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1. 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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2. The genomics of heart failure: design and rationale of the HERMES consortium

Author

R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith

Subjects
Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Published
2021
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3. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021
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4. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers

Subjects
Science
Abstract

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

Published
2020
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5. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Published
2021
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6. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

Author

Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs

Subjects
Medicine
Abstract

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Published
2017
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7. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Published
2016
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8. The Detection of Metabolite-Mediated Gene Module Co-Expression Using Multivariate Linear Models.

Author

Trishanta Padayachee, Tatsiana Khamiakova, Ziv Shkedy, Markus Perola, Perttu Salo, and Tomasz Burzykowski

Subjects
Medicine, Science
Abstract

Investigating whether metabolites regulate the co-expression of a predefined gene module is one of the relevant questions posed in the integrative analysis of metabolomic and transcriptomic data. This article concerns the integrative analysis of the two high-dimensional datasets by means of multivariate models and statistical tests for the dependence between metabolites and the co-expression of a gene module. The general linear model (GLM) for correlated data that we propose models the dependence between adjusted gene expression values through a block-diagonal variance-covariance structure formed by metabolic-subset specific general variance-covariance blocks. Performance of statistical tests for the inference of conditional co-expression are evaluated through a simulation study. The proposed methodology is applied to the gene expression data of the previously characterized lipid-leukocyte module. Our results show that the GLM approach improves on a previous approach by being less prone to the detection of spurious conditional co-expression.

Published
2016
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9. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

Published
2015
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10. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

Author

Jennifer E Huffman, Eva Albrecht, Alexander Teumer, Massimo Mangino, Karen Kapur, Toby Johnson, Zoltán Kutalik, Nicola Pirastu, Giorgio Pistis, Lorna M Lopez, Toomas Haller, Perttu Salo, Anuj Goel, Man Li, Toshiko Tanaka, Abbas Dehghan, Daniela Ruggiero, Giovanni Malerba, Albert V Smith, Ilja M Nolte, Laura Portas, Amanda Phipps-Green, Lora Boteva, Pau Navarro, Asa Johansson, Andrew A Hicks, Ozren Polasek, Tõnu Esko, John F Peden, Sarah E Harris, Federico Murgia, Sarah H Wild, Albert Tenesa, Adrienne Tin, Evelin Mihailov, Anne Grotevendt, Gauti K Gislason, Josef Coresh, Pio D'Adamo, Sheila Ulivi, Peter Vollenweider, Gerard Waeber, Susan Campbell, Ivana Kolcic, Krista Fisher, Margus Viigimaa, Jeffrey E Metter, Corrado Masciullo, Elisabetta Trabetti, Cristina Bombieri, Rossella Sorice, Angela Döring, Eva Reischl, Konstantin Strauch, Albert Hofman, Andre G Uitterlinden, Melanie Waldenberger, H-Erich Wichmann, Gail Davies, Alan J Gow, Nicola Dalbeth, Lisa Stamp, Johannes H Smit, Mirna Kirin, Ramaiah Nagaraja, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Susan M Farrington, Evropi Theodoratou, Antti Jula, Veikko Salomaa, Cinzia Sala, Christian Hengstenberg, Michel Burnier, Reedik Mägi, Norman Klopp, Stefan Kloiber, Sabine Schipf, Samuli Ripatti, Stefano Cabras, Nicole Soranzo, Georg Homuth, Teresa Nutile, Patricia B Munroe, Nicholas Hastie, Harry Campbell, Igor Rudan, Claudia Cabrera, Chris Haley, Oscar H Franco, Tony R Merriman, Vilmundur Gudnason, Mario Pirastu, Brenda W Penninx, Harold Snieder, Andres Metspalu, Marina Ciullo, Peter P Pramstaller, Cornelia M van Duijn, Luigi Ferrucci, Giovanni Gambaro, Ian J Deary, Malcolm G Dunlop, James F Wilson, Paolo Gasparini, Ulf Gyllensten, Tim D Spector, Alan F Wright, Caroline Hayward, Hugh Watkins, Markus Perola, Murielle Bochud, W H Linda Kao, Mark Caulfield, Daniela Toniolo, Henry Völzke, Christian Gieger, Anna Köttgen, and Veronique Vitart

Subjects
Medicine, Science
Abstract

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

Published
2015
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11. Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

Author

Emília Ilona Gaál, Perttu Salo, Kati Kristiansson, Karola Rehnström, Johannes Kettunen, Antti-Pekka Sarin, Mika Niemelä, Antti Jula, Olli T Raitakari, Terho Lehtimäki, Johan G Eriksson, Elisabeth Widen, Murat Günel, Mitja Kurki, Mikael von und Zu Fraunberg, Juha E Jääskeläinen, Juha Hernesniemi, Marjo-Riitta Järvelin, Anneli Pouta, International Consortium for Blood Pressure Genome-Wide Association Studies, Christopher Newton-Cheh, Veikko Salomaa, Aarno Palotie, and Markus Perola

Subjects
Genetics, QH426-470
Abstract

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

Published
2012
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12. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.

Author

Melanie Kolz, Toby Johnson, Serena Sanna, Alexander Teumer, Veronique Vitart, Markus Perola, Massimo Mangino, Eva Albrecht, Chris Wallace, Martin Farrall, Asa Johansson, Dale R Nyholt, Yurii Aulchenko, Jacques S Beckmann, Sven Bergmann, Murielle Bochud, Morris Brown, Harry Campbell, EUROSPAN Consortium, John Connell, Anna Dominiczak, Georg Homuth, Claudia Lamina, Mark I McCarthy, ENGAGE Consortium, Thomas Meitinger, Vincent Mooser, Patricia Munroe, Matthias Nauck, John Peden, Holger Prokisch, Perttu Salo, Veikko Salomaa, Nilesh J Samani, David Schlessinger, Manuela Uda, Uwe Völker, Gérard Waeber, Dawn Waterworth, Rui Wang-Sattler, Alan F Wright, Jerzy Adamski, John B Whitfield, Ulf Gyllensten, James F Wilson, Igor Rudan, Peter Pramstaller, Hugh Watkins, PROCARDIS Consortium, Angela Doering, H-Erich Wichmann, KORA Study, Tim D Spector, Leena Peltonen, Henry Völzke, Ramaiah Nagaraja, Peter Vollenweider, Mark Caulfield, WTCCC, Thomas Illig, and Christian Gieger

Subjects
Genetics, QH426-470
Abstract

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Published
2009
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13. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), 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 National de la Recherche Scientifique (CNRS), 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 de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), 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), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering

Subjects
Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021

14. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine

Subjects
Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021

15. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract

The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.

Published
2021

17. High-sensitivity cardiac troponin I and NT-proBNP as predictors of incident dementia and Alzheimer’s disease: the FINRISK Study

Author

Perttu Salo, Tiina Laatikainen, Aki S. Havulinna, Veikko Salomaa, Stefan Blankenberg, Tanja Zeller, Juho Tynkkynen, and Jussi Hernesniemi

Subjects
Adult, Apolipoprotein E, medicine.medical_specialty, Neurology, medicine.drug_class, Population, Blood Pressure, Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Internal medicine, Natriuretic Peptide, Brain, medicine, Natriuretic peptide, Humans, Dementia, education, Finland, Aged, Proportional Hazards Models, education.field_of_study, Proportional hazards model, business.industry, Troponin I, Hazard ratio, Middle Aged, medicine.disease, Peptide Fragments, 3. Good health, Cholesterol, Multivariate Analysis, Physical therapy, Neurology (clinical), business, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) are known to associate with incident dementia. The purpose of our study was to examine whether high-sensitivity cardiac troponin I (hs-TnI) and NT-proBNP are associated with incident dementia and Alzheimer's disease (AD) independently of each other. Our study was a part of the national population-based health examination survey, FINRISK 1997, with a total sample of 7114 subjects, including 407 incident dementia cases and 319 AD cases during the follow-up time of 18 years. Using multivariate Cox regression analyses, we calculated the hazard ratios (HR) for hs-TnI and NT-proBNP. Analyses were adjusted for the previously known dementia/AD risk factors, including the apoE genotype. NT-proBNP was independently associated with incident dementia (HR 1.32, 95% CI 1.17-1.49) and AD (HR 1.30, 95% CI 1.13-1.5). Hs-TnI was also associated with incident dementia (HR 1.12, 95% CI 1.02-1.23), but not independent of NT-proBNP (HR 1.10, 95% CI 0.99-1.21). Hs-TnI was not associated with incident AD. The results remained similar in cause-specific Cox regression models and among subjects over 40 years of age. NT-proBNP and hs-TnI improved the reclassification of dementia risk in 10 years follow-up, and hs-TNI also in 18 years of follow-up. Neither hs-TnI nor NT-proBNP was able to outperform each other in risk reclassification of dementia. Both cardiovascular biomarkers, NT-proBNP and hs-TnI, were associated with incident dementia independently of traditional dementia risk factors including the apoE genotype. NT-proBNP was also associated with AD. Both markers offered a better dementia risk reclassification compared with traditional risk factors.

Published
2016

18. Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

Author

Stefan Gross, Honghuang Lin, Diane T. Smelser, März W, Niek Verweij, Alexander Niessner, Peter M. Visscher, Ruth C. Lovering, Erik Ingelsson, Nicholas L. Smith, Lars Lind, Jerome I. Rotter, Anna Helgadottir, David J. Stott, Michelle L. O'Donoghue, Daniel I. Chasman, Karoline Kuchenbaecker, Morris Ad, Michael W. Nagle, Morris Ap, Steven A. Lubitz, Giedraitis, Abirami Veluchamy, Paul M. Ridker, David J. Carey, Benoit Tyl, Carolina Roselli, Laura M. Yerges-Armstrong, Michael R. Brown, Faiez Zannad, Aroon D. Hingorani, Åsa K. Hedman, Nilesh J. Samani, Daníel F. Guðbjartsson, Maris Teder-Laving, Stephan B. Felix, Christopher Newton-Cheh, Marcus Dörr, Thomas P. Cappola, Daniel I. Swerdlow, Leonard Buckbinder, Xiaosong Wang, Alex S. F. Doney, C. Andersson, Jonathan H. Chung, Joshua D. Backman, Tõnu Esko, Mohsen Ghanbari, Joop Jukema, Ian Ford, Gunnar Engström, Kent D. Taylor, Johan Ärnlöv, P.E Weeke, Kenneth B. Margulies, Peter Svensson, Folkert W. Asselbergs, Lars Køber, Michael V. Holmes, Anders Mälarstig, Chim C. Lang, Krishna G. Aragam, Samuel C. Dudley, Christian Torp-Pedersen, Bruce M. Psaty, Alexander Teumer, John J.V. McMurray, Raul Weiss, Smith Jg, Patrick T. Ellinor, Anjali T. Owens, Ify R. Mordi, G Sveinbjörnsson, Luca A. Lotta, John S. Gottdiener, Christopher M. Haggerty, Christopher P. Nelson, C M Lindgren, Hilma Holm, Michael E. Dunn, Albert Henry, Helen M. Parry, Salomaa, Huilin Xing, Kenneth Rice, Marcus E. Kleber, Spiros Denaxas, Chris Finan, Xu Chen, Unnur Thorsteinsdottir, Naveed Sattar, Bing Yu, Kerri L. Wiggins, Alaa Shalaby, Romaine Spr., Patrik K. E. Magnusson, Adriaan A. Voors, Lumbers Rt, Stella Trompet, Maryam Kavousi, Kari Stefansson, Jian'an Luan, Harry Hemingway, van Setten J, Anubha Mahajan, Olle Melander, Uwe Völker, Peter Almgren, Chaffin, Palmer Cna., Eliana Portilla-Fernandez, Stefan Stender, Markus Perola, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Teemu J. Niiranen, Nicholas J. Wareham, Andrea Koekemoer, James P. Cook, Jeff Brandimarto, Jian Yang, Mary L. Biggs, Claudia Langenberg, Perttu Salo, Sonia Shah, A.G. Uitterlinden, Mari-Liis Tammesoo, Jemma B. Wilk, Craig L. Hyde, Graciela E. Delgado, van der Harst P, Alanna C. Morrison, Kay-Tee Khaw, Barry London, Rebecca Gutmann, Thomas M. Morgan, Franco Giulianini, Abbas Dehghan, Heather L. Bloom, William A. Chutkow, Dawn M. Waterworth, Ramachandran S. Vasan, Jing Hua Zhao, Morley Mp, and Sahar Ghasemi

Subjects
2. Zero hunger, 0303 health sciences, business.industry, Atrial fibrillation, Genome-wide association study, 030204 cardiovascular system & hematology, Quantitative trait locus, medicine.disease, Bioinformatics, Genetic architecture, 3. Good health, Coronary artery disease, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Heart failure, medicine, Mendelian inheritance, symbols, business, 030304 developmental biology, Genetic association
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

Published
2019
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19. A multivariate linear model for investigating the association between gene-module co-expression and a continuous covariate

Author

Tomasz Burzykowski, Tatsiana Khamiakova, Perttu Salo, Markus Perola, Trishanta Padayachee, and Ziv Shkedy

Subjects
Statistics and Probability, Generalized linear model, Computer science, Association (object-oriented programming), Gene Expression, computer.software_genre, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, Covariate, Genetics, Humans, Gene Regulatory Networks, Longitudinal Studies, 0101 mathematics, Molecular Biology, Selection (genetic algorithm), 030304 developmental biology, Statistical hypothesis testing, General linear model, 0303 health sciences, Function (mathematics), Expression (mathematics), Computational Mathematics, Linear Models, Data mining, computer
Abstract

A way to enhance our understanding of the development and progression of complex diseases is to investigate the influence of cellular environments on gene co-expression (i.e. gene-pair correlations). Often, changes in gene co-expression are investigated across two or more biological conditions defined by categorizing a continuous covariate. However, the selection of arbitrary cut-off points may have an influence on the results of an analysis. To address this issue, we use a general linear model (GLM) for correlated data to study the relationship between gene-module co-expression and a covariate like metabolite concentration. The GLM specifies the gene-pair correlations as a function of the continuous covariate. The use of the GLM allows for investigating different (linear and non-linear) patterns of co-expression. Furthermore, the modeling approach offers a formal framework for testing hypotheses about possible patterns of co-expression. In our paper, a simulation study is used to assess the performance of the GLM. The performance is compared with that of a previously proposed GLM that utilizes categorized covariates. The versatility of the model is illustrated by using a real-life example. We discuss the theoretical issues related to the construction of the test statistics and the computational challenges related to fitting of the proposed model.

Published
2019

20. Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Author

Jerko Štambuk, Eugene D Pakhomov, Toma Keser, Frano Vučković, Ozren Polasek, Ivan Gudelj, James F. Wilson, Helen M. Colhoun, Anne Richmond, Yakov A. Tsepilov, Igor Rudan, Malcolm G. Dunlop, Rosina Plomp, Markus Perola, Hae-Won Uh, Massimo Mangino, Maja Pučić-Baković, Susan M. Farrington, Yurii S. Aulchenko, Evropi Theodoratou, Jasminka Krištić, Veronique Vitart, Paula Dobrinić, Eline Slagboom, Camilla Drake, Edouard Louis, Chloe M. Stanton, Jelena Mlinarec, Timo Tõnis Sikka, Harry Campbell, Manfred Wuhrer, Marian Beekman, Barbara Jelusic, Tõnu Esko, Caroline Hayward, Michel Georges, Alexander K. Grishchenko, Gordan Lauc, Vlatka Zoldoš, Lucija Klaric, Stuart J. McGurnaghan, Irena Trbojević-Akmačić, Perttu Salo, Tim D. Spector, Joris Deelen, Tamara Pavić, Sodbo Zh Sharapov, Julia Dmitrieva, Krista Fischer, Ivo Ugrina, Mairead L. Bermingham, Marija Vilaj, and Maria Timofeeva

Subjects
Glycosylation, Immunoglobulin G, Linkage Disequilibrium, chemistry.chemical_compound, 0302 clinical medicine, Non-U.S. Gov't, Research Articles, Regulation of gene expression, 0303 health sciences, Gene knockdown, Multidisciplinary, biology, Research Support, Non-U.S. Gov't, SciAdv r-articles, Phenotype, 3. Good health, Cell biology, lipids (amino acids, peptides, and proteins), Algorithms, Research Article, Glycan, Fucosyltransferase, animal structures, Immunology, macromolecular substances, Research Support, Polymorphism, Single Nucleotide, 03 medical and health sciences, Polysaccharides, Journal Article, Humans, General, Transcription factor, Alleles, 030304 developmental biology, Inflammation, immunoglobulin G, glycosylation, GWAS, glycogenes, inflammatory diseases, Models, Genetic, Computational Biology, Human Genetics, carbohydrates (lipids), chemistry, Gene Expression Regulation, Genetic Loci, biology.protein, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Variation in key transcription factors and glycogenes modifies IgG glycosylation and has an influence on inflammatory diseases., Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

Published
2019

21. A distinctive DNA methylation pattern in insufficient sleep

Author

Perttu Salo, Alexandra Lahtinen, Natalia Pervjakova, Päivi Vanttola, Sonja Sulkava, Mikko Härmä, Markus Perola, Sampsa Puttonen, Lili Milani, Tiina Paunio, Katriina Viitasalo, Auli Toivola, Anni Joensuu, Department of Psychiatry, University of Helsinki, Clinicum, HUS Psychiatry, Quantitative Genetics, Diabetes and Obesity Research Program, Research Programs Unit, and Tampere University

Subjects
Male, 0301 basic medicine, Gene Expression, lcsh:Medicine, PROTEIN, PHENOTYPE, Bioinformatics, INCREASE, Epigenesis, Genetic, Shift work, 0302 clinical medicine, Sleep Initiation and Maintenance Disorders, Insomnia, Prospective Studies, lcsh:Science, GENE-EXPRESSION, DAMAGE, Regulation of gene expression, Multidisciplinary, 1184 Genetics, developmental biology, physiology, Middle Aged, FRONTAL-CORTEX, Smith–Magenis syndrome, Circadian Rhythm, PREVALENCE, SMITH-MAGENIS SYNDROME, Chromosome 17 (human), DNA methylation, medicine.symptom, Adult, METABOLISM, Article, 03 medical and health sciences, Sleep Disorders, Circadian Rhythm, medicine, Humans, Circadian rhythm, Gene, business.industry, lcsh:R, DNA Methylation, medicine.disease, Cross-Sectional Studies, 030104 developmental biology, lcsh:Q, GENDER, 3111 Biomedicine, Sleep, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: “Nervous System Development” (FDR P value

Published
2019

22. Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome

Author

Johanna Nokelainen, Mikko I. Mäyränpää, Perttu Salo, Krista Salli, Aki S. Havulinna, Marja Marchesani, Juhani Junttila, Heikki J. Niemi, Heikki V. Huikuri, Pekka J. Karhunen, Jani Lappalainen, Markku S. Nieminen, Jaume Marrugat, Marja-Liisa Lokki, Annika Wennerström, Roberto Elosua, Riitta Paakkanen, Veikko Salomaa, Markus Perola, Satu Männistö, Petri T. Kovanen, Aarno Palotie, Efthymia Vlachopoulou, Kjell Nikus, T. Petteri Arstila, Juha Sinisalo, Carla Lluis-Ganella, and Markku Eskola

Subjects
Male, 0301 basic medicine, Acute coronary syndrome, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Major histocompatibility complex, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, Risk Factors, Genotype, Genetics, medicine, Humans, Acute Coronary Syndrome, Allele, Genetics (clinical), Aged, Aged, 80 and over, Membrane Glycoproteins, Butyrophilins, biology, Macrophages, Haplotype, Middle Aged, medicine.disease, Coronary Vessels, Plaque, Atherosclerotic, 3. Good health, 030104 developmental biology, Haplotypes, Immunology, biology.protein, Female, Cardiology and Cardiovascular Medicine, HLA-DRB1 Chains, 030215 immunology
Abstract

Background— The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non–human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. Methods and Results— We conducted a large-scale genetic analysis on a case–control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels ( r =0.760; P + FOXP3 + regulatory T cell proliferation significantly (blocking versus nonblocking; P Conclusions— In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3 + T cell proliferation, especially in patients homozygous for the risk alleles. Clinical Trial Registration— https://www.clinicaltrials.gov ; Unique Identifier: NCT00417534.

Published
2016

23. Sequential double cross-validation for assessment of added predictive ability in high-dimensional omic applications

Author

Bart Mertens, Markus Perola, Jeanine Houwing-Duistermaat, Mar Rodríguez-Girondo, Tomasz Burzykowski, Perttu Salo, Rodriguez-Girondo, Mar, Salo, Perttu, BURZYKOWSKI, Tomasz, Perola, Markus, HOUWING-DUISTERMAAT, Jeanne, Mertens, Bart, Rodriguez-Girondo M., Salo P., Burzykowski T., Perola M., Houwing-Duistermaat J., and Mertens B.

Subjects
Statistics and Probability, FOS: Computer and information sciences, Computer science, Added predictive ability, double cross-validation, regularized regression, multiple omics sets, Population, High dimensional, Machine learning, computer.software_genre, 01 natural sciences, Cross-validation, Set (abstract data type), Methodology (stat.ME), 010104 statistics & probability, 03 medical and health sciences, Resampling, Added value, 0101 mathematics, education, Statistics - Methodology, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, education.field_of_study, business.industry, Regression analysis, Omics, 3. Good health, Modeling and Simulation, Artificial intelligence, Statistics, Probability and Uncertainty, business, computer, Multiple omics set
Abstract

Enriching existing predictive models with new biomolecular markers is an important task in the new multi-omic era. Clinical studies increasingly include new sets of omic measurements which may prove their added value in terms of predictive performance. We introduce a two-step approach for the assessment of the added predictive ability of omic predictors, based on sequential double cross-validation and regularized regression models. We propose several performance indices to summarize the two-stage prediction procedure and a permutation test to formally assess the added predictive value of a second omic set of predictors over a primary omic source. The performance of the test is investigated through simulations. We illustrate the new method through the systematic assessment and comparison of the performance of transcriptomics and metabolomics sources in the prediction of body mass index (BMI) using longitudinal data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort from Finland. Work supported by Grant MIMOmics of the European Union's Seventh Framework Programme (FP7-Health-F5-2012) number 305280. The DILGOM transcriptomics dataset was funded by Sigrid Juselius Foundation and Yrjo Jahnsson Foundation. The DILGOM NMR metabolomic dataset was funded by Yrjo Jahnsson Foundation.

Published
2018

24. Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B-Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population

Author

Stefan Blankenberg, Johannes Kettunen, Terho Lehtimäki, Mika Kähönen, Tanja Zeller, Kati Kristiansson, Aki S. Havulinna, Antti Jula, Taru Tukiainen, Veikko Salomaa, Markus Perola, Perttu Salo, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Institute for Molecular Medicine Finland, Quantitative Genetics, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, University of Helsinki, Diabetes and Obesity Research Program, Research Programs Unit, and Complex Disease Genetics

Subjects
0301 basic medicine, Male, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Mechanical stretching, DISEASE, Cohort Studies, 0302 clinical medicine, Atrial natriuretic peptide, Natriuretic Peptide, Brain, Natriuretic peptide, Medicine, Myocytes, Cardiac, genes, Genetics (clinical), Finland, TRANSGENIC MICE, RISK, education.field_of_study, blood pressure, Middle Aged, 3. Good health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, cardiovascular system, HEART-FAILURE, Female, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, Atrial Natriuretic Factor, circulatory and respiratory physiology, Genetically modified mouse, Adult, medicine.medical_specialty, hypertension, medicine.drug_class, brain, Population, Article, CLONING, 03 medical and health sciences, Internal medicine, Genetics, Humans, cardiovascular diseases, education, Aged, genome-wide association study, natriuretic peptide, business.industry, ta1184, Genetic Variation, DNA, Original Articles, ta3121, medicine.disease, MODEL, 030104 developmental biology, Endocrinology, Blood pressure, 3121 General medicine, internal medicine and other clinical medicine, Heart failure, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract

Supplemental Digital Content is available in the text., Background— Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP. Methods and Results— We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide–associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT-proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N-acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post-translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2×10−4). Conclusions— Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure–lowering effect of ANP in the general population.

Published
2017

25. Evaluation of HLA-DRB1 imputation using a Finnish dataset

Author

Marja-Liisa Lokki, Annika Wennerström, Efthymia Vlachopoulou, Elisa Lahtela, Markku S. Nieminen, Aki S. Havulinna, Markus Perola, Juha Sinisalo, Veikko Salomaa, and Perttu Salo

Subjects
Genetics, education.field_of_study, Linkage disequilibrium, Immunology, Population, Haplotype, Locus (genetics), General Medicine, Human leukocyte antigen, Biology, Biochemistry, Immunology and Allergy, Allele, education, HLA-DRB1, Imputation (genetics)
Abstract

Owing to the vast amount of alleles, high-resolution human leukocyte antigen (HLA) typing is expensive and time-consuming. Scientists have attempted to develop computational approaches to define HLA alleles with high confidence. We tested the reliability of HLA*IMP and SNP2HLA for imputing HLA-DRB1 alleles in a Finnish material (n=161). The per-individual success rates varied between 16.68% and 25.4% using both softwares. One of the most prominent example was HLA-DRB1*01:01 allele showing approximately a 30% success rate while being the most common wrongly imputed allele. In Finland, isolation and migration history have shaped the gene pool narrower showing HLA haplotype frequencies typical to the Finnish population when compared to Europeans. The imputation success for HLA-DRB1 alleles was very low pointing to the importance of population-specific reference material.

Published
2014

26. On the Combination of Omics Data for Prediction of Binary Outcomes

Author

Rob A. E. M. Tollenaar, Mar Rodríguez-Girondo, Markus Perola, Alexia Kakourou, Perttu Salo, Jeanine J. Houwing-Duistermaat, Bart Mertens, and Wilma E. Mesker

Subjects
0301 basic medicine, Computer science, Calibration (statistics), Context (language use), Computational biology, medicine.disease, computer.software_genre, Mass spectrometry, Omics, 01 natural sciences, 3. Good health, Omics data, 010104 statistics & probability, 03 medical and health sciences, 030104 developmental biology, Metabolomics, medicine, Biomarker (medicine), Data mining, 0101 mathematics, Metabolic syndrome, computer
Abstract

Enrichment of predictive models with new biomolecular markers is an important task in high-dimensional omic applications. Increasingly, clinical studies include several sets of such omics markers available for each patient, measuring different levels of biological variation. As a result, one of the main challenges in predictive research is the integration of different sources of omic biomarkers for the prediction of health traits. We review several approaches for the combination of omic markers in the context of binary outcome prediction, all based on double cross-validation and regularized regression models. We evaluate their performance in terms of calibration and discrimination and we compare their performance with respect to single-omic source predictions. We illustrate the methods through the analysis of two real datasets. On the one hand, we consider the combination of two fractions of proteomic mass spectrometry for the calibration of a diagnostic rule for the detection of early stage breast cancer. On the other hand, we consider transcriptomics and metabolomics as predictors of obesity using data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort, from Finland.

Published
2016

27. Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

Author

Eero Pukkala, Antti Koivusalo, Päivi J Miettinen, Markus Perola, Perttu Salo, Johanna Arola, Valtter B. Virtanen, Reetta Kivisaari, Mikko Pakarinen, and Risto Rintala

Subjects
Adult, Calcitonin, Male, Oncology, endocrine system, Cancer Research, medicine.medical_specialty, Pathology, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Population, Thyroid Gland, Disease, Papillary thyroid cancer, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Humans, Hirschsprung Disease, Thyroid Neoplasms, education, Multiple endocrine neoplasia, Thyroid cancer, Aged, Ultrasonography, 0303 health sciences, education.field_of_study, business.industry, Proto-Oncogene Proteins c-ret, 030305 genetics & heredity, Thyroid, Medullary thyroid cancer, Exons, Middle Aged, medicine.disease, 3. Good health, Cancer registry, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Female, business
Abstract

The objective of this study was to assess the occurrence of thyroid cancer and co-occurringRETmutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950–1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer,RETmutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52–1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer withoutRETmutations was detected by clinical screening. Four subjects (aged 31–50 years) with co-occurringRETmutations in exons 10 (C609R;n=1) and 13 (Y791F,n=3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associatedRETmutations were restricted to exons 10 and 13 affecting ∼5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.

Published
2013

28. Apolipoproteins and HDL cholesterol do not associate with the risk of future dementia and Alzheimer's disease: the National Finnish population study (FINRISK)

Author

Aki S. Havulinna, Jussi Hernesniemi, Jaana Leiviskä, Jouko Sundvall, Juho Tynkkynen, Tiina Laatikainen, Veikko Salomaa, and Perttu Salo

Subjects
0301 basic medicine, Oncology, Gerontology, Male, Aging, Time Factors, Apolipoprotein B, Disease, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Prospective Studies, Finland, education.field_of_study, biology, Incidence, Hazard ratio, General Medicine, Middle Aged, lipids (amino acids, peptides, and proteins), Female, Original Article, Psychology, Cohort study, Adult, medicine.medical_specialty, Population, White People, 03 medical and health sciences, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, Clinical significance, education, Aged, Apolipoproteins B, Proportional Hazards Models, Apolipoprotein A-I, Cholesterol, Cholesterol, HDL, medicine.disease, 030104 developmental biology, chemistry, biology.protein, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Biomarkers
Abstract

Data on associations of apolipoproteins A-I and B (apo A-I, apo B) and HDL cholesterol (HDL-C) with dementia and Alzheimer’s disease (AD) are conflicting. Our aim was to examine, whether apo B, apoA-I, their ratio, or HDL-C are significant, independent predictors of incident dementia and AD in the general population free of dementia at baseline. We analyzed the results from two Finnish prospective population-based cohort studies in a total of 13,275 subjects aged 25 to 74 years with mainly Caucasian ethnicity. The follow-up time for both cohorts was 10 years. We used Cox proportional hazards regression to evaluate hazard ratios (HR) for incident dementia (including AD) (n = 220) and for AD (n = 154). Cumulative incidence function (CIF) analysis was also performed to adjust the results for competing risks of death. Adjusted for multiple dementia and AD risk factors, log-transformed apo A-I, log HDL-C, log apo B, and log apo B/A-I ratio were not associated with incident dementia or AD. HDL-C was inversely associated with AD risk when adjusted for competing risks but no other statistically significant associations were observed in the CIF analyses. Apo A-I, HDL-C, apo B, or apo B/A-I ratio were not associated with future dementia or AD. HDL-C was inversely associated with incident AD risk when adjusted for competing risks of death, but the finding is unlikely to be of clinical relevance. Our study does not support the use of these risk markers to predict incident dementia or AD.

Published
2016

29. Evaluation of O2PLS in Omics data integration

Author

Perttu Salo, Said el Bouhaddani, Hae-Won Uh, Geurt Jongbloed, Markus Perola, Jeanine J Houwing-Duistermaat, Bouhaddani S., Houwing-Duistermaat J., Salo P., Perola M., Jongbloed G., and Uh H.-W.

Subjects
Adult, Male, 0301 basic medicine, Latent variable regression, Relation (database), Computer science, Systems biology, Statistics as Topic, computer.software_genre, Biochemistry, Set (abstract data type), 03 medical and health sciences, Metabolomics, Integration of Omics data, O2PLS, Structural Biology, Partial least squares regression, Statistics, Metabolome, Humans, Obesity, Least-Squares Analysis, Molecular Biology, Aged, Systems Biology, Applied Mathematics, Dimensionality reduction, Genomics, Middle Aged, Diet, Computer Science Applications, Proceedings, 030104 developmental biology, Cohort, Dimension reduction, Data analysis, Female, Data mining, Transcriptome, computer
Abstract

BackgroundRapid computational and technological developments made large amounts of omics data available in different biological levels. It is becoming clear that simultaneous data analysis methods are needed for better interpretation and understanding of the underlying systems biology. Different methods have been proposed for this task, among them Partial Least Squares (PLS) related methods. To also deal with orthogonal variation, systematic variation in the data unrelated to one another, we consider the Two-way Orthogonal PLS (O2PLS): an integrative data analysis method which is capable of modeling systematic variation, while providing more parsimonious models aiding interpretation.ResultsA simulation study to assess the performance of O2PLS showed positive results in both low and higher dimensions. More noise (50 % of the data) only affected the systematic part estimates. A data analysis was conducted using data on metabolomics and transcriptomics from a large Finnish cohort (DILGOM). A previous sequential study, using the same data, showed significant correlations between the Lipo-Leukocyte (LL) module and lipoprotein metabolites. The O2PLS results were in agreement with these findings, identifying almost the same set of co-varying variables. Moreover, our integrative approach identified other associative genes and metabolites, while taking into account systematic variation in the data. Including orthogonal components enhanced overall fit, but the orthogonal variation was difficult to interpret.ConclusionsSimulations showed that the O2PLS estimates were close to the true parameters in both low and higher dimensions. In the presence of more noise (50 %), the orthogonal part estimates could not distinguish well between joint and unique variation. The joint estimates were not systematically affected. Simultaneous analysis with O2PLS on metabolome and transcriptome data showed that the LL module, together with VLDL and HDL metabolites, were important for the metabolomic and transcriptomic relation. This is in agreement with an earlier study. In addition more gene expression and metabolites are identified being important for the joint covariation.

Published
2016

30. The Detection of Metabolite-Mediated Gene Module Co-Expression Using Multivariate Linear Models

Author

Ziv Shkedy, Markus Perola, Perttu Salo, Tomasz Burzykowski, Tatsiana Khamiakova, and Trishanta Padayachee

Subjects
0301 basic medicine, Multivariate statistics, Test Statistics, Gene regulatory network, Gene Expression, Inference, lcsh:Medicine, Biochemistry, Mathematical and Statistical Techniques, Metabolites, Leukocytes, Gene Regulatory Networks, lcsh:Science, Regulation of gene expression, Genetics, Multidisciplinary, 3-Hydroxybutyric Acid, Fatty Acids, Linear model, Genomics, Lipids, Cholesterol, Physical Sciences, Regression Analysis, Lipoproteins, HDL, Transcriptome Analysis, Statistics (Mathematics), Research Article, Computational biology, Linear Regression Analysis, Biology, Research and Analysis Methods, Linoleic Acid, 03 medical and health sciences, Metabolomics, Computer Simulation, Statistical Methods, Particle Size, Statistical hypothesis testing, General linear model, Models, Genetic, Cholesterol, HDL, lcsh:R, Biology and Life Sciences, Computational Biology, Genome Analysis, Metabolism, 030104 developmental biology, Gene Expression Regulation, Linear Models, lcsh:Q, Mathematics
Abstract

Investigating whether metabolites regulate the co-expression of a predefined gene module is one of the relevant questions posed in the integrative analysis of metabolomic and transcriptomic data. This article concerns the integrative analysis of the two high-dimensional datasets by means of multivariate models and statistical tests for the dependence between metabolites and the co-expression of a gene module. The general linear model (GLM) for correlated data that we propose models the dependence between adjusted gene expression values through a block-diagonal variance-covariance structure formed by metabolicsubset specific general variance-covariance blocks. Performance of statistical tests for the inference of conditional co-expression are evaluated through a simulation study. The proposed methodology is applied to the gene expression data of the previously characterized lipid-leukocyte module. Our results show that the GLM approach improves on a previous approach by being less prone to the detection of spurious conditional co-expression. This research was funded by the MIMOmics grant of the European Union's Seventh Framework Programme (FP7-Health-F5-2012) under the grant agreement number 305280. The support of the IAP Research Network of the Belgian state (Belgian Science Policy) P7/06 is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2016

31. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author

John R. B. Perry, James B. Meigs, José Dupuis, Luigi Ferrucci, Johan G. Eriksson, Vilmundur Gudnason, Eric J.G. Sijbrands, Jeanette S. Andrews, Jonna L. Grimsby, Lawrence F. Bielak, Peter Kovacs, Panos Deloukas, Marijana Peričić, Johannes H. Smit, Ruth J. F. Loos, Gonneke Willemsen, Eric Boerwinkle, Ben A. Oostra, Manuel Serrano-Ríos, Alena Stančáková, Meena Kumari, Antti Jula, Michael Marmot, Caroline S. Fox, Simon Heath, Guo Li, Ola Hansson, Gerard Waeber, Anne U. Jackson, Nicholas L. Smith, Markku Laakso, George Dedoussis, Aarno Palotie, Sara M. Willems, John F. Peden, Elisabeth Widen, Caroline Hayward, Alan F. Wright, Claes Ladenvall, May E. Montasser, María Teresa Martínez-Larrad, Peter Vollenweider, Louis Pérusse, Tamara B. Harris, Wen Hong L. Kao, Danijela Budimir, Denis Rybin, David B. Savage, Michael A. Province, Alisa K. Manning, Bruna Gigante, Najaf Amin, Lenore J. Launer, Naveed Sattar, Lori L. Bonnycastle, Göran Hallmans, Jeffrey R. O'Connell, Stéphane Lobbens, Jacques S. Beckmann, Gemma Cadby, J. Wouter Jukema, Maria Dimitriou, Michael Stumvoll, Max Vikström, Rona J. Strawbridge, Hugh Watkins, Lyle J. Palmer, Johanna Kuusisto, Aimo Ruokonen, Hanieh Yaghootkar, Yan V. Sun, Inês Barroso, Amy J. Swift, Nancy L. Pedersen, Lars Lind, Mladen Boban, Nita G. Forouhi, Ken K. Ong, Ivana Kolcic, Anke Tönjes, Timothy M. Frayling, Paul W. Franks, Narisu Narisu, Karin Leander, Serge Hercberg, Diana Zelenika, Sharon L.R. Kardia, Min A. Jhun, Marjo-Riitta Järvelin, Stella Trompet, Jaakko Kaprio, Toshiko Tanaka, David S. Siscovick, Toby Johnson, Cornelia M. van Duijn, Veikko Salomaa, Jose C. Florez, James F. Wilson, Leena Peltonen, Pilar Galan, Robert Clarke, Andrew A. Hicks, Claudia Langenberg, Anders Hamsten, David Couper, Albert Hofman, Dawn M. Waterworth, John Blangero, James S. Pankow, Nabila Bouatia-Naji, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Valeriya Lyssenko, Leif Groop, Brenda W.J.H. Penninx, Ching-Ti Liu, Anuj Goel, Marina Pehlić, Michael Boehnke, Mika Kivimäki, Maria Sabater-Lleal, Emil Rehnberg, Ingrid B. Borecki, Ozren Polasek, Eco J. C. de Geus, Peter P. Pramstaller, Igor Rudan, Richard M. Watanabe, Pierre Meneton, Iva Miljkovic, Vincent Mooser, G. Mark Lathrop, John Beilby, Laura J. Rasmussen-Torvik, Arturo Corbató-Anchuelo, Yvonne Böttcher, Richard N. Bergman, Daniel R. Barnes, Paul C. D. Johnson, Mustafa Atalay, Aroon D. Hingorani, Olga D. Carlson, Perttu Salo, Jacqueline C.M. Witteman, Udo Seedorf, Timo Saaristo, Jian'an Luan, Nicholas J. Wareham, Gudny Eiriksdottir, Matti Uusitupa, Yongmei Liu, Jaakko Tuomilehto, Yurii S. Aulchenko, Peter Schwarz, Robert A. Scott, Lina Zgaga, Joseph Hung, Reedik Mägi, Maria Grazia Franzosi, Eric J. Brunner, Claude Bouchard, Ian Ford, Francis S. Collins, Ulf de Faire, Benjamin F. Voight, Erik Ingelsson, Mario A. Morken, Stefania Bandinelli, Nicole L. Glazer, Dmitry Shungin, Lars Lannfelt, André G. Uitterlinden, Tatijana Zemunik, Markus Perola, Kenneth Rice, Veronique Vitart, Kerrin S. Small, Jouke-Jan Hottenga, Han Chen, Jerome I. Rotter, Philippe Froguel, Karen L. Mohlke, Marie-Claude Vohl, Dorret I. Boomsma, Harry Campbell, Peter S. Chines, Pau Navarro, Vasiliki Lagou, Albert V. Smith, Kathleen Stirrups, Josephine M. Egan, Alan R. Shuldiner, Katri Räikkönen, Inga Prokopenko, Ping An, Rainer Rauramaa, Beverley Balkau, Thor Aspelund, Eleanor Wheeler, Mariza de Andrade, Richa Saxena, Jari Lahti, Cécile Lecoeur, Timo A. Lakka, Jennie Hui, Michael R. Erdos, Stavroula Kanoni, Kirsten Ohm Kyvik, Bengt Sennblad, Sarah H. Wild, Patricia A. Peyser, Patrik K. E. Magnusson, Claire Bellis, Elodie Eury, Jaana Lindström, Boston University [Boston] (BU), Broad Institute of Harvard and MIT, Partenaires INRAE, Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Department of Medicine, Université de Sherbrooke (UdeS), Addenbrooke's Hospital, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Epidemiology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Center for Social Epidemiology and Population Health, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], The Netherlands Cancer Institute, Ontario Institute for Cancer Research, Mount Sinai Hospital [Toronto, Canada] (MSH), VU University Amsterdam, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Michigan System, Queen Mary University of London (QMUL), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Diabetes Centre, Lund University, University of Helsinki, Wake Forest School of Medicine, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, University of Maryland School of Medicine, University of Maryland System, University of Edinburgh, University of Exeter, Department of Twin Research and Genetic Epidemiology, King's College London, London, Northwestern University [Evanston], National Institute of Health and Welfare, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Lund University Diabetes Centre, Umeå University, National Institutes of Health, Centre for Medical Systems Biology, Netherlands Genomics Initiative, Washington University in Saint Louis (WUSTL), Department of Health Sciences Research, Mayo Clinic, Wake Forest University, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, Institute of Biomedicine, Physiology, University of Eastern Finland, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S 1018, Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Department of Medical Genetics, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois (CHUV), Queen Elizabeth II Medical Centre, Research Institute, University of Southern California (USC), University of Split, The University of Texas Health Science Center at Houston (UTHealth), Leipzig University, Pennington Biomedical Research Center, Department of Epidemiology & Public Health, University College of London [London] (UCL), San Carlos Clinical Hospital, University of North Carolina, Harokopio University, National Institute on Aging, Folkhälsan Research Centre, Vaasa Central Hospital, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Epidemiology, Immunology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Ophthalmology, Internal Medicine, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Blood Glucose, Netherlands Twin Register (NTR), medicine.medical_treatment, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Type 2 diabetes, SUSCEPTIBILITY, Body Mass Index, GLUCOSE, Blood Glucose/metabolism, Cholesterol, HDL/metabolism, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Humans, Insulin/metabolism, Insulin Resistance/genetics, Polymorphism, Single Nucleotide, 0302 clinical medicine, Insulin, 2. Zero hunger, Genetics, 0303 health sciences, COMMON VARIANTS, 3. Good health, ENVIRONMENT INTERACTION, OBESITY, CORONARY-ARTERY-DISEASE, medicine.medical_specialty, 030209 endocrinology & metabolism, Accounting, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, 030304 developmental biology, Genetic association, Glycemic, loci, SNP, insulin, business.industry, Cholesterol, HDL, medicine.disease, Obesity, POLYMORPHISM, ASSOCIATION ANALYSIS, Endocrinology, Diabetes Mellitus, Type 2, TYPE-2 DIABETES RISK, Insulin Resistance, business
Abstract

Group Authors : DIAGRAM Consortium MUTHER Consortium variants influencing fasting glycemic traits and insulin resistance Seuls les 100 premiers auteurs ont été conservés dans la publication. La liste complète des auteurs et des des affiliations est disponible sur la publication https://www.nature.com/articles/ng.2274.pdf p. 667-669.; International audience; Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

32. Patient Overcrowding in Hospital Wards as a Predictor of Diagnosis-Specific Mental Disorders Among Staff

Author

Marko Elovainio, Katinka Tuisku, Marianna Virtanen, Kirsi Terho, Mika Kivimäki, Kirsi Ahola, Jussi Vahtera, George David Batty, Tuula Oksanen, Perttu Salo, and Jaana Pentti

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Patients, Adjustment disorders, Specialty, Workload, Risk Factors, Humans, Medicine, Prospective Studies, Prospective cohort study, Depression (differential diagnoses), Proportional Hazards Models, business.industry, Mental Disorders, Overcrowding, medicine.disease, Mental health, Comorbidity, Personnel, Hospital, Psychiatry and Mental health, Crowding, Emergency medicine, Female, business, Hospital Units, Cohort study
Abstract

Objective: Hospital ward patient overcrowding has been hypothesized to increase psychiatric morbidity among staff, but it is unknown whether the association is specific to depressive disorders. This study examined whether patient overcrowding in hospital wards predicts diagnosis-specific mental disorders among staff.Method: A 2-year prospective cohort study was conducted, in which the extent of hospital ward overcrowding was determined using routinely recorded patient bed occupancy rates between 2003 and 2004 and linked to sickness absence for 5,166 nurses and physicians in 203 somatic illness wards in 16 Finnish acute-care hospitals. Medically certified long-term (> 9 days) sickness absence spells in 2004 and 2005 with physician-determined diagnosis (based on ICD-10 criteria) were obtained from the register of the Social Insurance Institution of Finland.Results: Cox proportional hazard models for recurrent events adjusted for sex, age, occupation, type and length of employment contract, hospital district, and specialty showed that health professionals working in wards with a patient occupancy level 10 percentage units above the optimal during a 1-year period experienced twice the risk of sickness absence due to depressive disorders (HR = 1.95; 95% CI, 1.18-3.24) relative to colleagues working in wards with optimal or below-occupancy levels. No significant association was found for diagnoses of severe stress and adjustment disorders or other psychiatric disorders.Conclusions: Chronic workload, as expressed by patient overcrowding in hospital wards, is associated with the onset of depressive disorders among staff. J Clin Psychiatry 2010;71(10):1308-1312 (C) Copyright 2010 Physicians Postgraduate Press, Inc.

Published
2010

33. Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population

Author

Antti-Pekka Sarin, Veikko Salomaa, Perttu Salo, Pekka J. Karhunen, Markus Perola, Kjell Nikus, Marja-Liisa Lokki, Matti Pirinen, Markku S. Nieminen, Aki S. Havulinna, Johannes Kettunen, Aarno Palotie, Samuli Ripatti, Markku Eskola, Satu Vaara, Juha Sinisalo, Heikki V. Huikuri, Institute for Molecular Medicine Finland, Children's Hospital, Clinicum, Medicum, Marja-Liisa Lokki / Principal Investigator, Transplantation Laboratory, Aarno Palotie / Principal Investigator, Department of Medicine, Kardiologian yksikkö, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Statistical and population genetics, Lääketieteen yksikkö - School of Medicine, and University of Tampere

Subjects
Male, LOCI, Myocardial Infarction, lcsh:Medicine, Genome-wide association study, UNIVERSAL DEFINITION, 030204 cardiovascular system & hematology, SUSCEPTIBILITY, Bioinformatics, Linkage Disequilibrium, 0302 clinical medicine, Risk Factors, ARTERY-DISEASE, Myocardial infarction, lcsh:Science, Prospective cohort study, Finland, RISK, 0303 health sciences, education.field_of_study, Multidisciplinary, ST elevation, Hazard ratio, Middle Aged, 3. Good health, Phenotype, Chromosomes, Human, Pair 1, Cohort, Cardiology, AUTOPHAGY, Female, Research Article, medicine.medical_specialty, Biolääketieteet - Biomedicine, Population, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, COHORT, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Genetic Association Studies, 030304 developmental biology, Aged, business.industry, ACUTE CORONARY SYNDROMES, lcsh:R, Genetic Variation, Membrane Proteins, Reproducibility of Results, Odds ratio, medicine.disease, Gene Expression Regulation, Genetic Loci, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, 3111 Biomedicine, business, Genome-Wide Association Study
Abstract

Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease-associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 × 10−10) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 × 10−12). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI. Public Library of Science open access

Published
2015

34. A RISK LOCUS FOR NON-ST-ELEVATION MYOCARDIAL INFARCTION ON CHROMOSOME 1P13.3 IS ALSO ASSOCIATED WITH PERIPHERAL ARTERY DISEASE IN PATIENTS WITH ACUTE CORONARY SYNDROME

Author

Satu Vaara, Veikko Salomaa, Juha Sinisalo, Markus Perola, Olavi Parkkonen, Aki S. Havulinna, Marja-Liisa Lokki, Perttu Salo, and Markku S. Nieminen

Subjects
medicine.medical_specialty, Acute coronary syndrome, Arterial disease, business.industry, Locus (genetics), Disease, medicine.disease, St elevation myocardial infarction, Internal medicine, Cardiology, medicine, In patient, Cardiology and Cardiovascular Medicine, business
Published
2017

35. A metabolic view on menopause and ageing

Author

Pasi Soininen, Veikko Salomaa, Jaakko Kaprio, Andres Metspalu, Mika Kähönen, Aila Tiitinen, Marjo Niironen, Johan G. Eriksson, Olli T. Raitakari, Anni Joensuu, Johannes Kettunen, Hannele Mattsson, Krista Fischer, Markus Perola, Perttu Salo, Mika Ala-Korpela, Antti J. Kangas, Kirsi Auro, Matti Jauhiainen, Antti Jula, Terho Lehtimäki, and Aki S. Havulinna

Subjects
Adult, Estonia, Male, medicine.medical_specialty, Aging, Adolescent, General Physics and Astronomy, Biology, General Biochemistry, Genetics and Molecular Biology, White People, Cohort Studies, Young Adult, Risk Factors, Internal medicine, medicine, Humans, Young adult, Endothelial dysfunction, Amino Acids, Finland, Aged, chemistry.chemical_classification, Aged, 80 and over, Multidisciplinary, General Chemistry, ta3121, Middle Aged, medicine.disease, Lipids, Amino acid, Menopause, Glutamine, Endocrinology, Blood, chemistry, Ageing, Cardiovascular Diseases, Female, Cohort study, Polyunsaturated fatty acid
Abstract

The ageing of the global population calls for a better understanding of age-related metabolic consequences. Here we report the effects of age, sex and menopause on serum metabolites in 26,065 individuals of Northern European ancestry. Age-specific metabolic fingerprints differ significantly by gender and, in females, a substantial atherogenic shift overlapping the time of menopausal transition is observed. In meta-analysis of 10,083 women, menopause status associates with amino acids glutamine, tyrosine and isoleucine, along with serum cholesterol measures and atherogenic lipoproteins. Among 3,204 women aged 40-55 years, menopause status associates additionally with glycine and total, monounsaturated, and omega-7 and -9 fatty acids. Our findings suggest that, in addition to lipid alterations, menopause may contribute to future metabolic and cardiovascular risk via influencing amino-acid concentrations, adding to the growing evidence of the importance of amino acids in metabolic disease progression. These observations shed light on the metabolic consequences of ageing, gender and menopause at the population level.

Published
2013

36. Type II antithrombin deficiency caused by a founder mutation Pro73Leu in the Finnish population: clinical picture

Author

Markus Perola, Kaija Javela, Perttu Salo, S. Engelbarth, and Marja Puurunen

Subjects
Adult, Male, medicine.medical_specialty, Proline, Population, Thrombophilia, Antithrombins, Cohort Studies, Young Adult, Leucine, Internal medicine, Medicine, Humans, education, Finland, Aged, DNA Primers, Genetics, Aged, 80 and over, education.field_of_study, Base Sequence, business.industry, Point mutation, Antithrombin, Antithrombin III deficiency, Hematology, Middle Aged, medicine.disease, Founder Effect, Venous thrombosis, Mutation (genetic algorithm), Mutation, Female, business, Founder effect, medicine.drug
Abstract

Summary Background It has been shown that some antithrombin (AT) activity assays do not correctly detect inherited type II AT deficiency, but erroneously classify these patients as normal. Objectives Our aim was to investigate the mutations causing type II AT deficiency and to correlate the AT activity results with the genetic findings. Patients/Methods A large population (n = 104; 42 families) of Finnish patients with known AT type II deficiency were interviewed for clinical data. Their AT activity was measured with five commercially available methods, and the SERPINC1 gene was genotyped. Results The mutations detected in type II AT-deficient patients were as follows: p.Pro73Leu (AT Basel) in 37 of 42 (88.1%) families; and p.Val30Glu, p.Arg425Cys and p.Pro439Ala in one family each. In two families, no mutation was detected. In the carriers of AT Basel two AT activity assays correctly identified most of the patients as AT-deficient, whereas three assays misclassified almost all of these patients as normal. Carriers of the founder mutation had, in addition to an elevated risk of venous thrombosis, a high risk of arterial thrombosis at young age, especially stroke. Conclusion In Finland, a population with a strong founder effect, AT type II deficiency is caused predominantly by a single point mutation, p.Pro73Leu. The mutation is associated with a significant thrombotic risk. Reduced AT activity caused by this mutation cannot be detected by all available screening methods. This must be taken into account in the choice of laboratory method used for screening.

Published
2013

37. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Author

Jacqueline C.M. Witteman, Nicole Probst-Hensch, Gail Davies, Anna Köttgen, Qunyuan Zhang, Pio D'Adamo, Nicholas G. Martin, Silvia Tore, Stephan J. L. Bakker, Gian Andri Thun, Cinzia Sala, Peter P. Pramstaller, Tamara B. Harris, Aaron Isaacs, Sheila Ulivi, Rossella Sorice, Xuan Liu, Andrew A. Hicks, Henry Völzke, Daniela Ruggiero, Arnold von Eckardstein, Yukinori Okada, Andres Metspalu, Jeffrey Metter, Serena Sanna, Jennifer E. Huffman, Philipp S. Wild, Florian Ernst, Eva Albrecht, Mary F. Feitosa, Claudia Schurmann, Kathrin Budde, Veikko Salomaa, Darina Czamara, Elizabeth G. Holliday, Marcel Bruinenberg, Laura Portas, Maris Laan, Alan J. Gow, Caroline Hayward, Tim D. Spector, Ozren Polasek, Ilja M. Nolte, Rodney J. Scott, Massimo Mangino, David S. Siscovick, Nilesh J. Samani, Toomas Haller, Laura Frogheri, A. Jula, Mika Kähönen, Bruce H. R. Wolffenbuttel, Caroline S. Fox, David R. Jacobs, Julia Shi, Yusuke Nakamura, Daniel I. Chasman, Fabian J. Theis, Alan F. Wright, Ayse Demirkan, Francesco Cucca, Paolo Gasparini, Paul M. Ridker, Olli T. Raitakari, Daniela Toniolo, Maristella Steri, Mario Pirastu, Susan Campbell, Maksim Struchalin, So-Youn Shin, Mark J. Caulfield, H.-Erich Wichmann, Grant W. Montgomery, Åsa Johansson, Alexander Teumer, Ulf Gyllensten, Robert M. Plenge, Michel Burnier, Michael Schallert, Jan Krumsiek, Jing Hua Zhao, Andres Salumets, Poorva Mudgal, Anke Tönjes, James F. Meschia, Gauti Kjartan Gislason, Perttu Salo, Angela Döring, Afshin Parsa, Vilmundur Gudnason, Patrick F. McArdle, Rita P. S. Middelberg, W. H. Linda Kao, Aldi Kraja, Christopher Oldmeadow, Adrienne Tin, Loic Yengo, Murielle Bochud, Gerjan Navis, Christian Gieger, Toshiko Tanaka, Cornelia M. van Duijn, Samuli Ripatti, Terho Lehtimäki, Claudia Langenberg, Bernhard O. Boehm, Conall M. O'Seaghdha, Eric Boerwinkle, Nicole Soranzo, Tõnu Esko, Susan M. Farrington, Mike A. Nalls, John F. Peden, Hyon K. Choi, Anuj Goel, Andrew D. Johnson, Norman Klopp, Anne Grotevendt, Halit Ongen, Marcus E. Kleber, Myriam Fornage, Malcolm G. Dunlop, Igor Rudan, Federico Murgia, Beverley Balkau, Jorma Viikari, Christopher P. Nelson, Gérard Waeber, Lenore J. Launer, Ivana Persico, Inga Prokopenko, Guo Li, Tatijana Zemunik, Elisabetta Trabetti, Tanja Zeller, Hugh Watkins, Qiong Yang, James F. Wilson, Peter Vollenweider, Veronique Vitart, Markus Perola, Nicola Pirastu, Olivier Devuyst, Irene Mateo Leach, John Attia, Bruce M. Psaty, Nicholas J. Wareham, Susanne Lucae, Josef Coresh, Ingrid B. Borecki, Claudia Hundertmark, Weihua Zhang, Luigi Ferrucci, Jaspal S. Kooner, Stefan Kloiber, Lynda M. Rose, Naoyuki Kamatani, Zoltán Kutalik, Giovanni Malerba, Ian J. Deary, Albert V. Smith, Helena Schmidt, Eva Lattka, Philippe Froguel, Harry Campbell, Medea Imboden, Antonio Lupo, Angelo L. Gaffo, Vasiliki Lagou, Alan R. Shuldiner, John Whitfield, Abbas Dehghan, Winfried März, Elin Org, Albert Hofman, Margus Viigimaa, Konstantin Strauch, Toshihiro Tanaka, Andrew B. Singleton, Stefania Bandinelli, Christian Hengstenberg, Xinzhong Li, Wiek H. van Gilst, Pim van der Harst, Giorgio Pistis, Jerome I. Rotter, Maria Grazia Piras, Gary C. Curhan, Brenda W.J.H. Penninx, Ramaiah Nagaraja, Nabila Bouatia-Naji, Christian Müller, Ronald P. Stolk, Pau Navarro, Lorna M. Lopez, Ruth J. F. Loos, Albert Tenesa, Johannes H. Smit, Peter Kraft, Giovanni Gambaro, Sarah H. Wild, Patricia B. Munroe, André G. Uitterlinden, Ivana Kolcic, Bernhard R. Winkelmann, Pankaj Sharma, John C. Chambers, Nicholas D. Hastie, Matthias Nauck, Harold Snieder, Michael Stumvoll, Reinhold Schmidt, Hans L. Hillege, Kiang Liu, Fernando Rivadeneira, Owen M. Woodward, Morris J. Brown, Margus Putku, Sabine Schipf, Mirna Kirin, Kay-Tee Khaw, Melanie Waldenberger, Evropi Theodoratou, Marina Ciullo, Michiaki Kubo, Köttgen, A, Albrecht, E, Teumer, A, Vitart, V, Krumsiek, J, Hundertmark, C, Pistis, G, Ruggiero, D, O'Seaghdha, Cm, Haller, T, Yang, Q, Tanaka, T, Johnson, Ad, Kutalik, Z, Smith, Av, Shi, J, Struchalin, M, Middelberg, Rp, Brown, Mj, Gaffo, Al, Pirastu, Nicola, Li, G, Hayward, C, Zemunik, T, Huffman, J, Yengo, L, Zhao, Jh, Demirkan, A, Feitosa, Mf, Liu, X, Malerba, G, Lopez, Lm, van der Harst, P, Li, X, Kleber, Me, Hicks, Aa, Nolte, Im, Johansson, A, Murgia, F, Wild, Sh, Bakker, Sj, Peden, Jf, Dehghan, A, Steri, M, Tenesa, A, Lagou, V, Salo, P, Mangino, M, Rose, Lm, Lehtimäki, T, Woodward, Om, Okada, Y, Tin, A, Müller, C, Oldmeadow, C, Putku, M, Czamara, D, Kraft, P, Frogheri, L, Thun, Ga, Grotevendt, A, Gislason, Gk, Harris, Tb, Launer, Lj, Mcardle, P, Shuldiner, Ar, Boerwinkle, E, Coresh, J, Schmidt, H, Schallert, M, Martin, Ng, Montgomery, Gw, Kubo, M, Nakamura, Y, Munroe, Pb, Samani, Nj, Jacobs DR, Jr, Liu, K, D'Adamo, ADAMO PIO, Ulivi, S, Rotter, Ji, Psaty, Bm, Vollenweider, P, Waeber, G, Campbell, S, Devuyst, O, Navarro, P, Kolcic, I, Hastie, N, Balkau, B, Froguel, P, Esko, T, Salumets, A, Khaw, Kt, Langenberg, C, Wareham, Nj, Isaacs, A, Kraja, A, Zhang, Q, Wild, P, Scott, Rj, Holliday, Eg, Org, E, Viigimaa, M, Bandinelli, S, Metter, Je, Lupo, A, Trabetti, E, Sorice, R, Döring, A, Lattka, E, Strauch, K, Theis, F, Waldenberger, M, Wichmann, He, Davies, G, Gow, Aj, Bruinenberg, M, Stolk, Rp, Kooner, J, Zhang, W, Winkelmann, Br, Boehm, Bo, Lucae, S, Penninx, Bw, Smit, Jh, Curhan, G, Mudgal, P, Plenge, Rm, Portas, L, Persico, I, Kirin, M, Wilson, Jf, Leach, Im, van Gilst, Wh, Goel, A, Ongen, H, Hofman, A, Rivadeneira, F, Uitterlinden, Ag, Imboden, M, von Eckardstein, A, Cucca, F, Nagaraja, R, Piras, Mg, Nauck, M, Schurmann, C, Budde, K, Ernst, F, Farrington, Sm, Theodoratou, E, Prokopenko, I, Stumvoll, M, Jula, A, Perola, M, Salomaa, V, Shin, Sy, Spector, Td, Sala, C, Ridker, Pm, Kähönen, M, Viikari, J, Hengstenberg, C, Nelson, Cp, Meschia, Jf, Nalls, Ma, Sharma, P, Singleton, Ab, Kamatani, N, Zeller, T, Burnier, M, Attia, J, Laan, M, Klopp, N, Hillege, Hl, Kloiber, S, Choi, H, Pirastu, M, Tore, S, Probst Hensch, Nm, Völzke, H, Gudnason, V, Parsa, A, Schmidt, R, Whitfield, Jb, Fornage, M, Gasparini, Paolo, Siscovick, D, Polašek, O, Campbell, H, Rudan, I, Bouatia Naji, N, Metspalu, A, Loos, Rj, van Duijn, Cm, Borecki, Ib, Ferrucci, L, Gambaro, G, Deary, Ij, Wolffenbuttel, Bh, Chambers, Jc, März, W, Pramstaller, Pp, Snieder, H, Gyllensten, U, Wright, Af, Navis, G, Watkins, H, Witteman, Jc, Sanna, S, Schipf, S, Dunlop, Mg, Tönjes, A, Ripatti, S, Soranzo, N, Toniolo, D, Chasman, Di, Raitakari, O, Kao, Wh, Ciullo, M, Fox, C, Caulfield, M, Bochud, M, Gieger, C, LifeLines Cohort, Study, Cardiogram, Consortium, Diagram, Consortium, Icbp, Consortium, Magic, Consortium, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Psychiatry, EMGO - Mental health, EMGO+ - Mental Health, LifeLines Cohort Study, CARDIoGRAM Consortium, DIAGRAM Consortium, ICBP Consortium, MAGIC Consortium, Epidemiology, Public Health, and Internal Medicine

Subjects
Candidate gene, Inhibins/genetics, Genome-wide association study, GENETIC-LOCI, chemistry.chemical_compound, 0302 clinical medicine, serum urate, Gene Frequency, Gout/blood, association analysis, serum urate, Glucose/metabolism, Settore MED/14 - NEFROLOGIA, Hyperuricemia, serum, urate, gene, POPULATION, METABOLIC SYNDROME, Genetics, 0303 health sciences, education.field_of_study, biology, Polymorphism, Single Nucleotide/genetics, 3. Good health, HYPERURICEMIA, Genetic Loci/genetics, SLC22A12, Single Nucleotide/genetics, SNPs, Signal Transduction, MOLECULAR PHYSIOLOGY, serum urate concentrations, gout, genome-wide meta-analysis, European Continental Ancestry Group, Population, Polymorphism, Single Nucleotide, White People, Uric Acid/blood, serum urate concentrations, genome-wide meta-analysis, 03 medical and health sciences, SDG 3 - Good Health and Well-being, uric acid, medicine, Humans, Inhibins, Polymorphism, education, 030304 developmental biology, 030203 arthritis & rheumatology, Analysis of Variance, GOUT, IDENTIFICATION, TRANSPORTER, CARDIOVASCULAR-DISEASE RISK, ta3121, medicine.disease, association analysis, Gout, meta-analysis, Glucose, chemistry, Genetic Loci, genome-wide association studies, biology.protein, Signal Transduction/genetics, Uric acid, URIC-ACID LEVELS, Genome-Wide Association Study, SLC2A9
Abstract

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.

Published
2013

38. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Author

Andrew A. Hicks, Han Chen, Anders Franco-Cereceda, Vilmundur Gudnason, David M. Evans, May E. Montasser, Ulf de Faire, Jeanette S. Andrews, Rainer Rauramaa, Ching-Ti Liu, Michael Boehnke, Panos Deloukas, Naveed Sattar, Jacques S. Beckmann, Marcus E. Kleber, Hanneke Basart, Bruna Gigante, Göran Hallmans, Francis S. Collins, Toshiko Tanaka, Stella Trompet, Kathleen Stirrups, Jula Antti, Ryan P. Welch, Sirkka Keinänen-Kiukaanniemi, Jaakko Kaprio, T. Saaristo, Jeffrey R. O'Connell, Bernhard O. Boehm, Eleanor Wheeler, Kijoung Song, John Beilby, Michael A. Province, Inga Prokopenko, Ping An, Dawn M. Waterworth, Nita G. Forouhi, Nicholas J. Timpson, George Dedoussis, Fernando Rivadeneira, Winfried Maerz, Anneli Pouta, Anuj Goel, Jackie F. Price, Sarah Edkins, Markus Perola, Inês Barroso, Albertine J. Oldehinkel, Igor Rudan, Peter Vollenweider, Philippe Froguel, Richard M. Watanabe, Kari E. North, Dorret I. Boomsma, Harry Campbell, G. Kees Hovingh, Paul C. D. Johnson, Cécile Lecoeur, Vasiliki Lagou, Denis Rybin, Pierre Meneton, Soumya Raychaudhuri, Jian'an Luan, Neil Robertson, Andrew P. Morris, Veikko Salomaa, Anubha Mahajan, Beate St Pourcain, Robert A. Scott, Evelin Mihailov, Gerard R Fowkes, Nancy L. Pedersen, Susan Campbell, Sonia Shah, Veronique Vitart, Mustafa Atalay, Richard N. Bergman, Ross M. Fraser, Anders Hamsten, Benjamin F. Voight, Wolfgang Rathmann, Christian Gieger, James F. Wilson, Wieland Kiess, Marcel Bruinenberg, Serge Hercberg, Ian Ford, James B. Meigs, Tibor V. Varga, George Davey Smith, Josée Dupuis, Stefania Bandinelli, John F. Peden, Mika Kivimäki, J. Wouter Jukema, Michael Stumvoll, Caroline Hayward, Emil Rehnberg, Ozren Polasek, Letizia Marullo, Andrew D. Morris, Brenda W.J.H. Penninx, Lori L. Bonnycastle, Jouke-Jan Hottenga, Martin Farrall, Albert V. Smith, Rona J. Strawbridge, Ingrid B. Borecki, Kari Stefansson, Kirsten Ohm Kyvik, Harald Grallert, Alan James, Tim D. Spector, Paul W. Franks, Lasse Folkersen, Sara M. Willems, Stephan J. L. Bakker, Iva Miljkovic, Nigel W. Rayner, Tamara B. Harris, Momoko Horikoshi, Linda S. Adair, Christian Herder, Tõnu Esko, Thomas Illig, Alan R. Shuldiner, Ruth J. F. Loos, Serena Sanna, Massimo Mangino, Alex S. F. Doney, Hugh Watkins, Erik Ingelsson, Colin N. A. Palmer, Pau Navarro, Claudia Langenberg, Mark I. McCarthy, Johanna Kuusisto, Anne U. Jackson, Martina Müller-Nurasyid, Perttu Salo, Ying Wu, Alan F. Wright, Lars Lind, Johannes H. Smit, Gonneke Willemsen, Stefan R. Bornstein, Jennie Hui, Peter Schwarz, Anke Toenjes, Albert Hofman, Markku Laakso, Maria Dimitriou, Marjo-Riitta Järvelin, Aaron Isaacs, Hyun Min Kang, James S. Pankow, Annette Peters, André G. Uitterlinden, Loic Yengo, Beverley Balkau, Augustine Kong, Toby Johnson, Cornelia M. van Duijn, Luigi Ferrucci, Samuli Ripatti, Mulas Antonella, Aroon D. Hingorani, Meena Kumari, Nicholas J. Wareham, Sarah H. Wild, Patricia B. Munroe, Nicholas D. Hastie, Stefan Gustafsson, Kerrin S. Small, Cecilia M. Lindgren, Jennifer L. Bolton, Matti Uusitupa, Peter P. Pramstaller, Tove Fall, Patricia A. Peyser, Dmitry Shungin, Yongmei Liu, Patrik K. E. Magnusson, Jaakko Tuomilehto, Francesco Cucca, Reedik Mägi, Karen L. Mohlke, Gudmar Thorleifsson, Hanneke Jansen, Mark J. Caulfield, Tanya M. Teslovich, Timo A. Lakka, Heather M. Stringham, Bruce M. Psaty, Niek Verweij, Heikki Oksa, Wei Zhao, Andres Metspalu, Jaana Lindström, Stavroula Kanoni, Bengt Sennblad, Carlo Sidore, Eco J. C. de Geus, Ben A. Oostra, Lawrence F. Bielak, Peter Kovacs, Laura J. Rasmussen-Torvik, Tatijana Zemunik, Jose C. Florez, Antje Körner, Pim van der Harst, Ramaiah Nagaraja, Peter S. Chines, Nabila Bouatia-Naji, Addenbrooke's Hospital, Wellcome Trust Ctr Human Genet, University of Oxford [Oxford], Michigan State University [East Lansing], Michigan State University System, Wellcome Trust Sanger Inst, Partenaires INRAE, University of Maryland [College Park], University of Maryland System, University of Tartu, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], The Wellcome Trust Sanger Institute [Cambridge], Northwestern University [Evanston], Université Lille Nord de France (COMUE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Lund University [Lund], Umeå University, Consiglio Nazionale delle Ricerche (CNR), Istituto di Virologia Vegetale, Università degli studi di Torino (UNITO), Università degli Studi di Sassari, University of Glasgow, Netherlands Heart Institute, Leiden University, Queen Mary University of London (QMUL), University of Groningen, deCODE genetics [Reykjavik], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), (IGE3 Inst Genet & Genom Geneva), University College of London [London] (UCL), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Natl Inst Hlth & Welf, University of Helsinki, University of Bristol [Bristol], North Carolina State University, Center for High Performance Simulation and Department of Chemical and Biomolecular Engineering, Wake Forest School of Medicine, Sir Charles Gairdner Hospital, University of Western Australia, PathW Lab Med WA, University of Edinburgh, Centre for Medical Systems Biology, Erasmus University Rotterdam, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Pennyslvania, Brigham and Women's Hospital, Boston University [Boston] (BU), Dept Med Genet, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire Vaudois (CHUV), National Human Genome Research Institute (NHGRI), GlaxoSmithKline, National Institute on Aging, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), National Institutes of Health [N01-AG-1-2100], National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), Althingi (the Icelandic Parliament), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Chemistry, Child and Adolescent Psychiatry / Psychology, Dermatology, Internal Medicine, Clinical Genetics, and VU University Amsterdam

Subjects
Netherlands Twin Register (NTR), Blood Glucose, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Genome-wide association study, Type 2 diabetes, Fasting/blood, Mice, 0302 clinical medicine, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Gene Frequency, Insulin, GENETICS & HEREDITY, Genetics, 0303 health sciences, INSULIN-RESISTANCE, Metabolic Networks and Pathways/genetics, gene, glucose, glycemic, GLUCOSE-METABOLISM, 11 Medical And Health Sciences, Fasting, CARDIOVASCULAR-DISEASE, SKELETAL-MUSCLE, Female, Life Sciences & Biomedicine, Metabolic Networks and Pathways, Adult, SUSCEPTIBILITY LOCI, Quantitative Trait Loci, 030209 endocrinology & metabolism, Blood Glucose/genetics, KAPPA-B, Quantitative trait locus, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Genome-Wide Association Study/statistics & numerical data, Quantitative Trait Loci/physiology, KLOTHO GENE POLYMORPHISMS, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, Allele frequency, 030304 developmental biology, Glycemic, Science & Technology, Osmolar Concentration, 06 Biological Sciences, medicine.disease, BODY-MASS INDEX, BINDING-PROTEIN-ALPHA, Insulin/blood, Developmental Biology, Genome-Wide Association Study
Abstract

Seuls les auteurs INRA et les 100 premiers auteurs figurent sur la notice. Group Authors : DIAbet Genetics Replication traits and provide insight into the underlying biological pathways La liste complète des auteurs et de leurs affiliations des auteurs est disponible sur la publication, p. 1004-1005, à l'adresse suivante : https://www.nature.com/articles/ng.2385.pdf; International audience; Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Published
2012

39. Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure

Author

Markus Perola, Karola Rehnström, Mitja I. Kurki, Aarno Palotie, Juha Hernesniemi, Elisabeth Widen, Johannes Kettunen, Terho Lehtimäki, Murat Gunel, Mikael von und zu Fraunberg, Antti-Pekka Sarin, Veikko Salomaa, Kati Kristiansson, Emilia Gaál, Christopher Newton-Cheh, Johan G. Eriksson, Anneli Pouta, Olli T. Raitakari, Mika Niemelä, Juha E. Jääskeläinen, Perttu Salo, Marjo-Riitta Järvelin, Antti Jula, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Technology Centre, Neurokirurgian yksikkö, Department of Neurosciences, Clinicum, Department of General Practice and Primary Health Care, Medicum, Research Programs Unit, Research Programme of Molecular Medicine, Haartman Institute (-2014), Quantitative Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, and Medical Research Council (MRC)

Subjects
Male, Cancer Research, Muscle Proteins, Genome-wide association study, Blood Pressure, Disease, Bioinformatics, Cardiovascular, CASE-FATALITY, 3124 Neurology and psychiatry, Cohort Studies, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, IMPUTATION, Genetics (clinical), Finland, Genetics, Genetics & Heredity, International Consortium for Blood Pressure Genome-Wide Association Studies, 0303 health sciences, education.field_of_study, PROLIFERATION, Zinc Fingers, Middle Aged, 3. Good health, Pulse pressure, Neurology, Medicine, Chromosomes, Human, Pair 5, Female, Life Sciences & Biomedicine, Research Article, Adult, lcsh:QH426-470, Population, Myocytes, Smooth Muscle, education, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, AGE, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Molecular Biology, Ecology, Evolution, Behavior and Systematics, SUBARACHNOID HEMORRHAGE, METAANALYSIS, 030304 developmental biology, Genetic association, 0604 Genetics, Science & Technology, IDENTIFICATION, HYPERTENSION, DISEASE RISK, Intracranial Aneurysm, ta3121, lcsh:Genetics, Blood pressure, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors, Developmental Biology
Abstract

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (nFIN = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (pFIN = 3.01E-05, pICBP-GWAS = 0.0007, pALL = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance., Author Summary When multiple genes or genetic regions contribute to the inherited risk of a disease, it is referred to as a complex disease. Genome-wide association studies (GWAS) aim to detect common genetic variations that associate with complex traits or diseases. Although GWAS have been successful in identifying strongly associated genetic loci, they lack the means to point out true, but less strong, associations. Studying conditions that are related to the disease of interest can help sort out less strong associations. Intracranial aneurysms (IA) are berry-like dilations in cerebral arteries. Most IAs do not give symptoms until they bleed, causing a highly fatal form of stroke. Half of the people who suffer bleeding of an IA die. IA is a complex disease. Both inherited risk and environmental factors contribute to the risk of developing IA. Women, smokers, those with high alcohol intake or high blood pressure are more prone to develop IA and bleeding. GWAS found 19 genetic regions increasing the risk of IA. Here we show that one of these loci, on the long arm of chromosome 5, in addition to raising IA risk also increases systolic blood pressure. We speculate that the cause is modified vascular wall structure.

Published
2012

40. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

Author

Nilesh J. Samani, Inke R. König, Mohammed J. R. Ghori, Alistair S. Hall, Christopher J. O'Donnell, Tim D. Spector, Jennifer G. Sambrook, Augusto Rendon, Christian Hengstenberg, Stefan Schreiber, Olle Melander, Jonathan Stephens, Philippa Burns, Simon C. Potter, Joseph M. Devaney, Suzannah Bumpstead, John R. Thompson, Markku S. Nieminen, Alexander Teumer, Mingyao Li, Nicole Soranzo, Heribert Schunkert, Angela Döring, Chris Tyler-Smith, Henry Völzke, Stephen E. Epstein, Leena Peltonen, Muredach P. Reilly, Klaus Stark, Yali Xue, Markus Perola, Swee Lay Thein, Brigitte Kühnel, Alexandre F.R. Stewart, Li Chen, David Altshuler, Alison H. Goodall, Veikko Salomaa, Hakon Hakonarson, Naomi Hammond, Uwe Völker, John Bradley, Perttu Salo, Mario Falchi, Robert Roberts, Mary-Susan Burnett, Christa Meisinger, Nicholas A. Watkins, David S. Siscovick, George A. Wells, Jovana Serbanovic-Canic, Holger Prokisch, Panos Deloukas, Stephan Menzel, Rhian Gwilliam, David A. van Heel, Roberto Elosua, Christian Gieger, Matthias Nauck, Juha Sinisalo, Wendy N. Erber, Thomas Illig, Benjamin J. Wright, Andreas Greinacher, Roman A. Laskowski, Christina Willenborg, H-Erich Wichmann, Catherine M. Rice, Stephen M. Schwartz, Willem H. Ouwehand, Christopher W. Knouff, Ida Surakka, Ruth McPherson, Benjamin F. Voight, Sekar Kathiresan, Jeanette Erdmann, Daniel J. Rader, Stephen F. Garner, Vincent Mooser, and Massimo Mangino

Subjects
Genetic Markers, medicine.medical_specialty, Genome-wide association study, Coronary Artery Disease, Disease, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, White blood cell, Genetic variation, Genetics, medicine, Humans, Selection, Genetic, 030304 developmental biology, 0303 health sciences, Blood Cells, Chromosomes, Human, Pair 12, Hematology, Genome, Human, Haplotype, medicine.disease, Blood Cell Count, 3. Good health, medicine.anatomical_structure, Immunology, Selective sweep, Genome-Wide Association Study
Abstract

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

Published
2009

41. Comparison of solution-based exome capture methods for next generation sequencing

Author

Caroline A. Heckman, Perttu Salo, Maija Lepistö, Taneli Raivio, Anna-Maija Kristiina Sulonen, Samuli Eldfors, Anu Suomalainen, Timo Miettinen, Janna Saarela, Henna Tyynismaa, Henrikki Almusa, Heikki Joensuu, Pekka Ellonen, and Sari Hannula

Subjects
Genotype, Sequence analysis, Genomics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, Humans, Computer Simulation, Exome, Alleles, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics, Base Composition, 0303 health sciences, Genome, Human, Research, Genetic Carrier Screening, Computational Biology, DNA, Sequence Analysis, DNA, 030220 oncology & carcinogenesis, Human genome, Reagent Kits, Diagnostic, Sequence Alignment, GC-content
Abstract

Background Techniques enabling targeted re-sequencing of the protein coding sequences of the human genome on next generation sequencing instruments are of great interest. We conducted a systematic comparison of the solution-based exome capture kits provided by Agilent and Roche NimbleGen. A control DNA sample was captured with all four capture methods and prepared for Illumina GAII sequencing. Sequence data from additional samples prepared with the same protocols were also used in the comparison. Results We developed a bioinformatics pipeline for quality control, short read alignment, variant identification and annotation of the sequence data. In our analysis, a larger percentage of the high quality reads from the NimbleGen captures than from the Agilent captures aligned to the capture target regions. High GC content of the target sequence was associated with poor capture success in all exome enrichment methods. Comparison of mean allele balances for heterozygous variants indicated a tendency to have more reference bases than variant bases in the heterozygous variant positions within the target regions in all methods. There was virtually no difference in the genotype concordance compared to genotypes derived from SNP arrays. A minimum of 11× coverage was required to make a heterozygote genotype call with 99% accuracy when compared to common SNPs on genome-wide association arrays. Conclusions Libraries captured with NimbleGen kits aligned more accurately to the target regions. The updated NimbleGen kit most efficiently covered the exome with a minimum coverage of 20×, yet none of the kits captured all the Consensus Coding Sequence annotated exons.

Published
2011

42. Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

Author

Angela Doering, Jacques S. Beckmann, Patricia B. Munroe, Alan F. Wright, Peter Vollenweider, Peter P. Pramstaller, M. Perola, Veikko Salomaa, Murielle Bochud, James F. Wilson, Sven Bergmann, Henry Völzke, Georg Homuth, Igor Rudan, Thomas Meitinger, Christian Gieger, Leena Peltonen, Martin Farrall, Jerzy Adamski, Anna F. Dominiczak, Mark J. Caulfield, H.-Erich Wichmann, Gérard Waeber, John Whitfield, Tim D. Spector, Uwe Völker, John M. C. Connell, Holger Prokisch, Åsa Johansson, Yurii S. Aulchenko, Harry Campbell, Veronique Vitart, Morris J. Brown, Rui Wang-Sattler, David Schlessinger, Mark I. McCarthy, Nilesh J. Samani, Massimo Mangino, Manuela Uda, John F. Peden, Serena Sanna, Chris Wallace, Perttu Salo, Ramaiah Nagaraja, Alexander Teumer, Ulf Gyllensten, Eva Albrecht, Dale R. Nyholt, Hugh Watkins, Matthias Nauck, Thomas Illig, Claudia Lamina, Dawn M. Waterworth, Melanie Kolz, Vincent Mooser, and Toby Johnson

Subjects
Male, genome-wide association, urate-anion exchanger, triglyceride levels, fasting glucose, serum urate, carnitine, gout, transport, protein, risk, Cancer Research, Gout, Urate transport, chemistry.chemical_compound, 0302 clinical medicine, Hyperuricemia, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Genetics and Genomics/Medical Genetics, Genetics, 0303 health sciences, Computational Biology/Systems Biology, biology, Genetics and Genomics/Functional Genomics, 3. Good health, Female, Genetic Variation, Genome-Wide Association Study, Gout/etiology, Humans, Uric Acid/blood, Colaus Study, Genetics and Genomics/Gene Discovery, SLC22A12, Research Article, medicine.medical_specialty, lcsh:QH426-470, Public Health and Epidemiology, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Computational Biology/Molecular Genetics, 03 medical and health sciences, Internal medicine, Genetics and Genomics/Population Genetics, medicine, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 030203 arthritis & rheumatology, uric acid, genome-wide association study, quantitative traits, genetics, Genetics and Genomics, medicine.disease, Uric Acid, Minor allele frequency, lcsh:Genetics, Endocrinology, chemistry, biology.protein, Uric acid, Public Health and Epidemiology/Epidemiology, Computational Biology/Population Genetics, SLC2A9
Abstract

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels., Author Summary Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. The regulation of serum uric acid levels is under a strong genetic control. This study describes the first meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent. We show that common DNA variants at nine different loci are associated with uric acid concentrations, five of which are novel. These variants are located within the genes coding for organic anion transporter 4 (SLC22A11), monocarboxylic acid transporter 9 (SLC16A9), glucokinase regulatory protein (GCKR), Carmil (LRRC16A), and near PDZ domain-containing 1 (PDZK1). Gender-specific effects are shown for variants within the recently identified genes coding for glucose transporter 9 (SLC2A9) and the ATP-binding cassette transporter (ABCG2). Based on screening of 163 metabolites, we show an association of one of the identified variants within SLC16A9 with DL-carnitine and propionyl-L-carnitine. Moreover, DL-carnitine and propionyl-L-carnitine were strongly correlated with serum UA levels, forming a triangle between SNP, metabolites and UA levels. Taken together, these associations highlight pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia.

Published
2009
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43. Identification of seven loci affecting mean telomere length and their association with disease

Author

Laura Kananen, Margaret J. Wright, Yanbin Dong, Inga Prokopenko, Peter S. Braund, Norman Klopp, Giuseppe Danilo Norata, Gonneke Willemsen, Anna-Liisa Hartikainen, Jaakko Kaprio, Jessica L. Buxton, Elena Dubinina, Marian Beekman, John R Thompson, Heribert Schunkert, Paul F. O'Reilly, P. Eline Slagboom, Massimo Mangino, Elisabeth M. van Leeuwen, Tim D. Spector, Xiaoling Wang, Cornelia M. van Duijn, Dirk J. van Veldhuisen, Samuli Ripatti, Jutta Palmen, H. Eka D. Suchiman, Anjali K. Henders, H-Erich Wichmann, Helen Pollard, Evelin Mihailov, Kai Xia, Eva Albrecht, Stefan Böhringer, Dehuang Guo, Johan G. Eriksson, Najaf Amin, Dale R. Nyholt, Irene Mateo Leach, Markus Perola, Anneli Pouta, Jouke-Jan Hottenga, Christopher P. Nelson, Willem H. Ouwehand, Perttu Salo, Ana M. Valdes, Jeanette Erdmann, Martin D. Tobin, Haidong Zhu, Xiangjun Xiao, Niek Verweij, Sarah E. Medland, Sekar Kathiresan, Katia Garlaschelli, Alistair S. Hall, Patrik K. E. Magnusson, Anthony J. Balmforth, Linda Broer, Lennart C. Karssen, Matthew Denniff, Satu Männistö, Alexandra I. F. Blakemore, Konstantinos Douroudis, Ana Viñuela, Marjo-Riitta Järvelin, Krista Fischer, Reedik Mägi, Andres Metspalu, Joris Deelen, Alberico L. Catapano, Sara Hägg, Annette Peters, Rudolf A. de Boer, Ida Surakka, Veikko Salomaa, Johannes Kettunen, Danish Saleheen, Nicholas G. Martin, Veryan Codd, Aarno Palotie, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Elisabeth Widen, Iiris Hovatta, Mary K. Matthews, Tõnu Esko, Pamela A. F. Madden, Ben A. Oostra, Muredach P. Reilly, Christian Gieger, Dorret I. Boomsma, Vasiliki Lagou, Pim van der Harst, Mark I. McCarthy, Nilesh J. Samani, Paul Burton, Wiek H. van Gilst, Grant W. Montgomery, Philippa J. Talmud, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, EMGO+ - Mental Health, Epidemiology, Surgery, Clinical Genetics, and Cardiovascular Centre (CVC)

Subjects
Male, Netherlands Twin Register (NTR), Candidate gene, FIBROBLASTS, STRESS, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, SUSCEPTIBILITY, VARIANTS, ACYP2, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Risk Factors, Genetics, medicine, Biomarkers, Tumor, Leukocytes, Humans, Genetic Predisposition to Disease, Allele, Telomerase, 030304 developmental biology, RISK, 0303 health sciences, Case-control study, Telomere, medicine.disease, CANCER, DYSFUNCTION, 3. Good health, ATHEROSCLEROSIS, Genetic Loci, CARDIOVASCULAR-DISEASE, 030220 oncology & carcinogenesis, Case-Control Studies, CORONARY-ARTERY-DISEASE, Female, Genome-Wide Association Study
Abstract

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P

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44. Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

Author

Perttu Salo, Tomas Wester, Anna Lof-Granstrom, Lili Milani, Markus Perola, Tiina Paunio, Mikko P. Pakarinen, Risto Rintala, Jia Cao, Agneta Nordenskjöld, Andres Metspalu, Outi Saarenpää-Heikkilä, Valtter B. Virtanen, Children's Hospital, Lastenkirurgian yksikkö, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland, Quantitative Genetics, Research Programs Unit, Diabetes and Obesity Research Program, Department of Psychiatry, and HUS Children and Adolescents

Subjects
EXPRESSION, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Neuregulin-1, Population, Genome-wide association study, Semaphorins, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Proto-Oncogene Mas, Frameshift mutation, 03 medical and health sciences, Exon, Gene Frequency, NERVOUS-SYSTEM DEVELOPMENT, Genotype, Genetic model, Genetics, GWAS, Humans, Hirschsprung Disease, Allele, Frameshift Mutation, education, Genetics (clinical), Genetic association, education.field_of_study, MUTATIONS, Proto-Oncogene Proteins c-ret, 1184 Genetics, developmental biology, physiology, Exons, General Medicine, GENE, 3. Good health, 030104 developmental biology, Female, 3111 Biomedicine, RET
Abstract

The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls. As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T > C; genotype TT, OR = 17.31, P = 1.462 x 10(-21)). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A > C; allele C, OR = 2.268, P = 0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A > G; allele G, OR = 1.567, P = 0.015; rs7835688, NC_000008.10:g.32411499G > C; allele C, OR = 1.567, P = 0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease. Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.

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