rudnicka, David P Strachan, and Christopher G Owen

Subjects
Medicine, Science
Abstract

Allergic conjunctivitis (AC) is a common condition, especially in childhood. The extent to which it occurs concurrently with or independently from allergic rhinitis (AR) has not been well described.To examine the inter-relationship between rhinitis and conjunctivitis and the epidemiological risk factors for these conditions in a rural UK population.Cross-sectional study of rural school children (aged 5-11 years). Parental questionnaires were used to diagnose allergic outcomes (including conjunctivitis, rhinitis and rhinoconjunctivitis), and to collect data on atopic history, demographic and environmental exposures. Odds ratios of allergic outcome by exposure were examined adjusted for age, sex, breastfeeding, family history of allergy, number of older and younger siblings.Prevalence of conjunctivitis was 17.5%, rhinitis 15.1% and rhinoconjunctivitis 13.0%. Seasonality of symptoms varied by condition: 64.7% of those with conjunctivitis had seasonal symptoms (April-Sept only), 46.7% of those with rhinitis and 92.2% of those with rhinoconjunctivitis. Living on a farm consistently reduced the risk of conjunctivitis (odds ratio 0.47, 95%CI 0.29-0.79, p = 0.004), rhinitis (OR 0.57, 95%CI 0.33-1.01, p = 0.05) and rhinoconjunctivitis (OR 0.57, 95%CI 0.32-1.03, p = 0.06). Exposure to farm animals (particularly in early life), current consumption of unpasteurised milk and playing in a barn or stable significantly reduced the risk of all three conditions.More children had parent-reported conjunctivitis than rhinitis. The majority of children with either condition also reported symptoms with the other condition. Farmers' children have less eye and/or nasal symptoms. A number of farming variables linked with the farm microbial environment are likely to be mediating the protective effect.

Published
2015
Full Text
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38. Author response for 'Worldwide time trends in prevalence of symptoms of rhinoconjunctivitis in children: Global Asthma Network Phase I'

Author

null David P Strachan, null Charlotte E Rutter, null M Innes Asher, null K Bissell, null Chen‐Yuan Chiang, null Asma El Sony, null Eamon Ellwood, null Philippa Ellwood, null Luis García‐Marcos, null Guy B Marks, null Eva Morales, null Kevin Mortimer, null Neil Pearce, null Virginia Pérez‐Fernández, null Steven Robertson, null Richard J Silverwood, and null The Global Asthma Network Phase I Study Group

Subjects
Time trends, business.industry, medicine, medicine.disease, business, Phase (combat), Asthma, Demography
Published
2021

39. The rising tide of dementia deaths: triangulation of data from three routine data sources using the Clinical Practice Research Datalink

Author

Iain M Carey, David P. Strachan, Shaleen Ahmad, Stephen DeWilde, Tess Harris, and Derek G Cook

Subjects
medicine.medical_specialty, medicine.medical_treatment, Prior diagnosis, Information Storage and Retrieval, Secondary care, 03 medical and health sciences, 0302 clinical medicine, Cause of Death, mental disorders, medicine, Humans, Dementia, 030212 general & internal medicine, Mortality, Retrospective Studies, Cause of death, Rehabilitation, business.industry, Death certificates, RC952-954.6, Retrospective cohort study, Primary care, medicine.disease, Clinical Practice, England, Geriatrics, Emergency medicine, Death certificate, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Research Article
Abstract

Background Dementia is currently the leading certified underlying cause of death in England. We assess how dementia recording on Office for National Statistics death certificates (ONS) corresponded to recording in general practice records (GP) and Hospital Episode Statistics (HES). Methods Retrospective study of deaths (2001-15) in 153 English General Practices contributing to the Clinical Practice Research Datalink, with linked ONS and HES records. Results Of 207,068 total deaths from any cause, 19,627 mentioned dementia on the death certificate with 10,253 as underlying cause; steady increases occurred from 2001 to 2015 (any mention 5.3 to 15.4 %, underlying cause 2.7 to 10 %). Including all data sources, recording of any dementia increased from 13.2 to 28.6 %. In 2015, only 53.8 % of people dying with dementia had dementia recorded on their death certificates. Among deaths mentioning dementia on the death certificate, the recording of a prior diagnosis of dementia in GP and HES rose markedly over the same period. In 2001, only 76.3 % had a prior diagnosis in GP and/or HES records; by 2015 this had risen to 95.7 %. However, over the same period the percentage of all deaths with dementia recorded in GP or HES but not mentioned on the death certificate rose from 7.9 to 13.3 %. Conclusions Dementia recording in all data sources increased between 2001 and 2015. By 2015 the vast majority of deaths mentioning dementia had supporting evidence in primary and/or secondary care. However, death certificates were still providing an inadequate picture of the number of people dying with dementia.

Published
2021

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

Author

Phuwanat Sakornsakolpat, James F. Wilson, María Soler Artigas, Beate Stubbe, Nicholas J. Wareham, James D. Crapo, Victoria E. Jackson, Eleftheria Zeggini, Olga G. Troyanskaya, Medea Imboden, A. Mesut Erzurumluoglu, Adam S. Butterworth, Carl A. Melbourne, Ian Sayers, Lars Lind, Stefan Weiss, Margaret M. Parker, Timmers Prhj, Edwin K. Silverman, John C. Whittaker, Ian P. Hall, Ozren Polasek, Mika Kähönen, Katherine A. Fawcett, Anna Hansell, Liming Li, David J. Porteous, Louise V. Wain, Robert A. Scott, Richard Packer, Richard J. Allen, Robin G Walters, Anna L. Guyatt, Terho Lehtimäki, Nicole Probst-Hensch, Shona M. Kerr, Christian Gieger, Matthias Wielscher, Rajesh Rawal, Jing Hua Zhao, John E. Hokanson, Holger Schulz, Nicola F. Reeve, Claudia Langenberg, Ke Hao, Corry-Anke Brandsma, Megan L. Paynton, Vitart, Dmitry Prokopenko, Jennie Hui, Eugene R. Bleecker, Ma'en Obeidat, John Danesh, Ralf Ewert, Benjamin B. Sun, Frank Dudbridge, Jian Zhou, Brian D. Hobbs, Blair H. Smith, Don D. Sin, Dawn L. DeMeo, Joseph C. Maranville, Ida Surakka, Alison Catherine Murray, Nicholas Locantore, Katherine A. Kentistou, Terri H. Beaty, Igor Rudan, Kuang Lin, Amund Gulsvik, Ian J. Deary, Ruth Tal-Singer, Kijoung Song, David C. Nickle, Michael H. Cho, Jian'an Luan, Joshua D. Hoffman, Georg Homuth, Zhengming Chen, Dandi Qiao, Heiko Runz, Per Bakke, Chiara Batini, Caroline Hayward, Stefan Karrasch, Alan James, Andrew P. Morris, Prescott G. Woodruff, Laura M Yerges Armstrong, David Sparrow, Ulf Gyllensten, James P. Cook, Jonathan Marten, Olli T. Raitakari, Nick Shrine, Deborah A. Meyers, Tobin, Ruth Boxall, Marjo-Riitta Järvelin, David P. Strachan, Sarah E. Harris, Philippe Joubert, Stefan Enroth, Xingnan Li, van den Berge M, Anubha Mahajan, Yohan Bossé, Peter K. Joshi, Shrine, Nick [0000-0003-3641-4371], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Sakornsakolpat, Phuwanat [0000-0002-4308-0974], Obeidat, Ma'en [0000-0002-5443-2752], Weiss, Stefan [0000-0002-3553-4315], Kentistou, Katherine A [0000-0002-5816-664X], Sun, Benjamin B [0000-0001-6347-2281], Enroth, Stefan [0000-0002-5056-9137], Vitart, Veronique [0000-0002-4991-3797], Allen, Richard J [0000-0002-8450-3056], Beaty, Terri H [0000-0002-7644-1705], Bossé, Yohan [0000-0002-3067-3711], Joshi, Peter K [0000-0002-6361-5059], Mahajan, Anubha [0000-0001-5585-3420], Murray, Alison [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Sayers, Ian [0000-0001-5601-5410], Smith, Blair H [0000-0002-5362-9430], Tal-Singer, Ruth [0000-0002-5275-8062], Timmers, Paul RHJ [0000-0002-5197-1267], Troyanskaya, Olga G [0000-0002-5676-5737], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Zeggini, Eleftheria [0000-0003-4238-659X], Hayward, Caroline [0000-0002-9405-9550], Morris, Andrew P [0000-0002-6805-6014], Butterworth, Adam S [0000-0002-6915-9015], Walters, Robin G [0000-0002-9179-0321], Cho, Michael H [0000-0002-4907-1657], Strachan, David P [0000-0001-7854-1366], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Groningen Research Institute for Asthma and COPD (GRIAC), UNIVERSITY OF OULU, and Commission of the European Communities

Subjects
Male, Smoking/genetics, LOCI, Genome-wide association study, VARIANTS, Bioinformatics, Genome-wide association studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GWAS, GENOME-WIDE ASSOCIATION, HERITABILITY, COPD, Lung, 11 Medical and Health Sciences, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Genetic Predisposition to Disease/genetics, Smoking, 1184 Genetics, developmental biology, physiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, 3. Good health, medicine.anatomical_structure, Meta-analysis, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Understanding Society Scientific Group, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Aged, Respiratory tract diseases, Science & Technology, Case-control study, Lung/physiopathology, 06 Biological Sciences, medicine.disease, Pulmonary Disease, Chronic Obstructive/genetics, respiratory tract diseases, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.

Published
2019

41. Retinal Vasculometry Associations with Cardiometabolic Risk Factors in the European Prospective Investigation of Cancer—Norfolk Study

Author

R.A. Welikala, David P. Strachan, Robert Luben, Paul J. Foster, Sarah Barman, Kay-Tee Khaw, Peter H. Whincup, Christopher G. Owen, Alicja R. Rudnicka, Shabina Hayat, Muhammad Moazam Fraz, Luben, Robert [0000-0002-5088-6343], Hayat, Shabina [0000-0001-9068-8723], Khaw, Kay-Tee [0000-0002-8802-2903], and Apollo - University of Cambridge Repository

Subjects
Male, BMI, body mass index, Blood Pressure, Type 2 diabetes, CHD, coronary heart disease, Body Mass Index, 0302 clinical medicine, Venules, Risk Factors, LDL, low-density lipoprotein, Medicine, Prospective Studies, Myocardial infarction, Prospective cohort study, Stroke, 0303 health sciences, Middle Aged, 3. Good health, Arterioles, Cardiovascular Diseases, Cardiology, Female, medicine.medical_specialty, Retinal Artery, HDL, high-density lipoprotein, CVD, cardiovascular disease, Article, 03 medical and health sciences, Retinal Diseases, Internal medicine, Diabetes mellitus, Humans, Triglycerides, Aged, 030304 developmental biology, Glycated Hemoglobin, EPIC, European Prospective Investigation into Cancer, HbA1c, hemoglobin A1c, business.industry, medicine.disease, Retinal Vein, United Kingdom, Confidence interval, CI, confidence interval, Ophthalmology, Blood pressure, Diabetes Mellitus, Type 2, Microvessels, 030221 ophthalmology & optometry, SD, standard deviation, business, Body mass index
Abstract

Purpose To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. Design Retinal imaging examination as part of the European Prospective Investigation into Cancer—Norfolk Eye Study. Participants Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. Methods Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. Main Outcomes Measures Retinal arteriolar and venular tortuosity and width. Results In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%–3.3% per 5 kg/m 2 ), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%–3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%–10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2–2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3–0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4–1.0 per 5 kg/m 2 ), HbA1c level (0.4 μm; 95% CI, –0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7–4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3–2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7–2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%–7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%–1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%–6.4%), and in those with prevalent stroke (8.3%; 95% CI, –0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6–1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4–0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0–0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7–1.6 μm per 1 mmol/l). Conclusions Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

Published
2019

42. Variants associated with HHIP expression have sex-differential effects on lung function

Author

Carl A. Melbourne, Caroline Hayward, Stefan Karrasch, Dirk Keidel, Katherine A. Fawcett, Susan M. Ring, Yohan Bossé, Carol A. Wang, Ben Michael Brumpton, Claudia Langenberg, Peter K. Joshi, Ke Hao, Igor Rudan, David J. Porteous, Don D. Sin, Raquel Granell, Blair H. Smith, Jian'an Luan, Kristian Hveem, Sarah E. Harris, Sandosh Padmanabhan, Archie Campbell, Sebastian May-Wilson, Veronique Vitart, Nicola Pirastu, Arnulf Langhammer, Craig E. Pennell, John M. Starr, Stefan Weiss, Karina Patasova, Nicholas J. Wareham, James F. Wilson, Deborah Jarvis, Tim D. Spector, Nick Shrine, David P. Strachan, Martin D. Tobin, Beate Stubbe, David M. Evans, Kirsi H. Pietiläinen, Mangino Massimo, Ian P. Hall, Graham L. Hall, Jaakko Kaprio, Ralf Ewert, Rachel E. Foong, Claudia Flexeder, Louise V. Wain, Ma'en Obeidat, Cristen J. Willer, Leo-Pekka Lyytikäinen, Olli T. Raitakari, John Henderson, Konstantin Strauch, Marta R Moksnes, Cosetta Minelli, Nicole Probst-Hensch, Pirro G. Hysi, Anna L. Guyatt, Henry Völzke, Thomas Meitinger, Peter D. Sly, Ozren Polasek, Anne Richmond, Mika Kähönen, Maarten van den Berge, Medea Imboden, Thibaud Boutin, Lucija Klaric, Laura Portas, Terho Lehtimäki, Ian J. Deary, Taina Rantanen, Catherine John, Teemu Palviainen, Fawcett, Katherine A [0000-0002-6675-2112], Obeidat, Ma'en [0000-0002-5443-2752], Shrine, Nick [0000-0003-3641-4371], Weiss, Stefan [0000-0002-3553-4315], May-Wilson, Sebastian [0000-0003-2668-5717], Boutin, Thibaud S [0000-0003-4754-1675], Portas, Laura [0000-0003-1789-1893], Harris, Sarah E [0000-0002-4941-5106], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Palviainen, Teemu [0000-0002-7847-8384], Keidel, Dirk [0000-0003-4706-5728], Minelli, Cosetta [0000-0001-9166-3958], Langenberg, Claudia [0000-0002-5017-7344], Bossé, Yohan [0000-0002-3067-3711], Van den Berge, Maarten [0000-0002-9336-7340], Sin, Don D [0000-0002-0756-6643], Campbell, Archie [0000-0003-0198-5078], Porteous, David [0000-0003-1249-6106], Padmanabhan, Sandosh [0000-0003-3869-5808], Smith, Blair H [0000-0002-5362-9430], Ring, Sue [0000-0003-3103-9330], Rantanen, Taina [0000-0002-1604-1945], Pennell, Craig E [0000-0002-0937-6165], Kaprio, Jaakko [0000-0002-3716-2455], Vitart, Veronique [0000-0002-4991-3797], Hayward, Caroline [0000-0002-9405-9550], Hall, Ian P [0000-0001-9933-3216], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Groningen Research Institute for Asthma and COPD (GRIAC), Technology Centre, University of Helsinki, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUS Abdominal Center, Department of Medicine, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Public Health, Research Programs Unit, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, and Department of Clinical Physiology and Nuclear Medicine

Subjects
0301 basic medicine, Spirometry, medicine.medical_specialty, HHIP, Medicine (miscellaneous), Expression, Genome-wide Interaction Study, Hhip, Lung Function, Sex, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Genome-wide interaction study, Lung function, Internal medicine, expression, medicine, sex, Allele, Enhancer, Gene, Lung, genome-wide interaction study, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, lung function, ALSPAC, Differential effects, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Published
2021

43. Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study

Author

M Innes Asher, Charlotte E Rutter, Karen Bissell, Chen-Yuan Chiang, Asma El Sony, Eamon Ellwood, Philippa Ellwood, Luis García-Marcos, Guy B Marks, Eva Morales, Kevin Mortimer, Virginia Pérez-Fernández, Steven Robertson, Richard J Silverwood, David P Strachan, Neil Pearce, Refiloe Masekela, David Strachan, Antonela Martinez-Torres, Stephen Robertson, Charlotte Rutter, Richard Silverwood, Javier Mallol, Manuel Soto-Martínez, Angelita Cabrera Aguilar, Konstantinos Douros, Mohammed Sabir, Meenu Singh, Virendra Singh, Thevaruparambil Unny Sukumaran, Shally Awasthi, Sushil Kumar Kabra, Sundeep Salvi, Roberto García-Almaráz, J. Valente Mérida-Palacio, Blanca E Del Río Navarro, Sandra Nora González-Díaz, Elsy Maureen Navarrete-Rodriguez, José Félix Sánchez, Adegoke G Falade, Heather J Zar, Angel López-Silvarrey Varela, Carlos González Díaz, Magde Nour, Gazal Dib, Yousser Mohammad, Jing-Long Huang, Sasawan Chinratanapisit, Manuel E Soto-Quirós, Pakit Vichyanond, Pedro Aguilar, Sergio Barba, Lata Kumar, S K Sharma, Francisco J Linares-Zapién, Babatunde O Onadeko, Omer Abdel Aziz Musa, Viviana Aguirre, Manuel Baeza-Bacab, Samira Mohammad, Eliana Cortez, Christina H Gratziou, Kamlesh Chopra, Neeta Milind Hanumante, Hugo Nelson, Alfonso Delgado Rubio, Kue-Hsiung Hsieh, and Jayant Shah

Subjects
Allergy, Tuberculosis, Cross-sectional study, Global Health, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, Wheeze, medicine, Humans, 030212 general & internal medicine, Child, Asthma, Response rate (survey), business.industry, Confounding, Asthma symptoms, General Medicine, medicine.disease, 3. Good health, wf_20, Cross-Sectional Studies, 030228 respiratory system, ws_280, medicine.symptom, business, wf_600, Demography
Abstract

Background\ud Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing.\ud Methods\ud This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993–95), ISAAC Phase III (2001–03), or both. We included individuals from two age groups (children aged 6–7 years and adolescents aged 13–14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders.\ud Findings\ud Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993–2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0·37, 95% CI –0·69 to –0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (–1·37, –2·47 to –0·27], in children and –1·67, –2·70 to –0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries.\ud Interpretation\ud Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma.\ud Funding\ud International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III.

Published
2021

44. Gut microbiota development during infancy: Impact of introducing allergenic foods

Author

W.H. Irwin McLean, Michael R. Perkin, Carsten Flohr, Suzana Radulovic, Joanna Craven, Serge A. Versteeg, Adam A. Witney, Heidi H. Kong, David P. Strachan, Ronald van Ree, Kenneth D. Bruce, Tom Marrs, Jay-Hyun Jo, Kirsty Logan, Damian W. Rivett, Gideon Lack, Experimental Immunology, APH - Global Health, APH - Personalized Medicine, Ear, Nose and Throat, and AII - Inflammatory diseases

Subjects
0301 basic medicine, Male, Immunology, The Environmental Determinants of Diabetes in the Young, Physiology, microbiome, Gut flora, Prevotellaceae, Article, Dermatitis, Atopic, 03 medical and health sciences, 0302 clinical medicine, Escherichia, medicine, Immunology and Allergy, Humans, Microbiome, bacteria, Feces, Atopic dermatitis, 2. Zero hunger, tolerance, biology, food, Infant, biology.organism_classification, medicine.disease, colonization, 3. Good health, Gastrointestinal Microbiome, 030104 developmental biology, Female, Proteobacteria, diet, environment, 030217 neurology & neurosurgery, Food Hypersensitivity
Abstract

Background\ud The gut microbiota potentially plays an important role in the immunologic education of the host during early infancy.\ud \ud Objective\ud We sought to determine how the infant gut microbiota evolve during infancy, particularly in relation to hygiene-related environmental factors, atopic disorders, and a randomized introduction of allergenic solids.\ud \ud Methods\ud A total of 1303 exclusively breast-fed infants were enrolled in a dietary randomized controlled trial (Enquiring About Tolerance study) from 3 months of age. In this nested longitudinal study, fecal samples were collected at baseline, with additional sampling of selected cases and controls at 6 and 12 months to study the evolution of their gut microbiota, using 16S ribosomal RNA gene-targeted amplicon sequencing.\ud \ud Results\ud In the 288 baseline samples from exclusively breast-fed infant at 3 months, the gut microbiota was highly heterogeneous, forming 3 distinct clusters: Bifidobacterium-rich, Bacteroides-rich, and Escherichia/Shigella-rich. Mode of delivery was the major discriminating factor. Increased Clostridium sensu stricto relative abundance at 3 months was associated with presence of atopic dermatitis on examination at age 3 and 12 months. From the selected cases and controls with longitudinal samples (n = 70), transition to Bacteroides-rich communities and influx of adult-specific microbes were observed during the first year of life. The introduction of allergenic solids promoted a significant increase in Shannon diversity and representation of specific microbes, such as genera belonging to Prevotellaceae and Proteobacteria (eg, Escherichia/Shigella), as compared with infants recommended to exclusively breast-feed.\ud \ud Conclusions\ud Specific gut microbiota characteristics of samples from 3-month-old breast-fed infants were associated with cesarean birth, and greater Clostridium sensu stricto abundance was associated with atopic dermatitis. The randomized introduction of allergenic solids from age 3 months alongside breast-feeding was associated with differential dynamics of maturation of the gut microbial communities.

Published
2021

45. Trends in worldwide asthma prevalence

Author

M. Innes Asher, Luis Garcia-Marcos, David P. Strachan, and Neil Pearce

Subjects
Pulmonary and Respiratory Medicine, Burden of disease, education.field_of_study, medicine.diagnostic_test, European community, business.industry, Cross-sectional study, Population, education, medicine.disease, Asthma, World health, Cross-Sectional Studies, Surveys and Questionnaires, Environmental health, Hypersensitivity, Prevalence, medicine, Humans, Respiratory sounds, business, Respiratory health, Respiratory Sounds
Abstract

This review of trends in worldwide asthma prevalence starts with defining how asthma prevalence is measured in populations and how it is analysed. Four population studies of asthma across at least two regions are described: European Community Respiratory Health Survey (ECRHS), the International Study of Wheezing in Infants (EISL), the International Study of Asthma and Allergies in Childhood (ISAAC) and the World Health Survey (WHS). Two of these (ISAAC and WHS) covered all the regions of the world; each using its own standardised questionnaire-based methodology with cross-sectional study design, suitable for large populations. EISL (2005 and 2012) and ISAAC (1996–1997 and 2002–2003) have undertaken a second cross-sectional population survey from which trends are available: EISL in three centres in two countries; ISAAC 106 centres in 56 countries (13–14 year olds) and 66 centres in 37 countries (6–7 year olds). Key results from these studies are presented. Unfortunately, there is no new worldwide data outside of EISL since 2003. Global Burden of Disease estimates of asthma prevalence have varied greatly. Recent reliable worldwide data on asthma prevalence and trends is needed; the Global Asthma Network Phase I will provide this in 2021.

Published
2020

46. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author

Kai-How Farh, Caleb Webber, Albert Hofman, George McMahon, Nicholas G. Martin, Paul M. Ridker, Lynn Cherkas, Mart Kals, Dorret I. Boomsma, George Davey Smith, Verneri Anttila, Tune H. Pers, Bertram Müller-Myhsok, Ville Artto, Benjamin M. Neale, Ester Cuenca-León, Anine H. Stam, Christopher Sivert Nielsen, Hieab H.H. Adams, Guntram Borck, Andres Metspalu, Maria Gudlaug Hrafnsdottir, Martin Dichgans, Reedik Mägi, Hailiang Huang, Daniel I. Chasman, Elizabeth Loehrer, John-Anker Zwart, Thomas Meitinger, Markus Färkkilä, Cornelia M. van Duijn, Arn M. J. M. van den Maagdenberg, Evie Stergiakouli, Johan G. Eriksson, Kauko Heikkilä, Hreinn Stefansson, Nicholas A. Furlotte, Minna Männikkö, Nicholas Eriksson, Jaakko Kaprio, David P. Strachan, Juho Wedenoja, Zameel M. Cader, Scott G. Gordon, Brenda W.J.H. Penninx, Linda M. Pedersen, Olli T. Raitakari, Phil Lee, André G. Uitterlinden, Ann-Louise Esserlind, Tobias Kurth, Arpo Aromaa, Priit Palta, Jes Olesen, Audun Stubhaug, Antti-Pekka Sarin, Andres Ingason, Stefan Schreiber, Salli Vepsäläinen, Hartmut Göbel, Kalle Pärn, Jouke-Jan Hottenga, Kari Stefansson, Bendik S. Winsvold, Markku Koiranen, Tim D. Spector, Evelin Mihailov, Mikko Muona, Marjo-Riitta Järvelin, Cynthia Sandor, Anne Francke Christensen, Lude Franke, Grant W. Montgomery, Tobias Freilinger, Caroline Ran, Thomas Werge, Maija Wessman, David A. Hinds, Lannie Ligthart, Terho Lehtimäki, Lili Milani, Mari A. Kaunisto, Lydia Quaye, Andrea Carmine Belin, Eija Hamalainen, M. Arfan Ikram, Veikko Salomaa, Mark J. Daly, Dale R. Nyholt, Pamela A. F. Madden, Andrew C. Heath, Tõnu Esko, Rainer Malik, Gisela M. Terwindt, Mitja I. Kurki, Aarno Palotie, Thomas Hansen, Padhraig Gormley, Michel D. Ferrari, Susan M. Ring, Julie E. Buring, Christian Kubisch, Mikko Kallela, Andrea Byrnes, Stacy Steinberg, Jie Huang, Markus Schürks, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, EMGO - Mental health, Internal Medicine, Epidemiology, Neurology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Biological Psychology, and Complex Trait Genetics

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), SMOOTH-MUSCLE-CELLS, Medizin, Genome-wide association study, Disease, Bioinformatics, Genome-wide association studies, 0302 clinical medicine, Familial hemiplegic migraine, GENE-EXPRESSION, Genetics, Genetics & Heredity, FAMILIAL HEMIPLEGIC MIGRAINE, International Headache Genetics Consortium, SINGLE-NUCLEOTIDE POLYMORPHISMS, 11 Medical And Health Sciences, Genomics, SDG 10 - Reduced Inequalities, 3. Good health, Migranya, Cortical spreading depression, SPREADING DEPRESSION, Life Sciences & Biomedicine, Gens, Genetic Markers, Migraine Disorders, Locus (genetics), Single-nucleotide polymorphism, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, 03 medical and health sciences, medicine, SYSTEMATIC ANALYSIS, Humans, Genetic Predisposition to Disease, Vascular Diseases, GENOME-WIDE ASSOCIATION, Migraine, Science & Technology, Case-control study, Muscle, Smooth, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genes, MYOCARDIAL-INFARCTION, Genetic Loci, Case-Control Studies, RECEPTOR-RELATED PROTEIN-1, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association ( GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms ( SNPs) significantly associated with migraine risk ( P

Published
2020

47. Comparison of individual-level and population-level risk factors for rhinoconjunctivitis, asthma, and eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three

Author

Richard J. Silverwood, Charlotte E Rutter, David P. Strachan, M. Innes Asher, Neil Pearce, Luis Garcia-Marcos, and Philippa Ellwood

Subjects
Pulmonary and Respiratory Medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Allergy, Immunology, Population, Breastfeeding, Eczema, Disease, Disease cluster, Article, 03 medical and health sciences, 0302 clinical medicine, Rhinoconjunctivitis, Environmental health, Epidemiology, medicine, Immunology and Allergy, Risk factor, 030223 otorhinolaryngology, education, Asthma, education.field_of_study, business.industry, Multimorbidity, Global, medicine.disease, 3. Good health, 030228 respiratory system, business, lcsh:RC581-607
Abstract

Background Symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in children cluster at both the individual and population levels. Objectives To assess individual-level and school-level risk factors for symptoms of rhinoconjunctivitis and compare them to corresponding associations with symptoms of asthma and eczema in Phase Three of the International Study of Asthma and Allergies in Childhood. Methods We studied 116,863 children aged 6–7 years from 2163 schools in 59 centres and 22 countries and 224,436 adolescents aged 13–14 years from 2037 schools in 97 centres in 41 countries. Multilevel logistic regression models were fitted with random intercepts for school, centre, and country, adjusting for sex and maternal education at the child level. Associations between symptoms and a range of lifestyle and environmental risk factors were assessed for both the child's exposure and mean exposure at the school. Models were fitted for rhinoconjunctivitis, asthma, and eczema singly (unimorbidity) and for combinations of these conditions (multimorbidity). Results Generally, associations between symptoms and exposures at the school level were similar in direction and magnitude to those at the child level. Associations with multimorbidity were stronger than for unimorbidity, particularly in individuals with symptoms of all three diseases, but risk factor associations found in conventional single disease analyses persisted among children with only one condition, after excluding multimorbid groups. Comparisons of individuals with only one disease showed that many risk factor associations were consistent across the three conditions. More strongly associated with asthma were low birthweight, cat exposure in infancy, and current maternal smoking. Current paracetamol use was more strongly associated with asthma and rhinoconjunctivitis than eczema. Breastfeeding was more strongly associated with eczema than asthma or rhinoconjunctivitis. The direction and magnitude of most risk factor associations were similar in affluent and non-affluent countries, although notable exceptions include farm animal contact in infancy and larger sibships, which were associated with increased risk of rhinoconjunctivitis in non-affluent countries but reduced risk in affluent countries. In both age groups, current paracetamol use increased risk of each disease to a greater extent in affluent countries than in non-affluent countries. Effects of paracetamol and antibiotics in infancy were more consistent between richer and poorer settings. Conclusions Most of the environmental and lifestyle correlates of rhinoconjunctivitis, asthma and eczema in childhood display similarity across the three conditions, even in less affluent settings where allergic sensitisation is less likely to explain the concordant epidemiological patterns. Trial registration Not applicable.

Published
2020

48. Variants associated with

Author

Katherine A, Fawcett, Ma'en, Obeidat, Carl, Melbourne, Nick, Shrine, Anna L, Guyatt, Catherine, John, Jian'an, Luan, Anne, Richmond, Marta R, Moksnes, Raquel, Granell, Stefan, Weiss, Medea, Imboden, Sebastian, May-Wilson, Pirro, Hysi, Thibaud S, Boutin, Laura, Portas, Claudia, Flexeder, Sarah E, Harris, Carol A, Wang, Leo-Pekka, Lyytikäinen, Teemu, Palviainen, Rachel E, Foong, Dirk, Keidel, Cosetta, Minelli, Claudia, Langenberg, Yohan, Bossé, Maarten, Van den Berge, Don D, Sin, Ke, Hao, Archie, Campbell, David, Porteous, Sandosh, Padmanabhan, Blair H, Smith, David M, Evans, Sue, Ring, Arnulf, Langhammer, Kristian, Hveem, Cristen, Willer, Ralf, Ewert, Beate, Stubbe, Nicola, Pirastu, Lucija, Klaric, Peter K, Joshi, Karina, Patasova, Mangino, Massimo, Ozren, Polasek, John M, Starr, Stefan, Karrasch, Konstantin, Strauch, Thomas, Meitinger, Igor, Rudan, Taina, Rantanen, Kirsi, Pietiläinen, Mika, Kähönen, Olli T, Raitakari, Graham L, Hall, Peter D, Sly, Craig E, Pennell, Jaakko, Kaprio, Terho, Lehtimäki, Veronique, Vitart, Ian J, Deary, Debbie, Jarvis, James F, Wilson, Tim, Spector, Nicole, Probst-Hensch, Nicholas J, Wareham, Henry, Völzke, John, Henderson, David P, Strachan, Ben M, Brumpton, Caroline, Hayward, Ian P, Hall, Martin D, Tobin, and Louise V, Wain

Subjects
genome-wide interaction study, HHIP, expression, sex, lung function, Articles, Research Article
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P

Published
2020

49. The burden of asthma, hay fever and eczema in adults in 17 countries: GAN Phase I study

Author

Kevin Mortimer, Maia Lesosky, Luis García-Marcos, M. Innes Asher, Neil Pearce, Eamon Ellwood, Karen Bissell, Asma El Sony, Philippa Ellwood, Guy B. Marks, Antonela Martínez-Torres, Eva Morales, Virginia Perez-Fernandez, Steven Robertson, Charlotte E. Rutter, Richard J. Silverwood, David P. Strachan, and Chen-Yuan Chiang

Subjects
Adult, Pulmonary and Respiratory Medicine, Cross-Sectional Studies, Adolescent, Surveys and Questionnaires, Eczema, Prevalence, Humans, Rhinitis, Allergic, Seasonal, Female, Middle Aged, Child, Asthma
Abstract

AimsAsthma, hay fever and eczema are three common chronic conditions. There have been no recent multi-country data on the burden of these three conditions in adults; the aims of this study are to fill this evidence gap.MethodsThe Global Asthma Network Phase I is a multi-country cross-sectional population-based study using the same core methodology as the International Study of Asthma and Allergies in Childhood Phase III. It provides data on the burden of asthma, hay fever and eczema in children and adolescents, and, for the first time, in their parents/guardians.ResultsData were available from 193 912 adults (104 061 female; mean±sdage 38±7.5 years) in 43 centres in 17 countries. The overall prevalence (range) of symptoms was 6.6% (0.9–32.7%) for current wheeze, 4.4% (0.9–29.0%) for asthma ever, 14.4% (2.8–45.7%) for hay fever ever and 9.9% (1.6–29.5%) for eczema ever. Centre prevalence varied considerably both between countries and within countries. There was a moderate correlation between hay fever ever and asthma ever, and between eczema ever and hay fever ever at the centre level. There were moderate to strong correlations between indicators of the burden of disease reported in adults and the two younger age groups.ConclusionWe found evidence for a substantial burden of asthma, hay fever ever and eczema ever in the countries examined, highlighting the major public health importance of these diseases. Prevention strategies and equitable access to effective and affordable treatments for these three conditions would help mitigate the avoidable morbidity they cause.

Published
2022

50. The burden of asthma, hay fever and eczema in children in 25 countries: GAN Phase I study

Author

Luis García-Marcos, M. Innes Asher, Neil Pearce, Eamon Ellwood, Karen Bissell, Chen-Yuan Chiang, Asma El Sony, Philippa Ellwood, Guy B. Marks, Kevin Mortimer, A. Elena Martínez-Torres, Eva Morales, Virginia Perez-Fernandez, Steven Robertson, Charlotte E. Rutter, Richard J. Silverwood, and David P. Strachan

Subjects
Pulmonary and Respiratory Medicine
Abstract

AimsThere have been no worldwide standardised surveys of prevalence and severity of asthma, rhinoconjunctivitis and eczema in school children for 15 years. The present study aims to provide this information.MethodsFollowing the exact International Study of Asthma and Allergies in Childhood (ISAAC) methodology (cross-sectional questionnaire-based survey), Global Asthma Network (GAN) Phase I was carried out between 2015 and 2020 in many centres worldwide.ResultsThe study included 157 784 adolescents (13–14 years of age) in 63 centres in 25 countries and 101 777 children (6–7 years of age) in 44 centres in 16 countries. The current prevalence of symptoms, respectively, was 11.0% and 9.1% for asthma, 13.3% and 7.7% for rhinoconjunctivitis and 6.4% and 5.9% for eczema. The prevalence of asthma ever was 10.5% and 7.6%, hay fever ever was 15.2% and 11.1% and eczema ever was 10.6% and 13.4%, respectively. Centres in low or lower middle gross national income countries (LICs or LMICs) had significantly lower prevalence of the three disease symptoms and diagnoses (except for hay fever). In children, the prevalence of asthma and rhinoconjunctivitis symptoms was higher in boys, while the reverse occurred among adolescents. For eczema, while the prevalence among female adolescents was double that of males, there was no sex difference among children. Centre accounted for non-negligible variability in all disease symptoms (10–20%).ConclusionThe burdens of asthma, rhinoconjunctivitis and eczema vary widely among the limited number of countries studied. Although symptom prevalence is lower in LICs and LMICs, it represents a considerable burden everywhere studied.

Published
2022

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